Cell Adaptation And Cell Injury

Question 1

How does the cell respond to injury?

Answer 1

Take note,(this is how you should respond. Start with the preamble below then continue)

The way the cell adapt to a stress or injury it depends on the following conditions:
Type or kind of stress or injury(for some organisms the fact that they’re in your body will make you have the disease but for others you’ll need an infective dose or a really high dose example salmonella 10 to the power 5 to have the disease so not all stresses are the same)
2.the severity of the stress or injury(disease is a kind of stress so if you have an organism that causes the disease that doesn’t mean you have the disease. The severity of the action of the organism is what will give you the disease)

3. the duration of the stress or injury(if the stress acts longer in the cell and acts faster the cell will not be able to adapt before it dies)
4. the immune state of the person(body’s ability to withstand certain stress or injury but if your immune state is compromised it’ll affect the cells ability to adapt),
5. the cell’s ability to adapt(not all cells can adapt.the ability for skeletal muscles to adapt to oxygen deprivation is not the same as the brain. If you deprive the brain of oxygen it’ll die at a faster rate as compared to the skeletal muscle )
6. the type of cell(if the cell has the ability to proliferate or synthesize proteins causing an increase in size or the cell has lost those abilities making it eat part of itself to survive the stress or injury),
7. pre existing conditions(people with certain pre existing contains will succumb to certain diseases at a faster rate as compared to other people)
8. basal cellular metabolism and
9. blood and nutrient supply.

The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. Thus, low doses of toxins or a brief duration of ischemia may lead to revers- ible cell injury, whereas larger toxin doses or longer ischemic intervals may result in irreversible injury and cell death

Learn to read in between lines and make sure your answer covers every part of the question and cuts across for all)

Question 2

Disease is a kind of stress

True or false

Answer 2

True

Question 3

How does atrophy occur

Answer 3

The cell is made up of lipids and for the cell to survive it’ll eat some of its lipid cell membrane. So doing this will cause a reduction in its size

Question 4

At what stage will the cell decide to adapt or die

Answer 4

When there’s an injury and the injury is sub lethal the cell will adapt
If it is severe the cell will die
The cell can try to adapt but can end up dying

Question 5

Processes of death

Answer 5

Necrosis

Apoptosis

Question 6

Define reversible and irreversible change

Answer 6

In the process of death,when the activation mechanisms occur ther are processes that will occur in the cell that if you take the injury or stress off,the cell will revert back to its normal state. So even if the cell wants to die,if the stress is taken off the cell will revert back

Irreversible is even if the stress if taken off the cell will still die

Question 7

Name the four adaptation mechanisms

Metaplasia is thought to arise by reprogramming of stem cells to differ- entiate along a new pathway rather than a phenotypic change (transdifferentiation) of already differentiated cell true or false

Answer 7

Hyperplasia-increase in cell numbers .hyperplasia (dis- cussed next) is characterized by an increase in cell number because of proliferation of differentiated cells

Hypertrophy-increase in cell size causing an increase in the organ or tissue size due to increase in protein synthesis within the cell

Atrophy-shrinkage of cells due to the loss of cellular substances in response to stress or injury. When a sufficient number of cells are involved, the entire tissue or organ diminishes in size, becoming atrophic The cellular substances are eaten up by the cells.some of these cellular substances are packaged vesicles and are used by the cells themselves and by doing this the cell size reduces and it affects the overall size of the organ causing a reduction

Metaplasia-When one differentiated cell is being replaced another differentiated cell when there’s an exposure to a stress that the residual cell cannot cope with so the cell is replaced by a cell or undergoes metaplasia to a cell that can withstand the stress.

Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. In this type of cellular adaptation, a cell type sensitive to a particular stress is replaced by another cell type better able to withstand the adverse environment.

True

Question 8

What type of cells hav the ability to increase in number

Answer 8

Labile cells

Question 9

How do labile cells use hyperplasia to increase their numbers when there’s stress

Answer 9

Labile cells are cells that are continuously dividing in the cell cycle . Because they’re already in the cell cycle it makes it easier for em to adapt using hyperplasia so they’re division rate increases and it increases their numbers . When there’s an injury to the cells of the epithelial linen of example the skin they can adapt thru hyperplasia cuz usually the cells of the epithelial lining of the breast are labile cells

Question 10

Types of hyperplasia and types of physiologic hyperplasia w explanations and examples

Answer 10

Pathologic-there’s an imbalance of tissues in response to hormonal stimulation the Cells overgrow . Example- in endometrial hyperplasia there’s an imbalance of estrogen and progesterone thereby causing an increase in proliferation of the endometrium lining and that leads to excess bleeding and can also lead to a malignant something or endoplasmic lesion(check) Most forms of pathologic hyperplasia are caused by exces- sive hormonal or growth factor stimulation. For example,
after a normal menstrual period there is a burst of uterine epithelial proliferation that is normally tightly regulated by stimulation through pituitary hormones and ovarian estrogen and by inhibition through proges- terone. However, a disturbed balance between estrogen and progesterone causes endometrial hyperplasia, which is a common cause of abnormal menstrual bleeding.
2. In the BPH there’s an over proliferation of the prostate cells thereby increasing the size of the prostate causing an obstruction of the bladder outlet causing difficulty to urinate.

Physiologic-cells undergoing hyperplasia receive normal stimulation from hormones or growth factors

Types-compensatory and hormonal

Compensatory-
Organ or tissues has lost a number of cells affecting the mass of the organ or tissue so the cells grow back to make up for what was loss. Example- when part of the liver is cut off the remaining hepatocytes under the influence of growth factor and growth factor receptors will proliferate and compensate for the lost part (. The stimuli for hyperplasia in this setting are polypeptide growth factors produced by uninjured hepatocytes as well as nonparenchymal cells in the liver (Chapter 2). After restoration of the liver mass, cell pro- liferation is “turned off” by various growth inhibitors. )
or An example of a compensatory hyperplasia is during wound healing

Hormonal-are under the influence of certain hormones
Example-females shed the layer of the endometrium so with the aid of estrogen and progesterone it grows back from the basal layer to replace the layer lost
example,by the proliferation of the glan- dular epithelium of the female breast at puberty and during pregnancy,

Question 11

All hyperplasia are benign and usually goes with hypertrophy and why
true or false

Answer 11

True

This is cuz although the cells are diving the cells will still synthesize protein so that each half will become whole again so there will be two daughter cells so when the proliferation occurs it’ll cause an increase in the cell size but hypertrophy doesn’t go w hyperplasia

Question 12

Difference between hyperplasia and cancer

Answer 12

Hyperplasia is regulated while cancer is not regulated so the division of cells occurs uncontrollably

Question 13

Types of hypertrophy and types of physiologic hypertrophy and give examples

Answer 13

Physiologic-normal increase in the size of a cell or tissue or an organ when stress is applied example during exercise the tissues or muscles involved in the exercise increases in size when they are stretched. Example The massive physiologic enlargement of the uterus during pregnancy occurs as a consequence of estrogen- stimulated smooth muscle hypertrophy and smooth muscle hyperplasia (Fig. 1–3). In contrast, in response to increased demand the striated muscle cells in both the skeletal muscle and the heart can undergo only hyper- trophy because adult muscle cells have a limited capac- ity to divide. Therefore, the chiseled physique of the avid weightlifter stems solely from the hypertrophy of individual skeletal muscles.

Types of physiologic hypertrophy-compensatory-

Hormonal-hormonal stimulation.
• The massive physiologic enlargement of the uterus during pregnancy occurs as a consequence of estrogen- stimulated smooth muscle hypertrophy and smooth muscle hyperplasia

Pathologic-example of pathologic cellular hypertrophy is the cardiac enlargement that occurs with hypertension or aortic valve disease

Question 14

Give an example of how the heart compensates for the pressure in the blood vessels during hypertension ,where physiologic hypertrophy occurs in the cell cycle and which cell,state the type of cells in the cell cycle,what happens when they are at rest

Answer 14

In physiologic hypertrophy it occurs in cells that are in G0(G not)(Cells in G0 phase are not actively preparing to divide. The cell is in a quiescent (inactive) stage that occurs when cells exit the cell cycle )but can enter into the cell cycle so there are labile cells,stable cells,permanent cells. Usually stable cells are not in the cell cycle but can be stimulated from G not and enter the cell cycle for division to occur. But sometimes when they’re at rest they won’t be dividing at a faster rate to increase the size of the organ but this time they’ll synthesize more proteins to withstand the pressure on the organ

example-in the heart during hypertension when the pressure in the blood vessels are too much the heart works harder to overcome resistance so the muscle synthesize protein to help to increase the size of the muscle to help it perform in initial stages but as the pressure continues and as the stress increases the protein synthesis the protein synthesis can be abnormal and the heart muscle won’t function properly
The heart muscle compensatory mechanism is by hypertrophy

Question 15

How do body builders muscles compensate for the body building

Answer 15

In body builders who lift muscles the skeletal muscle compensate that act using hypertrophy not hyperplasia

Question 16

Causes of atrophy

Answer 16

Decreased protein synthesis
Increased protein degradation

What will lead to a decrease in protein synthesis and increased protein degradation causing atrophy

1. Loss of innervation
2. Aging
3. disuse(decreased workload (e.g., immobilization of a limb to permit healing of a fracture),
4. inadequate nutrition
5. diminished blood flow
6. pressure
7. Loss of function
8. Loss of endocrine stimulation

Question 17

Metaplasia doesn’t necessarily lead to cancer or are not pre malignant but it increases your risk of getting cancer
True or false

Answer 17

True

Question 18

In diabetes patients there is a shrinkage of something not because of an overworking of the cells but because the overworking of the cells to produce insulin is leading to something and that something is causing the shrinkage
True or false

Answer 18

True

Question 19

When cells are going to die what occurs

Answer 19

They start with some changes that are reversible
There is no specific biochemical point where it is said that if you take the dress off at a certain point the cells will revert back to normal

When they’re beginning to die the cells swell up(when there’s an injury that affects the synthesis of ATP by the cell and ATP production decreases it affects transport mechanism across the cell. Sodium is transported against its concern gradient so it’s moved from outside the cell to inside the cell. If too much sodium gets into the cell there are mechanism that take it out but because the mechanism isnt working well,the sodium goes into the cell and it moves with water causing the swelling of the cell)
2. It affects the transportation mechanism for calcium (calcium also goes into the cell and calcium attracts water causing the swelling of the cell. The calcium plenty can cause a reaction with a component of the plasma membrane causing the destruction of the plasma membrane)
3. It destroys or decreases the efficiency of the mitochondrion
When the mitochondria is damaged severely such that protein and DNA synthesis are affected the cells cannot revert back

Question 20

What will make a cell die completely

Answer 20

When there is severe mitochondrial damage the cells will reach a point of no return

Question 21

Define homeostasis

Answer 21

Cells are active participants in their environment, con- stantly adjusting their structure and function to accommo- date changing demands and extracellular stresses. Cells normally maintain a steady state called homeostasis in which the intracellular milieu is kept within a fairly narrow range of physiologic parameters

Question 22

rs. As cells encounter physi- ologic stresses or pathologic stimuli, they can undergo
adaptation, achieving a new steady state and preserving viability and function.
True or false

Answer 22

True

Question 23

Define cell injury and cellular adaptation

Answer 23

1.If the adaptive capability is exceeded of the cell or 2.if the external stress the cells are exposed to is inherently harmful or the cell suffer intrinsic abnormalities example damage to DNA ,cell injury develops

cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently dam- aging agents or suffer from intrinsic abnormalities (e.g., in DNA or proteins).

Different injurious stimuli affect many metabolic pathways and cellular organelles. Injury may progress through a reversible stage and culminate in cell death (Fig. 1–1).

Cellular adaptation occurs when stress is imposed on a cell and the cell undergoes changes in its size,function,number,phenotype

Question 24

Causes of cell death

Answer 24

ischemia (lack of blood flow), infections, toxins, and immune reactions.

Question 25

. Cell death is one of the most crucial events in the evolution of disease in any tissue or organ. It results from diverse causes, including ischemia (lack of blood flow), infections, toxins, and immune reactions. Cell death also is a normal and essential process in embryogenesis, the development of organs, and the maintenance of homeostasis. True or false and name examples of cell death being pathological or physiological

Answer 25

True In short cell death can be pathological or physiological Example of pathological-infections,ischemia,toxins Physiological-embryogenesis ,development of organs and maintenance of homeostasis

Question 26

Explain the relationship between cell adaptation,cell injury,cell death in the myocardium subjected to stress

Answer 26

Myocardium subjected to persistent increased load, as in hypertension or with a narrowed (stenotic) valve, adapts by undergoing hypertrophy—an increase in the size of the individual cells and ultimately the entire heart—to gener- ate the required higher contractile force. If the increased demand is not relieved, or if the myocardium is subjected to reduced blood flow (ischemia) from an occluded coro- nary artery, the muscle cells may undergo injury. Myocar- dium may be reversibly injured if the stress is mild or the arterial occlusion is incomplete or sufficiently brief, or it may undergo irreversible injury and cell death (infarction) after complete or prolonged occlusion. Also,stresses and injury affect not only the morphology but also the functional status of cells and tissues. Thus, reversibly injured myocytes are not dead and may resemble normal myocytes morphologically; however, they are transiently noncontractile, so even mild injury can have a significant

Question 27

Myocytes are , they are transiently noncontractile, so even mild injury can have a significant clinical impact true or false

Answer 27

True

Question 28

Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment. True or false

Answer 28

True

Question 29

What are physiologic and pathologic adaptations | And give one example each

Answer 29

Physiologic adap- tations usually represent responses of cells to normal stimu- lation by hormones or endogenous chemical mediators (e.g., the hormone-induced enlargement of the breast and uterus during pregnancy). Pathologic adaptations are responses to stress that allow cells to modulate their struc- ture and function and thus escape injury. Such adaptations can take several distinct forms.

Question 30

Name three differences between hypertrophy and hyperplasia

Answer 30

in pure hypertrophy there are no new cells, just bigger cells containing increased amounts of structural proteins and organelles. Hyperplasia is an adaptive response in cells capable of replication, whereas hypertrophy occurs when cells have a limited capacity to divide. Hypertrophy and hyperplasia also can occur together, and obviously both result in an enlarged (hypertrophic) organ.

Question 31

Explain the signals involved in the mechanisms with cardiac hypertrophy that explain the statement “how an adaptation to stress can progress to functionally significant cell injury if the stress is not relieved”

Answer 31

The mechanisms driving cardiac hypertrophy involve at least two types of signals: mechanical triggers, such as stretch, and trophic triggers, which typically are soluble mediators that stimulate cell growth, such as growth factors and adrenergic hormones. These stimuli turn on signal transduction pathways which in turn stimulate synthesis of many cellular proteins, including growth factors and struc- tural proteins. The result is the synthesis of more proteins and myofilaments per cell, which increases the force gener- ated with each contraction, enabling the cell to meet increased work demands. There may also be a switch of contractile proteins from adult to fetal or neonatal forms. For example, during muscle hypertrophy, the α-myosin heavy chain is replaced by the β form of the myosin heavy chain, which produces slower, more energetically econom- ical contraction. Whatever the exact mechanisms of hypertrophy, a limit is reached beyond which the enlargement of muscle mass can no longer compensate for the increased burden. When this happens in the heart, several “degenerative” changes occur in the myocardial fibers, of which the most important are fragmentation and loss of myofibrillar contractile ele- ments. There may be finite limits of the vasculature to adequately supply the enlarged fibers, of the mitochondria to supply adenosine triphosphate (ATP), or of the biosynthetic machinery to provide the contractile proteins or other cyto- skeletal elements. The net result of these changes is ven- tricular dilation and ultimately cardiac failure, a sequence of events that illustrates how an adaptation to stress can progress to functionally significant cell injury if the stress is not relieved.

Question 32

Most forms of pathologic hyperplasia are caused by exces- sive hormonal or growth factor stimulation True or false

Answer 32

True

Question 33

How does hyperplasia help in wound healing

Answer 33

Hyperplasia also is an important response of connective tissue cells in wound healing, in which pro- liferating fibroblasts and blood vessels aid in repair (Chapter 2). In this process, growth factors are produced by white blood cells (leukocytes) responding to the injury and by cells in the extracellular matrix. Stimula- tion by growth factors also is involved in the hyperplasia that is associated with certain viral infections; for example, papillomaviruses cause skin warts and mucosal lesions composed of masses of hyperplastic epithelium. Here the growth factors may be encoded by viral genes or by the genes of the infected host cells. An important point is that in all of these is the hyperplastic process remains controlled; if the signals that initi- ate it abate, the hyperplasia disappears. It

Question 34

Difference between pathologic hyperplasia and cancer and give an example of how pathological hyperplasia is a fertile soil for cancer to develop

Answer 34

the hyperplastic process remains controlled; if the signals that initi- ate it abate, the hyperplasia disappears. It is this responsiveness to normal regulatory control mechanisms that distin- guishes pathologic hyperplasias from cancer, in which the growth control mechanisms become dysregulated or inef- fective Nevertheless, in many cases, pathologic hyperplasia constitutes a fertile soil in which cancers may eventually arise. For example, patients with hyperplasia of the endometrium are at increased risk of developing endo- metrial cancer (

Question 35

What is atrophy

Answer 35

Shrinkage in the size of the cell by the loss of cell substance is known as atrophy. When a sufficient number of cells are involved, the entire tissue or organ diminishes in size, becoming atrophic

Question 36

Atrophy is physiologic or pathologic Give with examples the fundamental cel- lular changes in both types of atrophy are identical. They represent a retreat by the cell to a smaller size at which survival is still possible; true or false

Answer 36

physiologic (e.g., the loss of hormone stimulation in menopause) and others pathologic (e.g., denervation), True

Question 37

Name the mechanism of atrophy

Answer 37

The mechanisms of atrophy consist of a combination of decreased protein synthesis and increased protein degradation in cells. -Protein synthesis decreases because of reduced meta- bolic activity. -The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome pathway. Nutrient deficiency and disuse may activate ubiquitin ligases, which attach mul- tiple copies of the small peptide ubiquitin to cellular proteins and target them for degradation in protea- somes. This pathway is also thought to be responsible for the accelerated proteolysis seen in a variety of cata- bolic conditions, including the cachexia associated with cancer. • In many situations, atrophy is also accompanied by increased autophagy, with resulting increases in the number of autophagic vacuoles.

Question 38

What happens in those who smoke concerning metaplasia and what is the effect of the metaplasia that occurs that’s why it’s termed as being a double edged sword In fact, squamous metaplasia of the respiratory epithelium often coexists with lung cancers composed of malignant squamous cells. True or false Moreover, the influences that induce metaplastic change, if per- sistent, may predispose to malignant transformation of the epi- thelium. True or false Metaplasia need not always occur in the direc- tion of columnar to squamous epithelium,give an example of which other direction it can occur

Answer 38

-Epithelial metaplasia is exemplified by the squamous change that occurs in the respiratory epithelium of habitual cigarette smokers .The normal ciliated columnar epithelial cells of the trachea and bronchi are focally or widely replaced by stratified squamous epithelial cells. The rugged stratified squamous epithelium may be able to survive the noxious chemicals in cigarette smoke that the more fragile specialized epithelium would not tolerate. -Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost, such as mucus secretion and ciliary clearance of particulate matter. Epithelial metaplasia is therefore a double-edged sword. It is thought that cigarette smoking initially causes squamous metaplasia, and cancers arise later in some of these altered foci. Since vitamin A is essential for normal epithelial differentiation, its deficiency may also induce squamous metaplasia in the respiratory epithelium. -in chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium. Metapla- sia may also occur in mesenchymal cells but in these situ- ations it is generally a reaction to some pathologic alteration and not an adaptive response to stress.

Question 39

• Metaplasia: change in phenotype of differentiated cells, often in response to chronic irritation, that makes cells better able to withstand the stress; usually induced by altered differentiation pathway of tissue stem cells; may result in reduced functions or increased propensity for malignant transformation True or false

Answer 39

True

Question 40

# Define reversible cell injury And cell death,the types of cell death, Necrosis is the major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma. True or false Whereas necrosis is always a patho- logic process, apoptosis serves many normal functions and is not necessarily associated with pathologic cell injury.true or false

Answer 40

Reversible cell injury. In early stages or mild forms of injury the functional and morphologic changes are reversible if the damaging stimulus is removed. At this stage, although there may be significant structural and functional abnormalities, the injury has typically not progressed to severe membrane damage and nuclear dissolution. - Cell death. With continuing damage, the injury becomes irreversible, at which time the cell cannot recover and it dies. - There are two types of cell death—necrosis and apoptosis—

Question 41

State seven causes of cell injury and explain State the difference between hypoxia and ischemia and hypoxemia Name some potentially toxic agents in the daily environment Name two examples of how disorders of nutrition rather than lack of nutrients are also important causes of morbidity and mortality; Many therapeutic drugs can cause cell or tissue injury in a susceptible patient or if used excessively or inap- propriately .Even oxygen at sufficiently high partial pressures is toxic.true or false ``` Genetic variations (polymorphisms) contribute to the development of many complex diseases and can influence the suscepti- bility of cells to injury by chemicals and other environmen- tal insults True or false ```

Answer 41

Most injurious stimuli can be grouped into the following categories. -Oxygen Deprivation Hypoxia, or oxygen deficiency, interferes with aerobic oxidative respiration and is a common cause of cell injury and death. While ischemia is the most common cause of hypoxia, oxygen deficiency can also result from inadequate oxygenation of the blood, as in pneumonia, or from reduc- tion in the oxygen-carrying capacity of the blood, as in blood loss anemia or carbon monoxide (CO) poisoning. (CO forms a stable complex with hemoglobin that prevents oxygen binding.)() -Chemical Agents Agents commonly known as poisons cause severe damage at the cellular level by altering membrane permeability, osmotic homeostasis, or the integrity of an enzyme or cofactor, and exposure to such poisons can culminate in the death of the whole organism. Other potentially toxic agents are encountered daily in the environment; these include air pollutants, insecticides, CO, asbestos, and “social stimuli” such as ethanol. -Infectious Agents Agents of infection range from submicroscopic viruses to meter-long tapeworms; in between are the rickettsiae, bacteria, fungi,protozoa s -Immunologic Reactions Although the immune system defends the body against pathogenic microbes, immune reactions can also result in cell and tissue injury. Examples are autoimmune reactions against one’s own tissues and allergic reactions against environmental substances in genetically susceptible indi- viduals. -Genetic Factors Genetic defects may cause cell injury as a consequence of deficiency of functional proteins, such as enzymes in inborn errors of metabolism, or accumula- tion of damaged DNA or misfolded proteins, both of which trigger cell death when they are beyond repair.. the single gene defect that results in a nonfunctional enzyme underlying a specific metabolic disease. -Nutritional Imbalances nutritional deficiencies remain a major cause of cell injury. Protein–calorie insufficiency among underprivileged pop- ulations is only the most obvious example; specific vitamin deficiencies are not uncommon. for example, obesity markedly increases the risk for type 2 diabetes mel- litus. Moreover, diets rich in animal fat are strongly impli- cated in the development of atherosclerosis as well as in increased vulnerability to many disorders, including cancer.over or under nutrition can cause imbalance -Physical Agents Trauma, extremes of temperature, radiation, electric shock, and sudden changes in atmospheric pressure all have wide-ranging effects on cells (Chapter 7). -Aging Cellular senescence leads to alterations in replicative and repair abilities of individual cells and tissues. All of these changes result in a diminished ability to respond to damage and, eventually, the death of cells and of the organism. The mechanisms underlying cellular aging are discus -Trauma Hypoxia (lack of oxygen in tissue)should be distinguished from ischemia, which is a loss of blood supply in a tissue due to impeded arterial flow or reduced venous drainage. hypoxemia-low levels of oxygen in the blood

Question 42

State six differences between apoptosis and necrosis by stating the feature and the difference between the two using the features

Answer 42

Necrosis-Cell size Enlarged (swelling) Apop-Reduced (shrinkage) Necrosis-Nucleus (this is what happens to the nucleus)-Pyknosis → karyorrhexis → karyolysis Apoptosis-(this is what happens to the nucleus)Fragmentation into nucleosome size fragments Plasma membrane is Disrupted in necrosis while it is Intact but its structure is altered especially orientation of lipids in apoptosis Cellular contents- Enzymatic digestion and the cellular contents may leak out of cell in necrosis It’s Intact and may be released in apoptotic bodies in apoptosis Adjacent inflammation is Frequent in necrosis, there’s none in apoptosis Physiologic or pathologic role :Invariably pathologic (culmination of Often physiologic; means of eliminating unwanted cells; may be irreversible cell injury) in necrosis Often pathologic after some forms of cell injury, especially DNA and protein damage in apoptosis protein damage

Question 43

All stresses and noxious influences exert their effects first at the molecular or biochemical level. Cellular function may be lost long before cell death occurs, and the morphologic changes of cell injury (or death) lag far behind both true or false and give an example of this

Answer 43

True For example, myocardial cells become noncontractile after 1 to 2 minutes of isch- emia, although they do not die until 20 to 30 minutes of ischemia have elapsed. These myocytes may not appear dead by electron microscopy for 2 to 3 hours, or by light microscopy for 6 to 12 hours.

Question 44

Name the two things that show an injury is irreversible

Answer 44

Although there are no definitive morphologic or biochemical correlates of irreversibility, two phenomena con- sistently characterize irreversibility: 1.the inability to correct mito- chondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury, and 2.profound disturbances in membrane function. As mentioned earlier, injury to lysosomal membranes results in the enzymatic dissolution of the injured cell, which is the culmination of injury progressing to necrosis.

Question 45

What are the two main morphological correlates of reversible injury and how do they occur, and what are the four intracellular changes that occur in reversible cell injury Cellular swelling is a reversible alteration that may be difficult to appreciate with the light microscope, but it may be more apparent at the level of the whole organ.true or false Fatty change is principally encountered in cells participating in fat metabolism (e.g., hepatocytes, myocardial cells) and is also reversible. True or false What are the three things that occur due to cellular swelling

Answer 45

The two main morphologic correlates of reversible cell injury are cellular swelling and fatty change. 1. Cellular swell- ing is the result of failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to main- tain ionic and fluid homeostasis. 2. Fatty change occurs in hypoxic injury and in various forms of toxic or metabolic injury and is manifested by the appearance of small or large lipid vacuoles in the cytoplasm. Fatty change is manifested by the appearance of lipid vacuoles in the cytoplasm. Injured cells may also show increased eosinophilic staining, which becomes much more pronounced with progression to necrosis When it affects many cells in an organ, it causes some pallor (as a result of compression of capillaries), increased turgor, and increase in weight of the organ This pattern of nonlethal injury(cellular swelling)is sometimes called hydropic change or vacuolar degen- eration. The intracellular changes associated with reversible injury (Fig. 1–6) include (1) plasma membrane alterations such as blebbing, blunting, or distortion of microvilli, and loosening of intercellular attachments; (2) mitochondrial changes such as swelling and the appearance of phospholipid-rich amor- phous densities; (3) dilation of the ER with detachment of ribosomes and dissociation of polysomes; and (4) nuclear alterations, with clumping of chromatin. The cytoplasm may contain phospholipid masses, called myelin figures, which are derived from damaged cellular membranes. Or in Reversible cell injury these morphological changes occur:cell swelling, fatty change, plasma membrane blebbing and loss of microvilli, mitochondrial swelling, dilation of the ER, eosinophilia (due to decreased cytoplasmic RNA) Morphological features seen 1. Cell swelling 2. Fatty change which occurs in cells that depend on lipid metabolism

Question 46

potentially injurious insults induce specific alterations in cellular organelles, like the ER. The smooth ER is involved in the metabolism of various chemi- cals, and cells that are exposed to these chemicals show hypertro- phy of the ER as an adaptive response and it may have important functional consequences. True or false and give an example that explains the statement

Answer 46

True For instance, barbiturates are metabolized in the liver by the cytochrome P-450 mixed-function oxidase system found in the smooth ER. Protracted use of barbiturates leads to a state of tolerance, with a decrease in the effects of the drug and the need to use increasing doses. This adaptation is because of the increased volume (hypertrophy) of the smooth ER of hepatocytes and consequent increased P-450 enzymatic activity. Although P-450–mediated modification is often thought of as “detox- ification,” many compounds are rendered more injurious by this process; In addition, the products formed by this oxidative metabolism include reactive oxygen species (ROS), which can injure the cell. Cells adapted to one drug have increased capacity to metabolize other compounds handled by the same system. Thus, if patients taking phe- nobarbital for epilepsy increase their alcohol intake, they may experience a drop in blood concentration of the anti- seizure medication to subtherapeutic levels because of induction of smooth ER in response to the alcohol.

Question 47

Define necrosis

Answer 47

Necrosis is the type of cell death that is associated with loss of membrane integrity and leakage of cellular contents cul- minating in dissolution of cells, largely resulting from the degradative action of enzymes on lethally injured cells. The leaked cellular contents often elicit a local host reaction, called inflammation, that attempts to eliminate the dead cells and start the subsequent repair process (Chapter 2). The enzymes responsible for digestion of the cell may be derived from the lysosomes of the dying cells themselves and from the lysosomes of leukocytes that are recruited as part of the inflammatory reaction to the dead cells. When damage to membranes is severe, enzymes leak out of lysosomes, enter the cytoplasm, and digest the cell, resulting in necrosis. Cellular contents also leak through the damaged plasma membrane into the extra- cellular space, where they elicit a host reaction (inflam- mation). Or unprogrammed kind of cell death or a spectrum of morphological changes which take place in the cell due to degradative actions of enzymes on lethally injured cells These enzymes come from lysosomes in the cells (Autolysis)

Question 48

Explain the morphology of necrosis and what is the fate of necrotic cells

Answer 48

MORPHOLOGY Necrosis is characterized by changes in the cytoplasm and nuclei of the injured cells • Cytoplasmic changes:Necrotic cells show a.increased eosinophilia (i.e., pink staining from the eosin dye—the E in the hematoxylin (blue stain)and eosin [H&E] stain), attributable in part to increased binding of eosin to denatured cyto- plasmic proteins and in part to loss of the basophilia that is normally imparted by the ribonucleic acid (RNA) in the cytoplasm (basophilia is the blue staining from the hema- toxylin dye—the H in “H&E”). Compared with viable cells, d.the cell may have a more glassy, homogeneous appear- ance, mostly because of the loss of glycogen particles. Myelin figures are more prominent in necrotic cells than during reversible injury. When enzymes have digested cytoplasmic organelles, b.the cytoplasm becomes vacuo- lated and appears “moth-eaten.” By electron microscopy, necrotic cells are characterized by discontinuities in plasma and organelle membranes, c.marked dilation of mitochon- dria with the appearance of large amorphous densities, disruption of lysosomes, and intracytoplasmic myelin figures. 2.Nuclear changes. Nuclear changes assume one of three patterns, all due to breakdown of DNA and chromatin. c.The basophilia of the chromatin may fade (karyolysis), presumably secondary to deoxyribonuclease (DNase) activity. a.A second pattern is (pyknosis)characterized by nuclear shrinkage and increased basophilia; the DNA con- denses into a solid shrunken mass. b.In the third pattern, (karyorrhexis) ,pyknotic nucleus undergoes fragmen- tation. In 1 to 2 days, the nucleus in a dead cell may completely disappear. Electron microscopy reveals pro- found nuclear changes culminating in nuclear dissolution. • Fates of necrotic cells. Necrotic cells may persist for some time or may be digested by enzymes and disappear. Dead cells may be replaced by myelin figures, which are either phagocytosed by other cells or further degraded into fatty acids. These fatty acids bind calcium salts, which may result in the dead cells ultimately becoming calcified. Or

Question 49

Patterns of Tissue Necrosis There are several morphologically distinct patterns of tissue necrosis, which may provide clues about the under- lying cause. Although the terms that describe these pat- terns do not reflect underlying mechanisms, such terms are in common use, and their implications are understood by both pathologists and clinicians. Most of these types of necrosis have distinct gross appearance; fibrinoid necrosis is detected only by histologic examination. Patterns of tissue necrosis: Under different conditions, necrosis in tissues may assume specific patterns: coagula- tive, liquefactive, gangrenous, caseous, fat, and fibrinoid. True or false

Answer 49

True

Question 50

Explain the types of necrosis with examples The area of caseous necrosis is often enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a granuloma . True or false In liquefactive necrosis If the process was initiated by acute inflammation, as in a bacterial infection, the material is frequently creamy yellow and is called pus. True or false On histologic exami- nation, the foci of fat necrosis contain shadowy outlines of necrotic fat cells with basophilic calcium deposits, sur- rounded by an inflammatory reaction.true or false Coagulative necrosis is characteristic of infarcts (areas of ischemic necrosis) in all of the solid organs except the brain.true or false

Answer 50

MORPHOLOGY 1.Coagulative necrosis is a form of necrosis in which the underlying tissue architecture is preserved for at least several days (Fig. 1–9). The affected tissues take on a firm texture. Presumably the injury denatures not only struc- tural proteins but also enzymes, thereby blocking the pro- teolysis of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks. Leukocytes are recruited to the site of necrosis, and the dead cells are digested by the action of lysosomal enzymes of the leu- kocytes. The cellular debris is then removed by phagocy- tosis. Or The cell components are dead but the architecture of the cell is maintained for several days cuz the injury denatures both proteins and enzymes in the cell so there is no enzyme to destroy the architecture of the cell. 2.Liquefactive necrosis is seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of inflammatory cells and the enzymes of leukocytes digest (“liquefy”) the tissue. For obscure reasons, hypoxic death of cells within the central nervous system often evokes liquefactive necrosis .Whatever the pathogenesis, the dead cells are completely digested, transforming the tissue into a liquid viscous mass. Eventually, the digested tissue is removed by phagocytes. Or it is the conversion of a tissue into a liquid viscous mass. Example usually abscess formations seen in disease conditions such as abscess in the lungs are mostly liquefactive necrosis Other types of necrosis Although gangrenous necrosis is not a distinctive pattern of cell death, the term is still commonly used in clinical practice. It usually refers to the condition of a limb, generally the lower leg, that has lost its blood supply and has undergone coagulative necrosis involving multiple tissue layers. When bacterial infection is superimposed, coagulative necrosis is modified by the liquefactive action of the bacteria and the attracted leukocytes (resulting in so-called wet gangrene). Example-10 Liquefactive necrosis. An infarct in the brain showing dissolution of the tissue. -Caseous necrosis is encountered most often in foci of tuberculous infection. Caseous means “cheese-like,” referring to the friable yellow-white appearance of the area of necrosis . On microscopic examination, the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous(shapeless) granular pink appearance in the usual H&E-stained tissue. Unlike with coagulative necrosis, the tissue architecture is completely obliterated and cellular outlines cannot be discerned. Example: Caseous necrosis. Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white (cheesy) debris. -Fat necrosis refers to focal areas of fat destruction, typi- cally resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. This occurs in the calamitous abdominal emergency known as acute pancreatitis.In this disorder, pancreatic enzymes that have leaked out of acinar cells and ducts liquefy the membranes of fat cells in the peri- toneum, and lipases split the triglyceride esters contained within fat cells. The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification), which enable the surgeon and the patholo- gist to identify the lesions . Example-Fat necrosis in acute pancreatitis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery. -Fibrinoid necrosis is a special form of necrosis, visible by light microscopy, usually in immune reactions in which complexes of antigens and antibodies are deposited in the walls of arteries. The deposited immune complexes, together with fibrin that has leaked out of vessels, produce a bright pink and amorphous appearance on H&E prepara- tions called fibrinoid (fibrin-like) by pathologists . Example-Fibrinoid necrosis in an artery In a patient with polyarteritis nodosa. The wall of the artery shows a circumferential bright pink area of necrosis with protein deposition and inflammation.

Question 51

How is tissue specific necrosis detected and give two examples Irreversible injury and cell death in these tissues result in increased serum levels of such proteins, and measurement of serum levels is used clinically to assess damage to these tissues.true or false

Answer 51

Leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific necrosis using blood or serum samples. 1.Cardiac muscle, for example, contains a unique isoform of the enzyme creatine kinase and of the contractile protein troponin, whereas 2.hepatic bile duct epithelium contains a temperature-resistant isoform of the enzyme alkaline phos- phatase, and hepatocytes contain transaminases. I

Question 52

In necrosis what morphological changes occur

Answer 52

Necrosis: increased eosinophilia; nuclear shrinkage, frag- mentation, and dissolution; breakdown of plasma mem- brane and organellar membranes; abundant myelin figures; leakage and enzymatic digestion of cellular conten

Question 53

Name the principles targets (biochemical mechanisms)relevant to most cell injury Multiple biochemical alterations may be triggered by any one injurious insult. It is therefore difficult to assign any one mechanism to a particular insult or clinical situation in which cell injury is prominent. For this reason, therapies that target individual mechanisms of cell injury may not be effective. True or false

Answer 53

. • Theconsequencesofaninjuriousstimulusdependonthetype, status, adaptability, and genetic makeup of the injured cell. The same injury has vastly different outcomes depend- ing on the cell type; thus, striated skeletal muscle in the leg accommodates complete ischemia for 2 to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20 to 30 minutes. The nutritional (or hor- monal) status can also be important; clearly, a glycogen- replete hepatocyte will tolerate ischemia much better than one that has just burned its last glucose molecule. Genetically determined diversity in metabolic pathways can contribute to differences in responses to injurious stimuli. For instance, when exposed to the same dose of a toxin, individuals who inherit variants in genes encod- ing cytochrome P-450 may catabolize the toxin at differ- ent rates, leading to different outcomes. • .The principal targets and biochemical mechanisms of cell injury are: (1) mitochondria and their ability to generate ATP and ROS under pathologic conditions; (2) disturbance in calcium homeostasis; (3) damage to cellular (plasma and lysosomal) mem- branes; and (4) damage to DNA and misfolding of proteins.

Question 54

Name the biochemical mechanism that occur in the cell during cell injury

Answer 54

``` ATP depletion Mitochondrial damage and dysfunction Influx of calcium Accumulation of oxygen derived free radicals(oxidative stress) Defects in membrane permeability ``` ATP depletion: failure of energy-dependent functions → reversible injury → necrosis • Mitochondrial damage: ATP depletion → failure of energy- dependent cellular functions → ultimately, necrosis; under some conditions, leakage of mitochondrial proteins that cause apoptosis • Influx of calcium: activation of enzymes that damage cel- lular components and may also trigger apoptosis • Accumulation of reactive oxygen species: covalent modifica- tion of cellular proteins, lipids, nucleic acids • Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis • Accumulation of damaged DNA and misfolded proteins: trig- gers apoptosis

Question 55

What occurs during ATP depletion and what does prolonged depletion of ATP cause and how does it cause cell injury Significant depletion of ATP has widespread effects on many critical cellular systems ,name three

Answer 55

ATP, the energy store of cells, is produced mainly by oxida- tive phosphorylation of adenosine diphosphate (ADP) during reduction of oxygen in the electron transport system of mitochondria. In addition, the glycolytic pathway can generate ATP in the absence of oxygen using glucose derived either from the circulation or from the hydrolysis of intracellular glycogen. The major causes of ATP deple- tion are reduced supply of oxygen and nutrients, mito- chondrial damage, and the actions of some toxins (e.g., cyanide). Tissues with a greater glycolytic capacity (e.g., the liver) are able to survive loss of oxygen and decreased oxidative phosphorylation better than are tissues with limited capacity for glycolysis (e.g., the brain). High-energy phosphate in the form of ATP is required for virtually all synthetic and degradative processes within the cell, includ- ing membrane transport, protein synthesis, lipogenesis, and the deacylation-reacylation reactions necessary for phospholipid turnover. It is estimated that in total, the cells of a healthy human burn 50 to 75 kg of ATP every day! Significant depletion of ATP has widespread effects on many critical cellular systems 1.The activity of plasma membrane ATP-dependent sodium pumps is reduced, resulting in intracellular accumulation of sodium and efflux of potassium. The net gain of solute is accompanied by iso-osmotic gain of water, causing cell swelling and dilation of the ER. 2.There is a compensatory increase in anaerobic glycolysis in an attempt to maintain the cell’s energy sources .When the cell isn’t getting ATP it produces its own ATP in the form of anaerobic glycolysis . As a consequence, intracellular glycogen stores are rapidly depleted, and lactic acid accumulates because of the anaerobic glycolysis , leading to decreased intracellular pH and decreased activity of many cellular enzymes and clumping of chromatins leading to DNA damage 3.Failure of ATP-dependent Ca2+ pumps leads to influx of Ca2+, with damaging effects on numerous cellular com- ponents, described later. Prolonged or worsening depletion of ATP causes: structural disruption of the protein synthetic apparatus, manifested as detachment of ribosomes from the rough ER (RER) and dissociation of polysomes into mono- somes, with a consequent reduction in protein synthesis. Ultimately, there is irreversible damage to mitochon- drial and lysosomal membranes, and the cell undergoes necrosis. On the cell there are pumps that require ATP to function such as sodium potassium ATPase which regulates the movement of sodium and potassium so when there’s ATP depletion these pumps don’t work properly so sodium can enter the cell freely and where sodium moves water follows causing cell swelling leading to swelling of the ENdoplasmic reticulum(this leads to detachment of the ribosomes and proteins won’t be synthesized causing cell injury and death )and leading to loss of microvilli and causing cell injury

Question 56

What are some of the abnormalities mitochondrial damage will cause?(name four) Name three examples of stimuli that’s injurious to the mitochondria Mitochondria may be viewed as “mini-factories” that produce life-sustaining energy in the form of ATP. True or false

Answer 56

. Mitochondria are sensitive to many types of injurious stimuli, including hypoxia, chemi- cal toxins, and radiation. Mitochondrial damage may result in several biochemical abnormalities: -Failure of oxidative phosphorylation leads to progressive depletion of ATP, culminating in necrosis of the cell, as described earlier. -Abnormal oxidative phosphorylation also leads to the formation of reactive oxygen species -Damage to mitochondria is often associated with the formation of a high-conductance channel in the mito- chondrial membrane, called the mitochondrial permea- bility transition pore. The opening of this channel leads to the loss of mitochondrial membrane potential and pH changes, further compromising oxidative phosphorylation. -The mitochondria also contain several proteins that, when released into the cytoplasm, tell the cell there is internal injury and activate a pathway of apoptosis, dis- cussed later. I When mitochondrion is damage there is depletion of ATP causes failure of calcium pumps causing influx of calcium into the cell and causes decreased permeability of the mitochondrial and inside the cell calcium is kept very low . The damage leads to the release of calcium and intracellularly calcium is found in the ER and the mitochondrion so when it’s damaged calcium leaks out of mitochondrion into the cytosol or cytoplasm and the leakage leads to low pH of cell and this low pH causes ATP depletion and this creates mitochondrial transition pore channel that’s where the calcium passes into the cytosol and the leakage also causes the formation of the apoptotic proteins,the caspases and cytochrome C and activation of enzymes example phospholipase which causes destruction of cell or plasma membrane,protease causes destruction of cytoskeleton of the cell

Question 57

What causes influx of calcium Increased cytosolic Ca2+ activates a number of enzymes, with potentially deleterious cellular effects . Name five of those enzymes Or name two effects of influx of calcium causing increased calcium intracellular levels

Answer 57

Cytosolic free calcium is normally maintained by ATP-dependent calcium transporters at concentrations as much as 10,000 times lower than the concentration of extra- cellular calcium or of sequestered intracellular mitochon- drial and ER calcium. (Meaning there’s more calcium outside than inside) Ischemia and certain toxins cause an increase in cytosolic calcium concentration, initially because of release of Ca2+ from the intracellular stores, and later resulting from increased influx across the plasma mem- brane. When calcium gets inside bunch it activates These enzymes which include phospholipases (which cause membrane damage by degrading the phospholipid layer), proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin fragmenta- tion), and adenosine triphosphatases (ATPases) (thereby hastening ATP depletion). ``` Increased intracellular Ca2+ levels may also induce apoptosis, by direct activation of caspases and by increasing mitochondrial permeability Rising Ca(2+) concentration in the cytoplasm causes Ca(2+) influx into mitochondria and nuclei. In mitochondria Ca(2+) accelerates and disrupts normal metabolism leading to cell death. In nuclei Ca(2+) modulates gene transcription and nucleases that control cell apoptosis ```

Question 58

What is a free radical? Name three ways in which free radicals function or cause damage? What are ROS? Cell injury in many circumstances involves damage by free radicals; these situations include ischemia- reperfusion (discussed later on), chemical and radiation injury, toxicity from oxygen and other gases, cellular aging, microbial killing by phagocytic cells, and tissue injury caused by inflammatory cells. True or false Mention two ways in which ROS are produced Damaged caused by ROS depends on what and what? How does oxidative stress occur?

Answer 58

Free radicals are chemical species with a single unpaired electron in an outer orbital. 2.Such chemical states are extremely unstable, and free radicals readily react with inorganic and organic chemicals; b.when generated in cells, they avidly attack nucleic acids as well as a variety of cel- lular proteins and lipids. Free radicals can react with molecules and cause oxidation of these molecules causing damage to them They can react w carbs,proteins Leading to oxidation of em and damage. c.In addition, free radicals initiate reactions in which molecules that react with free radicals are themselves converted into other types of free radicals, thereby propagating the chain of damage. Reactive oxygen species (ROS) are a type of oxygen- derived free radical whose role in cell injury is well estab- lished. There are different types of ROS, and they are produced by two major pathways 1. ROS are produced normally in small amounts in all cells during the reduction-oxidation (redox) reactions that occur during mitochondrial respiration and energy genera-.mitochondria normally undergoes respiration and in the process it uses oxidative phosphorylation to produce ATP by reducing oxygen in the electron transport chain to water. This reaction is imperfect, however, and small amounts of highly reactive but short-lived toxic intermediates are generated when oxygen is only partially reduced. So instead of oxygen being reduced to water it’s reduced to a more oxidized form superoxide (O2• ), making it more reactive.sometimes the superoxide is converted to hydro- gen peroxide (H2O2) spontaneously and by the action of the enzyme superoxide dismutase. H2O2 is more permeable and can cross the biologic membranes. In the pres- ence of metals, such as Fe2+, H2O2 is converted to the highly reactive hydroxyl radical •OH by the Fenton reaction. 2. • ROS are produced in phagocytic leukocytes, mainly neutro- phils and macrophages, as a weapon for destroying ingested microbes and other substances during inflam- mation and host defense . The ROS are gener- ated in the phagosomes and phagolysosomes of leukocytes by a process that is similar to mitochondrial respiration and is called the respiratory burst (or oxida- tive burst). In this process, a phagosome membrane enzyme catalyzes the generation of superoxide, which is converted to H2O2. H2O2 is in turn converted to a highly reactive compound hypochlorite (the major component of household bleach) by the enzyme myeloperoxidase, which is present in leukocytes. • Nitric oxide (NO) is another reactive free radical pro- duced in leukocytes and other cells. It can react with O2• to form a highly reactive compound, peroxynitrite, which also participates in cell injury The damage caused by free radicals is determined by their rates of production and removal .When the production of ROS increases or the scavenging systems are ineffective, the result is an excess of these free radicals, leading to a condition called oxidative stress.

Question 59

When is the generation of free radicals increased

Answer 59

The generation of free radicals is increased under several circumstances: • The absorption of radiant energy (e.g., ultraviolet light, x-rays). Ionizing radiation can hydrolyze water into hydroxyl (•OH) and hydrogen (H•) free radicals. • Theenzymaticmetabolismofexogenouschemicals(e.g., carbon tetrachloride—see later) • Inflammation, in which free radicals are produced by leukocytes

Question 60

How do cells remove the free radicals to minimize injury Cells have developed many mechanisms to remove free radi- cals and thereby minimize injury. Free radicals are inher- ently unstable and decay spontaneously. True or false

Answer 60

I’m There are also nonenzymatic and enzymatic systems that contribute to inactivation of free radicals • The rate of decay of superoxide is significantly increased by the action of superoxide dismutases (SODs) found in many cell types. • Glutathione (GSH) peroxidases are a family of enzymes whose major function is to protect cells from oxidative damage. The most abundant member of this family, glu- tathione peroxidase 1, is found in the cytoplasm of all cells. It catalyzes the breakdown of H2O2 by the reaction 2 GSH (glutathione) + H2O2 → GS-SG + 2 H2O. The intracellular ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) is a reflection of this enzyme’s activity and thus of the cell’s ability to catabolize free radicals. • Catalase, present in peroxisomes, catalyzes the decom- position of hydrogen peroxide (2H2O2 → O2 + 2H2O). It is one of the most active enzymes known, capable of degrading millions of molecules of H2O2 per second. • Endogenous or exogenous antioxidants (e.g., vitamins E, A, and C and β-carotene) may either block the forma- tion of free radicals or scavenge them once they have formed. Rea

Question 61

Name and explain three ways in which Reactive oxygen species cause cell injury

Answer 61

• Lipid peroxidation of membranes. Double bonds in mem- brane polyunsaturated lipids are vulnerable to attack by oxygen-derived free radicals. The lipid–radical interac- tions yield peroxides, which are themselves unstable and reactive, and an autocatalytic chain reaction ensues. • Cross-linking and other changes in proteins. Free radicals promote sulfhydryl-mediated protein cross-linking, resulting in enhanced degradation or loss of enzymatic activity. Free radical reactions may also directly cause polypeptide fragmentation. • DNA damage. Free radical reactions with thymine in nuclear and mitochondrial DNA produce single-strand breaks. Such DNA damage has been implicated in cell death, aging, and malignant transformation of cells. In addition to the role of ROS in cell injury and killing of microbes, low concentrations of ROS are involved in numer- ous signaling pathways in cells and thus in many physio- logic reactions. Therefore, these molecules are produced normally but, to avoid their harmful effects, their intracel- lular concentrations are tightly regulated in healthy cells.

Question 62

What are the mechanisms that’ll cause membrane permeability

Answer 62

Increased membrane permeability leading ultimately to overt membrane damage is a consistent feature of most forms of cell injury that culminate in necrosis. The plasma membrane can be damaged by ischemia, various microbial toxins, lytic complement components, and a variety of physical and chemical agents. Several biochemical mecha- nisms may contribute to membrane damage (Fig. 1–20): • Decreased phospholipid synthesis. The production of phos- pholipids in cells may be reduced whenever there is a fall in ATP levels, leading to decreased energy-dependent enzymatic activities. The reduced phospholipid synthe- sis may affect all cellular membranes, including the membranes of mitochondria, thus exacerbating the loss of ATP. • Increased phospholipid breakdown. Severe cell injury is associated with increased degradation of membrane phospholipids, probably owing to activation of endog- enous phospholipases by increased levels of cytosolic Ca2+. • ROS. Oxygen free radicals cause injury to cell mem- branes by lipid peroxidation, discussed earlier. • Cytoskeletal abnormalities. Cytoskeletal filaments act as anchors connecting the plasma membrane to the cell interior, and serve many functions in maintaining normal cellular architecture, motility, and signaling. Activation of proteases by increased cytosolic Ca2+ may cause damage to elements of the cytoskeleton, leading to membrane damage. • Lipid breakdown products. These include unesterified free fatty acids, acyl carnitine, and lysophospholip- ids, all of which accumulate in injured cells as a result of phospholipid degradation. These catabolic products have a detergent effect on membranes. They may also either insert into the lipid bilayer of the membrane or exchange with membrane phospholipids, causing changes in permeability and electrophysiologic alteration Increased membrane permeability causes Increaser movement of sodium into the cell and calcium enters the cell causing swelling of the cell and the calcium entrance into the cell will cause the activation of enzymes involved in hydrolysis example phospholipase and these cause destruction of the cell

Question 63

What are the most important sites of membrane damage during cell injury

Answer 63

The most important sites of membrane damage during cell injury are the mitochondrial membrane, the plasma mem- brane, and membranes of lysosomes. • Mitochondrial membrane damage. As discussed earlier, damage to mitochondrial membranes results in decreased production of ATP, with many deleterious effects culminating in necrosis. • Plasma membrane damage. Plasma membrane damage leads to loss of osmotic balance and influx of fluids and ions, as well as loss of cellular contents. The cells may also leak metabolites that are vital for the reconstitution of ATP, thus further depleting energy stores. • Injury to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of the acid hydrolases in the acidic intracellular pH of the injured (e.g., ischemic) cell. Lysosomes contain ribonucleases (RNases), DNases, proteases, glucosidases, and other enzymes. Activation of these enzymes leads to enzy- matic digestion of cell components, and the cells die by necrosis. Damage to D

Question 64

What causes the damage in DNA and proteins

Answer 64

Cells have mechanisms that repair damage to DNA, but if this damage is too severe to be corrected (e.g., after radia- tion injury or oxidative stress), the cell initiates its suicide program and dies by apoptosis. A similar reaction is trig- gered by the accumulation of improperly folded proteins, which may result from inherited mutations or external trig- gers such as free radicals. Since these mechanisms of cell injury typically cause apoptosis, they are discussed later in the chapter Accumulation of damaged DNA and misfolded proteins: trig- gers apoptosis Lactic acid from anaerobic respiration to get ATP can lower the pH and the low pH causes clumping of chromatins causing damage of DNA

Question 65

1.in ischemia why won’t there be no glycolysis occurring for energy to be produced thereby causing cell injury and death(name the two ways) and how those two ways cause the cell injury 2.what type of glycolysis occurs in hypoxia and state the difference between hypoxia and ischemia with respect to glycolysis 3.which of it injures the tissue faster 4.What are the major cellular abnormalities in oxygen deprived cells? And what is the major cellular abnormalities in hypoxic cells 5.name four things that happen when there is loss of ATP

Answer 65

Ischemic and Hypoxic Injury Ischemia, or diminished blood flow to a tissue, is a common cause of acute cell injury underlying human disease. With hypoxia due to less amount of oxygen and not less blood flow energy can be generated thru anaerobic glycolysis but in ischemia energy can’t be generated thru anaerobic glycolysis because there is reduced delivery of substrates for glycolysis causing no energy to be generated at all because the substrates stored are used up or glycolysis is inhibited by the accumulation of metabolites that would’ve been removed if blood was flowing to the tissues. Anaerobic glycolysis occurs in hypoxia Therefore, ischemia injures tissues faster and usually more severely than does hypoxia. The major cellular abnormalities in oxygen-deprived cells are decreased ATP generation, mitochondrial damage, and accumulation of ROS, with its downstream consequences. The most important biochemical abnormality in hypoxic cells that leads to cell injury is decreased ability of the cell to produce ATP intracellulary because of reduced supply of oxygen. 5.loss of ATP leads to the failure of many energy- dependent cellular systems, including (1) ion pumps (leading to cell swelling, and influx of Ca2+, with its delete- rious consequences); (2) depletion of glycogen stores and accumulation of lactic acid, thus lowering the intracellular pH; and (3) reduction in protein synthesis. The functional consequences may be severe at this stage. For instance, heart muscle ceases to contract within 60 seconds of coronary occlusion. 4.If hypoxia continues, wors- ening ATP depletion causes further deterioration, with loss of microvilli and the formation of “blebs” (At this time, the entire cell and its organelles (mitochondria, ER) are markedly swollen, with increased concentrations of water, sodium, and chloride and a decreased concentration of potassium. If oxygen is restored, all of these disturbances are reversible, and in the case of myocardium, contractility returns.

Question 66

What 3things will cause ischemia reperfusion injury to make cell injury worse

Answer 66

Several mechanisms may account for the exacerbation of cell injury resulting from reperfusion into ischemic tissues: • New damage can occur when the ischemic tissue gets increased blood flow to it by causing increased generation of ROS (from parenchymal and endothelial cells and from infiltrating leukocytes):This happens because mitochondrial damage leads to incomplete reduction of oxygen, and because of the action of oxi- dases in leukocytes, endothelial cells, or parenchymal cells. Or it’ll cause increased generation of ROS due to the fact that already the ischaemic tissues have a damaged mitochondria so instead of the oxygen that has come from the blood coming to the ischaemic tissues to be reduced to water it is reduced to superoxide which will lead to more ROS being produced and it’ll accumulate cuz there isn’t enough antioxidative agents because of the ischaemia to remove the ROS from the tissues and increased accumulation of free radicals • 2.The inflammation that is induced by ischemic injury may increase with reperfusion because of increased influx of leukocytes and plasma proteins. The products of acti- vated leukocytes may cause additional tissue injury . 3.Activation of the complement system may also contribute to additional injury. Comple- ment proteins may bind in the injured tissues, or to antibodies that are deposited in the tissues, and subse- quent complement activation generates by-products that exacerbate the cell injury and inflammation.

Question 67

In what two ways does chemical or toxins induce cell injury with regards to being a cause of cell injury and necrosis and give one example each

Answer 67

Chemicals induce cell injury by one of two general mechanisms: 1.Some chemicals act directly by combining with a critical molecular component or cellular organelle. For example, a.in mercuric chloride poisoning (as may occur from inges- tion of contaminated seafood) ,mercury binds to the sulfhydryl groups of various cell membrane proteins, causing inhibition of ATP-dependent transport and increased membrane permeability. b.Many antineo- plastic chemotherapeutic agents also induce cell damage by direct cytotoxic effects. In such instances, the greatest damage is sustained by the cells that use, absorb, excrete, or concentrate the compounds. 2.Many other chemicals are not intrinsically biologically active but are converted to reactive toxic metabolites, which then act on target cells. Although the metabolites might cause membrane damage and cell injury by direct cova- lent binding to protein and lipids, the most important mechanism of cell injury involves the formation of free radicals. Example-Carbon tetrachloride (CCl4)—once widely used in the dry cleaning industry but now banned—and the analgesic acetaminophen belong in this category. The effect of CCl4 is still instructive as an example of chemi- cal injury. CCl4 is converted to the toxic free radical CCl•3, principally in the liver, and this free radical is the cause of cell injury, mainly by membrane phospholipid peroxidation. How-In less than 30 minutes after exposure to CCl4, there is breakdown of ER membranes with a decline in hepatic protein synthesis of enzymes and plasma proteins; within 2 hours, swelling of the smooth ER and dissociation of ribosomes from the smooth ER have occurred. There is reduced lipid export from the hepatocytes, as a result of their inability to synthesize apoprotein to form complexes with triglycerides and thereby facilitate lipoprotein secretion; the result is the “fatty liver” of CCl4 poisoning. the plasma membranes are further damaged by fatty aldehydes produced by lipid peroxidation in the ER. The end result can be calcium influx and eventually cell death.

Question 68

Explain apoptosis, 2.why doesn’t apoptosis elicit inflammatory response from the host 3. name the differences between apoptosis and necrosis with regards to inflammation and plasma membrane 4. how it and necrosis coexist, and 5. how phosphatidylserine works

Answer 68

Apoptosis is a pathway of cell death in which cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins or It’s a pathway of cell death in which its tightly regulated by intracellular programs where cells that are destined to die induce enzymes that degrade their own DNA and cytoplasmic and nuclear proteins . When a cell is deprived of growth factors, or the cell’s DNA or proteins are damaged beyond repair, typically the cell kills itself by another type of death, called apoptosis, which is charac- terized by nuclear dissolution without complete loss of membrane integrity. 2., In apoptosis the plasma membrane is intact as compared to necrosis but the membrane is altered in such a way that the cell and its fragments become avid targets for phagocytes. The dead cell and its fragments are rapidly cleared before cellular contents have leaked out, so apoptotic cell death does not elicit an inflammatory reac- tion in the host. 3. In necrosis there is inflammation cuz of the leakage of enzymes and molecules into the extra cellular part which can recruit inflammatory cells to cause inflammation but there’s no inflammation in apoptosis cuz the plasma membrane is intact but altered in a way that it can be recognized But the plasma membrane is modified . 4. . However, apoptosis and necrosis sometimes coexist, and apoptosis induced by some pathologic stimuli may pro- gress to necrosis. 5. Phosphatidylserine is a kind of phospholipid. In a normal cell it’s on the plasma membrane but it’s hidden inward so it doesn’t show but in apoptosis when the plasma membrane is altered that kind of phospholipid is revealed so the macrophages recognize it and go to the cell and engulf it

Question 69

Explain five examples of physiologic apoptosis

Answer 69

Causes of Apoptosis Apoptosis in Physiologic Situations It is important in the following physiologic situations: 1.The programmed destruction of cells during embryogenesis(during this there’s death of cells and making of new cells) . By embryo genesis the cell population is maintained.Normal development is associated with the death of some cells and the appearance of new cells and tissues. The term programmed cell death was originally coined to denote this death of specific cell types at defined times during the development of an organism. Apoptosis is a generic term for this pattern of cell death, regardless of the context, but it is often used interchangeably with programmed cell death. 2. Involution of hormone-dependent tissues upon hormone deprivation, such as endometrial cell breakdown during the menstrual cycle, and regression of the lactating breast after weaning. Cells that have served their usefulness also die by apoptosis example-shedding of the functional layer of the endometrium is due to apoptosis. When they lack the survival factors or growth factors then they die and shed off by apoptosis 3. Cell loss in proliferating cell populations, such as intestinal crypt epithelia, in order to maintain a constant number • 4.Elimination of cells that have served their useful purpose, such as neutrophils in an acute inflammatory response and lymphocytes at the end of an immune response. In these situations, cells undergo apoptosis because they are deprived of necessary survival signals, such as growth factors. 5. Elimination of potentially harmful self-reactive lymphocytes, either before or after they have completed their matura- tion, in order to prevent reactions against the body’s own tissues 6. Cell death induced by cytotoxic T lymphocytes, a defense mechanism against viruses and tumors that serves to kill virus-infected and neoplastic cells

Question 70

Explain 4 pathologic causes of apoptosis

Answer 70

Apoptosis in Pathologic Conditions . Death by apoptosis is responsible for loss of cells in a variety of pathologic states: 1.DNA damage -If repair mechanisms cannot cope with the injury, the cell triggers intrinsic mechanisms that induce apop- tosis. In these situations, elimination of the cell may be a better alternative than risking mutations in the damaged DNA, which may progress to malignant trans- formation. These injurious stimuli cause apoptosis if the insult is mild, but larger doses of the same stimuli result in necrotic cell death. 2. Accumulation of misfolded proteins. Improperly folded proteins may arise because of mutations in the genes encoding these proteins or because of extrinsic factors, such as damage caused by free radicals. Excessive accu- mulation of these proteins in the ER leads to a condition called ER stress, which culminates in apoptotic death of cells. 3. Cell injury in certain infections, particularly viral infec- tions, in which loss of infected cells is largely due to apoptotic death that may be induced by the virus (as in adenovirus and human immunodeficiency virus infec- tions) or by the host immune response (as in viral hepatitis). 4.Pathologicatrophyinparenchymalorgansafterductobstruc- tion, such as occurs in the pancreas, parotid gland, and kidney MORPH

Question 71

1.In the morphology of apoptosis what things show apoptosis is occurring and 2.at the molecular level state how this is reflected in fragmentation of DNA into nucleosome sized pieces

Answer 71

2.at the molecular level this is reflected in fragmentation of DNA into nucleosome-sized pieces. The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound vesicles of cytosol and organelles 1.a.Cell shrinkage , b.condensation of chromatins If cell shrinks cytoplasm will shrink and organelles become tightly packed c.I.Formation of blebs(As apoptosis progresses, blebs may break away from the cell body to form membrane-clad apoptotic bodies) in the apoptotic bodies due to destruction of exoskeleton and there’ll be fragmentation to ii.form the apoptotic bodies (Karyorrhexis )leads to formation of apoptotic bodies d.Phagocytosis of apoptotic bodies by macrophages Shrinkage,chromatin condensation and aggregation and, ultimately, karyorrhexis

Question 72

Apoptosis occurs from the activation of what kind of enzymes and why are those enzymes called what they’re called and name the two distinct pathways thru which the enzymes are activated

Answer 72

Apoptosis results from the activation of enzymes called caspases (so named because they are cysteine proteases that cleave proteins after aspartic residues). The activation of caspases depends on a finely tuned balance between production of pro- and anti-apoptotic proteins. Two distinct pathways converge on caspase activation: the mitochondrial pathway and the death receptor pathway .

Question 73

The permeability of the mitochondria is controlled by what? What is the name of the sensors that are activated when cells are deprived of growth factors and why are they called what they’re called? Explain the mitochondrial mediated or intrinsic pathway of apoptosis The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of caspases. True or false

Answer 73

The choice between cell survival and death is determined by the permeability of mitochondria, which is controlled by a family of more than 20 proteins, the proto- type of which is Bcl-2 When cells are deprived of growth factors and other survival signals, or are exposed to agents that damage DNA, or accumulate unacceptable amounts of misfolded proteins ,, a number of sensors are activated. These sensors are members of the Bcl-2 family called “BH3 proteins” (because they contain only the third of multiple conserved domains of the Bcl-2 family). They in turn activate two pro-apoptotic members of the family called Bax and Bak, which insert into the mito- chondrial membrane causing increased membrane permeability and form channels through which cytochrome c and other mitochondrial proteins escape into the cytosol. If the cytochrome C and the apoptotic molecules leaks it binds to the APAF1(subscript one (apoptosis activation factor 1)(it’s already in the cytoplasm) So when the cytochrome C and apoptotic molecules binds to APAF1 it stimulates procaspase 9 . This cleaves other caspases and we get the executional caspases (caspase 3 and caspase 6) these are executional enzymes and cause destruction of the cytoskeleton the nuclear protein the cytoplasmic proteins and destruction of the DNA The BH3 sensors also inhibit the anti-apoptotic molecules Bcl-2 and Bcl-xL(which regulate membrane permeability of the mitochondria)enhancing the leakage of mitochondrial proteins. Cytochrome c, together with some cofactors, activates caspase-9. The net result is the activation of the caspase cascade, ultimately leading to nuclear fragmentation. True

Question 74

4.Explain the extrinsic or death receptor mediated pathway of apoptosis 3.Fas ligand (FasL) is a membrane protein expressed mainly on activated T lymphocytes. (T cells) True or false 2. Where is the death domain located and why is the death domain called a death domain? 1. What kind of death receptors that trigger apoptosis are located on the cell surface?

Answer 74

The prototypic death receptors are the type I TNF receptor (Tumor Necrosis Factor ) and Fas (CD95). 2.The cytoplasmic regions of the TNF receptor family contain a conserved death domain. so named because it mediates interaction with other proteins involved in cell death. When T cells recognize Fas-expressing targets, Fas molecules are cross-linked by FasL (fas ligand) and bind adaptor proteins via the death domain. These in turn recruit and activate caspase-8. OR On the plasma membrane there are death receptors (TNFreceptors (type 1)and FAS receptors (also known as CD95) ) The TNF receptors have a death domain in the cytosol and have a ligand binding area outside FAS receptors binds to the ligand (which is on the surface of the plasma membrane) and cross links with three or more FAS receptors so they become three When they’re cross linked ,the fas associated protein with death domain (FADD ) can cross over to the death domain to bind to it to activate the procaspase 8 and it will cleave other caspases further down to give the executional caspases needed to cause cell death. The FADD(this is the adaptor protein) ,which is also called MORT 1,can only bind to the death domain when the receptors are cross linked

Question 75

How are initiator caspases and executioner caspases activated and how do they function State the difference between imitator and executioner caspases

Answer 75

1.Procaspases are the inactive forms of the caspase. The mitochondrial and death receptor pathways lead to the activation of the initiator caspases, caspase-9 and -8, respec- tively. Active forms of these enzymes are produced, and these cleave and thereby activate another series of caspases that are called the executioner caspases. 2. These activated cas- pases cleave numerous targets, culminating in activation of nucleases that degrade DNA and nucleoproteins. Caspases also degrade components of the nuclear matrix and cyto- skeleton, leading to fragmentation of cells. 3. Initiator caspases initiate the apoptosis signal while the executioner caspases carry out the mass proteolysis that leads to apoptosis

Question 76

Explain the three ways that apoptotic cells are cleared And give 2 examples of how necrosis and apoptosis co exist naturally

Answer 76

The cells are cleared by phagocytosis 1. Apoptotic cells entice phagocytes by producing “eat-me” signals. In normal cells phosphatidylserine is present on the inner leaflet of the plasma membrane, but in apoptotic cells this phospholipid “flips” to the outer leaflet, where it is recognized by tissue macrophages and leads to phago- cytosis of the apoptotic cells. 2. Cells that are dying by apop- tosis also secrete soluble factors that recruit phagocytes. This facilitates prompt clearance of the dead cells before they undergo secondary membrane damage and release their cellular contents (which can induce inflammation). 3.Some apoptotic bodies express adhesive glycoproteins that are recognized by phagocytes, and macrophages them- selves may produce proteins that bind to apoptotic cells (but not to live cells) and target the dead cells for engulf- ment. Numerous macrophage receptors have been shown to be involved in the binding and engulfment of apoptotic cells. For instance, DNA damage (seen in apoptosis) activates an enzyme called poly-ADP(ribose) polymerase, which depletes cellular sup- plies of nicotinamide adenine dinucleotide, leading to a fall in ATP levels and ultimately necrosis. In fact, even in common situations such as ischemia, it has been suggested that early cell death can be partly attributed to apoptosis, with necrosis supervening later as ischemia worsens.

Question 77

Name 5 situations that will causes apoptosis to occur and explain When the DNA is damaged which protein accumulated in the cells and triggers apoptosis? What happens when that protein that accumulates is mutated or absent as occurs in some cancers? How does unfolded protein response occur as an adaptation to misfolded proteins accumulation

Answer 77

Cell death in many situations is caused by apoptosis 1.Growth Factor Deprivation Hormone-sensitive cells deprived of the relevant hormone, lymphocytes that are not stimulated by antigens and cyto- kines, and neurons deprived of nerve growth factor die by apoptosis. In all these situations, apoptosis is triggered by the mitochondrial pathway and is attributable to activation of pro-apoptotic members of the Bcl-2 family and decreased synthesis of Bcl-2 and Bcl-xL. 2.DNA Damage Exposure of cells to radiation or chemotherapeutic agents induces DNA damage, which if severe may trigger apop- totic death. When DNA is damaged, the p53 protein accu- mulates in cells. It first arrests the cell cycle (at the G1 phase) to allow the DNA to be repaired before it is replicated However, if the damage is too great to be repaired successfully, p53 triggers apoptosis, mainly by stimulating sensors that ultimately activate Bax and Bak, and by increasing the synthesis of pro-apoptotic members of the Bcl-2 family. 3.Accumulation of Misfolded Proteins: ER Stress During normal protein synthesis, chaperones in the ER control the proper folding of newly synthesized proteins, and misfolded polypeptides are everywhere and targeted for proteolysis. If, however, unfolded or misfolded pro- teins accumulate in the ER because of inherited mutations or environmental perturbations, they induce a protective cellular response that is called the unfolded protein response .but when the accumulation of the misfolded proteins overwhelms this response then ER stress occurs causing activation of caspases and cell death 4.Apoptosis of Self-Reactive Lymphocytes Lymphocytes capable of recognizing self antigens are nor- mally produced in all individuals. If these lymphocytes encounter self antigens, the cells die by apoptosis. Both the mitochondrial pathway and the Fas death receptor pathway have been implicated in this process.Failure of apoptosis of self-reactive lymphocytes is one of the causes of autoimmune diseases. 5.Cytotoxic T Lymphocyte–Mediated Apoptosis Cytotoxic T lymphocytes (CTLs) recognize foreign anti- gens presented on the surface of infected host cells and tumor cells On activation, CTL granule prote- ases called granzymes enter the target cells. Granzymes cleave proteins at aspartate residues and are able to activate cellular caspases. In this way, the CTL kills target cells by directly inducing the effector phase of apoptosis, without engaging mitochondria or death receptors. CTLs also express FasL on their surface and may kill target cells by ligation of Fas receptors. When p53 is mutated or absent (as it is in certain cancers), cells with damaged DNA that would otherwise undergo apoptosis survive. In such cells, the DNA damage may result in mutations or DNA rearrange- ments (e.g., translocation) This response activates signaling pathways that increase the production of chaperones and retard protein translation, thus reducing the levels of misfolded proteins in the cell. In circumstances in which the accumulation of misfolded proteins overwhelms these adaptations, the result is ER stress, which leads to the activation of caspases and ultimately apoptosis.

Question 78

Name 5 diseases caused by misfolding of proteins ,the affected proteins and the pathogenesis

Answer 78

Cystic fibrosis Cystic fibrosis transmembrane conductance regulator (CFTR) Loss of CFTR leads to defects in chloride transport. When the protein is not working correctly, chloride -- a component of salt -- becomes trapped in cells. Without the proper movement of chloride, water cannot hydrate the cellular surface. This leads the mucus covering the cells to become thick and sticky, causing many of the symptoms associated with cystic fibrosis. The CFTr protein is mutated and this causes the misfolding of the CFTR protein 2.Familial hypercholesterolemia LDL receptor Loss of LDL receptor leading to hypercholesterolemia (buildup of cholesterol cuz LDL takes cholesterol to the arteries ) 3. Tay-Sachs disease Hexosaminidase β subunit Lack of the lysosomal enzyme (hexosaminidase A)leads to storage of gangliosides (fats or lipids)in neurons or brain or nerve cells. GM2 ganglioside is necessary for normal functioning the lysosomal enzyme which breaks down fatty acids. Absence of the enzyme causes destruction of the nerve cells 4.Alpha-1-antitrypsin deficiency α-1 antitrypsin Storage of nonfunctional protein in hepatocytes causes apoptosis; absence of enzymatic activity in lungs causes destruction of elastic tissue giving rise to emphysema 5. Creutzfeldt-Jacob disease Prions Abnormal folding of prions due to a mutation in the gene that produces the Prion protein causes neuronal cell death. CJD appears to be caused by an abnormal infectious protein called a prion. These prions accumulate at high levels in the brain and cause irreversible damage to nerve cells, resulting in the symptoms described above. 6.Alzheimer disease Aβ (beta is subscript)peptide Abnormal folding of Aβ(Amyloid beta )peptides causes aggregation within neurons causing abnormal build up of proteins in and around brain cells and apoptosis 8.Type 2 diabetes Islet amyloid polypeptide Misfolding if this causes mutation of insulin gene or misfoldupancreafic proteins 7. Cell death as a result of protein misfolding is now recognized as a feature of a number of neurodegenerative diseases, including Alzheimer, Hun- tington, and Parkinson diseases, and possibly type 2 dia- betes. Deprivation of glucose and oxygen and stresses such as infections also result in protein misfolding, culminating in cell injury and death.

Question 79

SUMMARY Apoptosis • Regulated mechanism of cell death that serves to elimi- nate unwanted and irreparably damaged cells, with the least possible host reaction • Characterized by enzymatic degradation of proteins and DNA, initiated by caspases; and by recognition and removal of dead cells by phagocytes • Initiated by two major pathways:  Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage and accumulation of mis- folded proteins (ER stress); associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they trigger caspase activa- tion; inhibited by anti-apoptotic members of the Bcl family, which are induced by survival signals including growth factor Death receptor (extrinsic) pathway is responsible for elim- ination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes; is initiated by engagement of death receptors (members of the TNF receptor family) by ligands on adjacent cells. True or false

Answer 79

True

Question 80

What is autophagy and what is involved in it and how is it initiated

Answer 80

Autophagy (“self-eating”) refers to lysosomal digestion of the cell’s own components. It is a survival mechanism in times of nutrient deprivation, such that the starved cell subsists by eating its own contents and recycling these contents to provide nutrients and energy. 2. In this process, intracellular organelles and portions of cytosol are first sequestered within an autophagic vacuole, which is postu- lated to be formed from ribosome-free regions of the ER .The vacuole fuses with lysosomes to form an autophagolysosome, in which lysosomal enzymes digest the cellular components 3. . Autophagy is initiated by multi- protein complexes that sense nutrient deprivation and stimulate formation of the autophagic vacuole. With time, the starved cell eventually can no longer cope by devour- ing itself; at this stage, autophagy may also signal cell death by apoptosis.

Question 81

Autophagy is also involved in the clearance of misfolded proteins, for instance, in neurons and hepatocytes. There- fore, defective autophagy may be a cause of neuronal death induced by accumulation of these proteins and, subsequently, neurodegenerative diseases. True or false

Answer 81

True

Question 82

What limits the buildup of misfolded proteins

Answer 82

Conversely, pharmacologic activation of autophagy limits the build-up of misfolded proteins in liver cells in animal models, thereby reducing liver fibrosis.

Question 83

Polymorphisms in a gene involved in autophagy have been associated with inflam- matory bowel disease, but the mechanistic link between autophagy and intestinal inflammation is not known. True or false

Answer 83

True

Question 84

What’s the four pathways of abnormal intracellular accumulatione

Answer 84

There are four main pathways of abnormal intracellular accumulations (Fig. 1–26): • Inadequateremovalofanormalsubstancesecondaryto defects in mechanisms of packaging and transport, as in fatty change in the liver • Accumulationofanabnormalendogenoussubstanceas a result of genetic or acquired defects in its folding, packaging, transport, or secretion, as with certain mutated forms of α1-antitrypsin • Failuretodegradeametaboliteduetoinheritedenzyme deficiencies. The resulting disorders are called storage diseases (Chapter 6). • Deposition and accumulation of an abnormal exogenous substance when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulation of carbon or silica particles is an example of this type of alteration. Or Mechanisms of intracellular accumulation: (1) Abnormal metabolism, as in fatty change in the liver. (2) Mutations causing altera- tions in protein folding and transport, so that defective molecules accu- mulate intracellularly. (3) A deficiency of critical enzymes responsible for breaking down certain compounds, causing substrates to accumulate in lysosomes, as in lysosomal storage diseases. (4) An inability to degrade phagocytosed particles, as in carbon pigment accumulatio

Question 85

What is fatty change

Answer 85

``` Fatty Change (Steatosis) Fatty change refers to any abnormal accumulation of triglyc- erides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabo- lism, but it may also occur in heart, skeletal muscle, kidney, and other organs. Steatosis may be caused by toxins, protein malnutrition, diabetes mellitus, obesity, or anoxia. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in indus- trialized nations. ```

Question 86

How does cholesterol and cholesteryl esters cause abnormal intracellular accumulation

Answer 86

Cholesterol and Cholesteryl Esters Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without significant intracellular accumulation. However, phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesteryl esters) in several different pathologic pro- cesses. Of these, atherosclerosis is the most important. The role of lipid and cholesterol deposition in the pathogenesis of atherosclerosis is discussed in Chapter 9.

Question 87

How are proteins accumulated intracellularly abnormally

Answer 87

Proteins Morphologically visible protein accumulations are much less common than lipid accumulations; they may occur when excesses are presented to the cells or if the cells syn- thesize excessive amounts. In the kidney, for example, trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal con- voluted tubules. However, in disorders with heavy protein leakage across the glomerular filter (e.g., nephrotic syn- drome), there is a much larger reabsorption of the protein, and vesicles containing this protein accumulate, giving the histologic appearance of pink, hyaline cytoplasmic drop- lets. The process is reversible: If the proteinuria abates, the protein droplets are metabolized and disappear. 2.Another example is the marked accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic Russell bodies. Other examples of protein aggregation are discussed else- where in this book (e.g., “alcoholic hyaline” in the liver in Chapter 15; neurofibrillary tangles in neurons in Chapter 22). Or Intracellular accumulation of proteins usually occur as rounded ,eosinophilic droplets,vacuoles, aggregates in the cytoplasm Reabsorption droplets are proximal tubules are seen in renal diseases associated with proteinuria Defects in protein folding may underlie some of these depositions Synthesis of excessive amounts of normal secretory proteins (Russel bodies

Question 88

Explain how glycogen is abnormally accumulated intracellularly

Answer 88

Glycogen Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either glucose or glycogen. In poorly controlled diabetes mellitus, the prime example of abnormal glucose metabolism, glycogen accu- mulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans. Glycogen also accumu- lates within cells in a group of closely related genetic dis- orders collectively referred to as glycogen storage diseases, or glycogenoses (Chapter 6

Question 89

Name some pigments that are synthesized in the body and outside the body

Answer 89

Pigments Pigments are colored substances that are either normal or abnormal constituents of the celland can be either exogenous, coming from outside the body, such as carbon(most common)or coal dust in anthacosis and tattoos or endog- enous, synthesized within the body itself, such as lipofus- cin, hemosiderin,bilirubin,melanin, and certain derivatives of hemoglobin.

Question 90

What is the most exogenous pigment

Answer 90

The most common exogenous pigment is carbon (an example is coal dust), a ubiquitous air pollutant of urban life. When inhaled, it is phagocytosed by alveolar macrophages (resident macrophages in the lungs)and transported through lymphatic chan- nels to the regional tracheobronchial lymph nodes and to the draining lymph nodes where they’re blackened by the carbon Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma or blackening due to the carbon (anthracosis) (Chapter 12).

Question 91

What is lipofuscin and where exactly does it accumulate

Answer 91

Lipofuscin, or “wear-and-tear pigment,” is an insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues (particularly the heart, liver, and brain) as a function of age or atrophy. Lipofuscin represents complexes of lipid and protein that derive from the free radical–catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. It is not injurious to the cell but is a marker of past free radical injury. The brown pigment (Fig. 1–27), when present in large amounts, imparts an appearance to the tissue that is called brown atrophy. By electron micros- copy, the pigment appears as perinuclear electron-dense granules (F

Question 92

Although melanocytes are the only source of melanin(located in epidermis), adjacent basal keratinocytes in the skin can accumulate the pigment (e.g., in freckles), as can dermal macrophages. True or false

Answer 92

True

Question 93

What is Hemosiderin and when does it accumulate in the tissues

Answer 93

Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles. Hemosiderin pigment represents large aggregates of these ferritin micelles, readily visualized by light and electron microscopy; the iron can be unambiguously identified by the Prussian blue histochemical reaction (Fig. 1–28). Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded. Excessive deposition of hemosid- erin, called hemosiderosis, and more extensive accumula- tions of iron seen in hereditary hemochromatosis, are described in Chapter 15.

Question 94

What is pathologic calcification,types of pathologic calcification

Answer 94

Pathologic calcification is a common process in a wide variety of disease states; it implies the abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals in tissues other than osteoid and enamel When the deposition occurs in dead or dying tissues, it is called dystrophic calci- fication; it occurs in the absence of derangements in calcium metabolism (i.e., with normal serum levels of calcium). In contrast, the deposition of calcium salts in normal tissues is known as metastatic calcification and is almost always sec- ondary to some derangement in calcium metabolism (hypercal- cemia). Of note, while hypercalcemia is not a prerequisite for dystrophic calcification, it can exacerbate it

Question 95

What is dystrophic calcification and give an example of it

Answer 95

Dystrophic Calcification Dystrophic calcification is encountered in areas of necrosis of any type. It is virtually inevitable in the atheromas of advanced atherosclerosis, associated with intimal injury in the aorta and large arteries and characterized by accumulation of lipids (Chapter 9). Although dystrophic calcification may be an incidental finding indicating insig- nificant past cell injury, it may also be a cause of organ dysfunction. For example, calcification can develop in aging or damaged heart valves, resulting in severely com- promised valve motion. Dystrophic calcification of the aortic valves is an important cause of aortic stenosis in elderly persons (Fig. 10-17, Chapter 10). Dystrophic calcification is deposition of calcium salt in degenerated tissues with the absence of a systemic mineral imbalance. Dystrophic soft tissue calcification is a type of soft-tissue calcification, which occurs in damaged or necrotic tissue, while the serum level of calcium and phosphorus are normal

Question 96

What is the pathogenesis of dystrophic calcification

Answer 96

The pathogenesis of dystrophic calcification involves initiation (or nucleation) and propagation, both of which may be either intracellular or extracellular; the ultimate end product is the formation of crystalline calcium phos- phate. 2Initiation in extracellular sites occurs in membrane- bound vesicles about 200 nm in diameter; in normal cartilage and bone they are known as matrix vesicles, and in pathologic calcification they derive from degenerating cells. It is thought that calcium is initially concentrated in these vesicles by its affinity for membrane phospholipids, while phosphates accumulate as a result of the action of membrane-bound phosphatases. 2.Initiation of intracellular calcification occurs in the mitochondria of dead or dying cells that have lost their ability to regulate intracellular calcium. After initiation in either location, propagation of crystal formation occurs. This is dependent on the concen- tration of Ca2+ and PO4−, the presence of mineral inhibitors, and the degree of collagenization, which enhances the rate of crystal growth.

Question 97

What is metastatic calcification and state the four major causes of hypercalcemia and how they cause hypercalcemia What is parathyroid hormone responsible for and how does an increase in parathyroid hormone cause hypercalcemia

Answer 97

Metastatic calcification can occur in normal tissues when- ever there is hypercalcemia. The major causes of hypercal- cemia are (1) increased secretion of parathyroid hormone, due to either primary parathyroid tumors or production of parathyroid hormone–related protein by other malignant tumors; (2) destruction of bone due to the effects of acceler- ated turnover (e.g., Paget disease), immobilization, or tumors (increased bone catabolism associated with multiple myeloma, leukemia, or diffuse skeletal metastases); (3) vitamin D(responsible for calcium absorption in the intestines) related disorders including vitamin D intoxication or hypervitaminosis (will cause a lot of absorption of calcium into the blood stream causing elevated calcium levels)and sarcoidosis (in which macrophages activate a vitamin D precursor); and (4) renal failure, in which phosphate reten- tion leads to secondary hyperparathyroidism. Parathyroid hormone is responsible for calcium metabolism When calcium level is raised calcitonin is supposed to bring it down. When it’s low parathyroid hormone raises it up When the parathyrohormone is produced it affects the osteoclasts causing release of calcium by breakdown of bones If there’s more parathyroid there’s more release of calcium causing increased calcium When the bone absorbs too much of calcium it’ll cause a release

Question 98

Where exactly does dystrophic and metastatic calcification occur in the body

Answer 98

Regardless of the site, calcium salts are seen on gross exami- nation as fine white granules or clumps, often felt as gritty deposits. Dystrophic calcification is common in areas of caseous necrosis in tuberculosis. Sometimes a tuberculous lymph node is essentially converted to radiopaque stone. On histologic examination, calcification appears as intracellular and/or extracellular basophilic deposits. Over time, hetero- topic bone may be formed in the focus of calcification. Metastatic calcification can occur widely throughout the body but principally affects the interstitial tissues of the vas- culature, kidneys, lungs, and gastric mucosa. The calcium deposits morphologically resemble those described in dys- trophic calcification. Although they generally do not cause clinical dysfunction, extensive calcifications in the lungs may be evident on radiographs and may produce respiratory defi- cits, and massive deposits in the kidney (nephrocalcinosis) can lead to renal damage.

Question 99

Abnormal deposits of materials such as lipids,proteins,glycogen in cells and tissues are the result of what kind of excessive intake or defective transport or catabolism ? State for each Pathologic calcifications  Dystrophic calcification: deposition of calcium at sites of cell injury and necrosis  Metastatic calcification: deposition of calcium in normal tissues, caused by hypercalcemia (usually a consequence of parathyroid hormone excess) True or false

Answer 99

1.Depositions of lipids  Fatty change: accumulation of free triglycerides in cells, resulting from excessive intake or defective transport (often because of defects in synthesis of transport pro- teins); manifestation of reversible cell injury  Cholesterol deposition: result of defective catabolism and excessive intake; in macrophages and smooth muscle cells of vessel walls in atherosclerosis •2.Deposition of proteins: reabsorbed proteins in kidney tubules; immunoglobulins in plasma cells 3.Deposition of glycogen: in macrophages of patients with defects in lysosomal enzymes that break down glycogen (glycogen storage diseases) 4.Deposition of pigments: typically indigestible pigments, such as carbon, lipofuscin (breakdown product of lipid peroxidation), or iron (usually due to overload, as in hemosiderosis) • True

Question 100

Perhaps one of the most striking discoveries about cellular aging is that it is not simply a consequence of cells’ “running out of steam,” but in fact is regulated by a limited number of genes and signaling pathways that are evolutionarily con- served from yeast to mammals. True or false

Answer 100

True

Question 101

What causes cell aging and what are the mechanics responsible for it In human cells, the mechanism of replicative senescence involves progressive shortening of telomeres, which ultimately results in cell cycle arrest. True or false Define telomeres, what causes the ends of chromosomes to be seen as broken thereby arresting the cell cycle, how is telomere length maintained ,what is telomerase,what cells is telomerase activity expressed in?

Answer 101

Cellular aging is the result of a progressive decline in the life span and functional capacity of cells. Several mechanisms are thought to be responsible for cellular aging (Fig. 1–29): • DNA damage. A variety of metabolic insults that accu- mulate over time may result in damage to nuclear and mitochondrial DNA. Although most DNA damage is repaired by DNA repair enzymes, some persists and accumulates as cells age. Some aging syndromes are associated with defects in DNA repair mechanisms.A role of free radicals in DNA damage leading to aging has been postulated 2/Decreased cellular replication. All normal cells have a limited capacity for replication, and after a fixed number of divisions cells become arrested in a terminally nondi- viding state, known as replicative senescence. Aging is associated with progressive replicative senescence of cells. Cells from children have the capacity to undergo more rounds of replication than do cells from older people. In contrast, cells from patients with Werner syn- drome, a rare disease characterized by premature aging, have a markedly reduced in vitro life span. Telomeres are short repeated sequences of DNA present at the ends of linear chromo- somes that are important for ensuring the complete rep- lication of chromosome ends and for protecting the ends from fusion and degradation. When somatic cells repli- cate, a small section of the telomere is not duplicated and telomeres become progressively shortened. As the telomeres become shorter, the ends of chromosomes cannot be protected and are seen as broken DNA, which signals cell cycle arrest. Telomere length is maintained by nucleotide addition mediated by an enzyme called telomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes. Telomerase activity is expressed in germ cells and is present at low levels in stem cells, but it is absent in most somatic tissues .Therefore, as most somatic cells age their telomeres become shorter and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. Conversely, in immortal- ized cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells to proliferate indefinitely. Telomere shortening may also decrease the regenerative capacity of stem cells, further contrib- uting to cellular aging. • 4.Defective protein homeostasis. Over time, cells are unable to maintain normal protein homeostasis, because of increased turnover and decreased synthesis caused by reduced translation of proteins and defective activity of chaperones (which promote normal protein folding), proteasomes (which destroy misfolded proteins) and repair enzymes. Abnormal protein homeostasis can have many effects on cell survival, replication, and functions. In addition, it may lead to accumulation of misfolded proteins, which can trigger pathways of apoptosis.

Question 102

Explain the two ways in which environmental stresses can affect what causes aging

Answer 102

It is now thought that certain environmental stresses, such as calorie restriction, alter signaling pathways that influence aging 1. It causes reduced signaling by insulin-like growth factor receptors, reduced activation of kinases (notably the “target of rapamycin,” [TOR], and the AKT kinase), and altered transcriptional activity. Ultimately these changes lead to improved DNA repair and protein homeostasis and enhanced immunity, all of which inhibit aging. 2. Environ- mental stresses may also activate proteins of the Sirtuin family, such as Sir2, which function as protein deacety- lases. These proteins may deacetylate and thereby activate DNA repair enzymes, thus stabilizing the DNA; in the absence of these proteins, DNA is more prone to damage.

Question 103

Summary of four causes of cellular injury

Answer 103

Cellular Aging • Results from combination of accumulating cellular damage (e.g., by free radicals), reduced capacity to divide (replica- tive senescence), and reduced ability to repair damaged DNA • Accumulation of DNA damage: defective DNA repair mech- anisms; conversely DNA repair may be activated by calorie restriction, which is known to prolong aging in model organisms • Replicative senescence: reduced capacity of cells to divide secondary to progressive shortening of chromosomal ends (telomeres) • Other factors: progressive accumulation of metabolic damage; possible roles of growth factors that promote aging in simple model organisms

Question 104

Ischemia could be arterial or venous true or false

Answer 104

True Example-arteriosclerosis of coronary vessels Narrowing of these vessels by artheroma and reduces blood flow the these organs and there’s venous congestion Blood doesn’t move so new blood doesn’t come

Question 105

Name some proapoptotic proteins and anti apoptotic proteins

Answer 105

Pro- BAK and BAX Anti-BCL-2 and BCL-X

Question 106

Cyt c is synthesized in the cytosol as an apoprotein and, upon translocation to the mitochondria, it associates with the heme prosthetic group. True or false

Answer 106

True

Question 107

Phospholipids is needed in maintaining the integrity of the plasma membrane so when there’s destruction of the phospholipids it’ll lead to damage of the plasma membrane true or false

Answer 107

True

Question 108

There is no specific marker that can show that the cell has reached the point of no return but there are some important features that when seen shows whether the Injury is reversible or not true or false

Answer 108

True

Question 109

Necrosis is physiologic and pathologic while apoptosis is pathological true or false

Answer 109

False Necrosis is pathological Apop is physiological and pathological

Question 110

What morphological changes are seen in irreversible injury

Answer 110

Severe mitochondrial damage | Profound membrane dysfunction

Question 111

What is the full meaning of caspase

Answer 111

cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases

Question 112

Difference between autolysis and heterolysis

Answer 112

Autolysis-destructive enzymes are from the cells Heterolysis -degradative enzymes are from the macrophages and the neutrophils recruited to the site to deal with the offending agents Or heterolysis refers to cellular necrosis by hydrolytic enzymes from surrounding (usually inflammatory) cells. On the other hand, Autolysis is cell necrosis of a cell by its own enzymes, usually due to various causes such as infective agents or physical agents.

Question 113

Autophagy is eating of a part of the cell by the cell itself true or false and what are lysosomes

Answer 113

True | An organelle containing enzymes in the cell and these enzymes cause destruction of the cell

Question 114

What kind of tissues undergo coagulative necrosis with what exception and why

Answer 114

All ischemic injury or necrosis of ischemic injury are coagulative w the exception of the brain The Brian undergoes liquefactive necrosis although it sometimes undergoes ischemic injury cuz it has plenty enzymes that will cause destruction of the cell Doesn’t mean only the brain undergoes liquefactive necrosis

Question 115

What are the contents of apoptotic bodies

Answer 115

Cytoplasm | Densely packed organelles with or without nuclear material

Question 116

What is the function of phosphatidylserine

Answer 116

Phosphatidylserine is a kind of phospholipid. In a normal cell it’s on the plasma membrane but it’s hidden inward so it doesn’t show but in apoptosis when the plasma membrane is altered that kind of phospholipid is revealed so the macrophages recognize it and go to the cell and engulf it

Question 117

What re the biochemical features found in apoptosis

Answer 117

Protein cleavage -caspases are activated and cause the destruction of the cytoskeleton so there’s protein destruction DNA breakdown Phagocytic recognition

Question 118

What are the two main mechanisms of apoptosis and state the two mechanism under the first phase

Answer 118

1.Initiation phase where enzymes are activated I.Intrinsic (mitochondrial mediator ) pathway II.Extrinsic (death receptor mediator) pathway 2. Execution phase-activated enzymes cause the cell death

Question 119

On the plasma membrane what kind of death receptors are there that have a death domain in the cytosol and state their full names

Answer 119

On the plasma membrane there are death receptors (TNFreceptors (type 1)and FAS receptors (also known as CD95) ) TNF-Tumor necrosis factor receptor type 1 Fas-apoptosis antigen 1 or CD95

Question 120

In the mitochondrion which initiator procaspase is there

Answer 120

ProCaspase 9

Question 121

What are intracellular accumulations and types of things accumulated

Answer 121

Normal substances accumulated in excess example lipids ,water,proteins,carbs(are being accumulated due to failure of transport systems Abnormal substances :either exogenous(accumulation outside the body)(minerals or products of infectious agents) or endogenous(inside the body) (product of abnormal synthesis or metabolism of a product) Pigments

Question 122

Name five examples of dystrophic calcification

Answer 122

Example- calcification seen in caseous necrosis ,liquefactive necrosis,enzymatic necrosis of fat Example-Gamna Gandy bodies(which is made up of calcium salts,hemosiderin and fibrous tissue)seen in the chronic something of the spleen Example-formation of thrombose causing deposition of calcium salts in it making it stony hard and it’s called a plegmbolate now. Deposition of calcium salts in a hematoma that’s close to a bone Deposition of Calcium salts in carcinoma of the breast ,in degenerative tissues (deteriorated tissues that lose their function due to an injury) Atheroma calcification Monckebergs medial calcific sclerosis-calcification in the tunica media common in muscular arteries and commonly seen in elderly people Tumours calcification Cysts being calcified

Question 123

What do calcium salts look like and what does the appearance of psammoma bodies mean,which disease conditions will you see these bodies?

Answer 123

Histologically they have a basophilic amorphorous granular sometimes clumped appearance Appearance of psammoma bodies in certain tumors shows there’s been metastatic calcification Papillary adenocarcinoma of the ovary or of the thyroid gland,prolactinoma of the pituitary gland,

Question 124

In necrosis the dead cells may become replaced by large masses composed of phospholipids in the form of myelin figures or they’ll be phagocytosed True or false

Answer 124

True

Question 125

What is ischemia reperfusion injury

Answer 125

Usually when cells are reversibly injured due to reduced blood flow ,the restoration of blood flow can result in cell recovery. But under certain circum- stances, the restoration of blood flow to ischemic but viable tissues results, in the death of cells that are not otherwise irreversibly injured. This ischemia- reperfusion injury is a clinically important process that may contribute significantly to tissue damage in myocardial and cerebral ischemia.

Question 126

What cytochrome is responsible for the conversion of inactive chemicals to active metabolites causing formation of free radicals and causing cell injury in chemical and toxic cell injury

Answer 126

This modification is usually accom- plished by the cytochrome P-450 in the smooth ER of the liver and other organs. EgCCl4 to CCl3

Question 127

Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, “falling off”). True or false

Answer 127

True

Question 128

Name four characteristics of necrosis

Answer 128

Apoptosis differs in this respect from necro- sis, which is characterized by loss of membrane integrity, enzymatic digestion of cells, leakage of cellular contents, and frequently a host reaction (Inflammation )

Question 129

How is apoptosis both physiological and pathological

Answer 129

Apoptosis occurs in many normal situations and serves to eliminate potentially harmful cells and cells that have out- lived their usefulness. It also occurs as a pathologic event when cells are damaged beyond repair, especially when the damage affects the cell’s DNA or proteins; in these situ- ations, the irreparably damaged cell is eliminated. Apoptosis eliminates cells that are genetically altered or injured beyond repair and does so without eliciting a severe host reaction, thereby keeping the extent of tissue damage to a minimum

Question 130

Death by apoptosis is a normal phenomenon that serves to elimi- nate cells that are no longer needed and to maintain a constant number of cells of various types in tissues. True or false

Answer 130

True

Question 131

Name three causes of DNA damage

Answer 131

Radiation, cytotoxic anticancer drugs, extremes of temperature, and even hypoxia can damage DNA, either directly or through production of free radi- cals.

Question 132

Inducing apoptosis of cancer cells is a desired effect of chemotherapeutic agents, many of which work by damaging DNA. True or false

Answer 132

True

Question 133

these fragments are quickly extruded and phagocytosed within little time sometimes histologically apoptosis won’t be seen true or false

Answer 133

True

Question 134

Mitochondria contain several proteins that are capable of inducing apoptosis; these proteins include cytochrome c and other proteins that neutralize endogenous inhibitors of apoptosis. True or false

Answer 134

True

Question 135

Other proteins that leak out of mitochondria block the activities of caspase antagonists that function as physiologic inhibitors of apoptosis .The mitochondrial pathway seems to be the pathway that is responsible for apoptosis in most situa- tions, True or false

Answer 135

True

Question 136

What causes the production of antiapoptotic proteins State their functions And what happens to cells that are deprived of growth factors

Answer 136

Conversely, if cells are exposed to growth factors and other survival signals, they synthesize anti-apoptotic members of the Bcl-2 family, the two main ones of which are Bcl-2 itself and Bcl-xL. These proteins antagonize Bax and Bak, and thus limit the escape of the mitochondrial pro-apoptotic proteins by reducing or preventing mitochondrial permeability Cells deprived of growth factors not only activate the pro-apoptotic Bax and Bak but also show reduced levels of Bcl-2 and Bcl-xL, thus further tilting the balance toward death.

Question 137

The mitochondrion has receptors for growth factors or survival molecule and these prevent apoptosis True or false

Answer 137

True

Question 138

Which other way can caspase 8 cause destruction

Answer 138

In many cell types caspase-8 may cleave and activate a pro-apoptotic member of the Bcl-2 family called Bid, thus feeding into the mitochondrial pathway.

Question 139

Name the importance of the death receptor mediated pathway | What is FLIp and what is it’s function

Answer 139

1. The death receptor pathway is involved in elimination of self-reactive lympho- cytes and in killing of target cells by some cytotoxic T lymphocytes. 2. Cellular proteins, notably a caspase antagonist called FLIP, block activation of caspases downstream of death receptors. Interestingly, some viruses produce homologues of FLIP, and it is suggested that this is a mechanism that viruses use to keep infected cells alive.

Question 140

What are executioner caspases and name them | And explain why caspase 3 is an executioner caspase

Answer 140

Executioner caspases can cleave an array of target proteins leading to characteristic apoptotic breakdown of a cell. Caspase 3,6,7 Caspase-3 is known as an executioner caspase in apoptosis because of its role in coordinating the destruction of cellular structures such as DNA fragmentation or degradation of cytoskeletal protein

Question 141

Which other way do misfolded proteins cause problems

Answer 141

Intracellular accumulation of abnormally folded proteins, caused by mutations, aging, or unknown environmental factors, may cause diseases by reducing the availability of the normal protein or by induc- ing cell injury