Cellular Adaptations 2

Question 1

What are characteristics of ischemic injury?

Answer 1

reduced blood supply

• Common cause of acute cell injury
• Energy can still be generated by anaerobic glycolysis
• Faster injury (vs. hypoxia) due to loss
of substrates or accumulation of metabolites needed for anaerobic respiration due to lack of blood flow

If ischemia persists, irreversible injury and necrosis ensue.

Question 2

What are characteristics of hypoxic injury?

Answer 2

reduced oxygen

-Reduced intracellular generation of ATP
ion pumps (leading to cell swelling, and influx of Ca 2+, with its deleterious consequences);

depletion of glycogen stores and accumulation of lactic acid, thus lowering the intracellular pH; and reduction in protein synthesis.

Question 3

T or F. Ischemic and hypoxic changes are reversible – to a point

Answer 3

T.

Question 4

With hypoxia and ischemia, does most cell death result from necrosis or apoptosis?

Answer 4

necrosis

Question 5

What is Ischemic-Reperfusion Injury?

Answer 5

certain cells that are reversibly injured in an event such as myocardial infarction (but don’t die), die as the result of restoration of blood flow to the cell (seemingly paradoxical)

common in myocardial and cerebral ischemia

1) New damage may be initiated during reoxygenation by increased generation of ROS from parenchymal and endothelial cells and from infiltrating leukocytes. When the supply of oxygen is increased, there may be a corresponding increase in the production of ROS, especially because mitochondrial damage leads to incomplete reduction of oxygen, and because of the action of oxidases in leukocytes, endothelial cells, or parenchymal cells. Cellular antioxidant defense mechanisms may also be compromised by ischemia, favoring the 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 activated leukocytes may cause additional tissue injury. Activation of the complement system may also contribute to ischemia-reperfusion injury. Complement proteins may bind in the injured tissues, or to antibodies that are deposited in the tissues, and subsequent complement activation generates by-products that exacerbate the cell injury and inflammation.

Question 6

What are some of the mechanisms may account for the exacerbation of cell injury resulting from reperfusion into ischemic tissues?

Answer 6

1) Increased generation of ROS
- Oxygen reintroduced, so more ROS
- Mitochondrial damage leads to incomplete reduction of oxygen
- Antioxidant defenses compromised by ischemia

2) Inflammation
- Activated leukocytes complement activation

Question 7

What re the two basic mechanisms of Chemical (toxic) Injury?

Answer 7

Direct action (i.e. many antineoplastic chemotherapeutic drugs)

Conversion to toxic metabolites (i.e. acetaminophen-tylenol)

Question 8

What is Apoptosis?

Answer 8

Cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins

Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, “falling off”). The plasma membrane of the apoptotic cell remains intact, 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. 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. However, apoptosis and necrosis sometimes coexist, and apoptosis induced by some pathologic stimuli may pro- gress to necrosis.

can be physiologic and pathologic

Question 9

What are the basic steps of apoptosis?

Answer 9

1. condensation of chromatin and formation of membrane blebs
2. cellular fragmentations and apoptotic body release
3. Phagocytosis of apoptotic bodies

Question 10

What are some physiologic causes of apoptosis?

Answer 10

• Embryogenesis
• Hormone driven (i.e. endometrium)
• Cell loss in Proliferating cell populations (i.e. GI tract) in order to maintain constant numbers
• Elimination of cells past their due date (i.e. neutrophils) In these situations, cells undergo apoptosis because they are deprived of necessary survival signals, such as growth factors.
• Elimination of potentially harmful self-reactive lymphocytes
• Cell death induced by cytotoxic T lymphocytes, a defense mechanism against viruses and tumors that serves to kill virus-infected and neoplastic cells

Question 11

What are some pathologic causes of apoptosis?

Answer 11

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.

• DNA damage
• Misfolded proteins
• Cell injury in infection
• Atrophy of surrounding tissue from duct obstruction (pancreas, salivary gland)

Question 12

What are apoptotic bodies?

Answer 12

shrunk cells composed of membrane-bound vesicles of cytosol and organelles

• Chromatin condensation and aggregation and, ultimately, karyorrhexis
• Molecular level = fragmentation of DNA
• No inflammation – Quick process – can be undetectable

Question 13

What is Pyknosis?

Answer 13

the irreversible condensation of chromatin

Question 14

What is the mechanism of apoptosis?

Answer 14

results from the activation of enzymes called caspases (so named because they are Cysteine proteases that cleave proteins after ASpartic residues)

Question 15

What two pathways converge on capsize activation?

Answer 15

the mitochondrial pathway (more common) and the death receptor pathway

Although these pathways can intersect, they are generally induced under different conditions, involve different molecules, and serve distinct roles in physiology and disease.

Question 16

Describe the mitochondrial (intrinsic) pathway of capsize activation.

Answer 16

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 thirdof multiple conserved domains of the Bcl-2 family). They in turn activate two pro-apoptotic members of the family called Bax and Bak, which dimerize, insert into the mitochondrial membrane, and form channels through which cytochrome c and other mitochondrial proteins escape into the cytosol. These sensors also inhibit the anti-apoptotic molecules Bcl-2 and Bcl-xL, enhancing the leakage of mitochondrial proteins. Cytochrome c, together with some cofactors, activates caspase-9. Other proteins that leak out of mitochondria block the activities of caspase antagonists that function as physiologic inhibitors of apoptosis. The net result is the activation of initiator caspases, which activate executioner caspases, which cause two things: endonuclease activation (causes nuclear fragmentation) and breakdown of the cytoskeleton.

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. 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. The mitochondrial pathway seems to be the pathway that is responsible for apoptosis in most situations.

Question 17

Describe the death receptor (extrinsic) pathway of capsize activation.

Answer 17

Many cells express surface molecules, called death receptors, that trigger apoptosis. Most of these are members of the tumor necrosis factor (TNF) receptor family, which contain in their cytoplasmic regions a conserved “death domain,” so named because it mediates interaction with other proteins involved in cell death. The prototypic death receptors are the type I TNF receptor and Fas (CD95). Fas ligand (FasL) is a membrane protein expressed mainly on activated T lymphocytes. When these T cells recognize Fas-expressing targets, Fas molecules are cross-linked by FasL and bind adaptor proteins via the death domain. These in turn recruit and activate caspase-8. In many cell types caspase-8 may cleave and activate a pro-apoptotic member of the Bcl-2 family called Bid, that activate initiator caspases, which activate executioner caspases, which cause two things: endonuclease activation (causes nuclear fragmentation) and breakdown of the cytoskeleton. The combined activation of both pathways delivers a lethal blow to the cell.

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. The death receptor pathway is involved in elimination of self-reactive lymphocytes and in killing of target cells by some cytotoxic T lymphocytes

Question 18

What are some (3) examples of apoptosis that are induced by growth factor deprivation?

Answer 18

• Hormone-sensitive cells deprived of the relevant hormone,
• lymphocytes that are not stimulated by antigens and cytokines, and
• neurons deprived of nerve growth factor ALL die by apoptosis.

In all these situations, apoptosis is triggered by the mitochondrial pathway and is attributable to activation of pro-apoptotic members of Bcl-2 family effectors (Bax/Bak) and decreased synthesis of the regulators Bcl-2 and Bcl-xL .

Question 19

How does DNA damage cause apoptosis?

Answer 19

Radiation or chemotherapeutic agents cause DNA damage and accumulation of p53 protein.

P53 triggers apoptosis by activation of Bax and Bak and by decreasing Bcl-2 and Bcl-xl (or at least arrests the cell in G1 phase to repair damage)

When p53 is mutated or absent (as it is in certain cancers), cells with damaged DNA that would otherwise undergo apoptosis survive.

Question 20

How does protein misfolding lead to apoptosis?

Answer 20

During normal protein synthesis, chaperones in the ER control the proper folding of newly synthesized proteins, and misfolded polypeptides are ubiquitinated and targeted for proteolysis. If, however, unfolded or misfolded proteins accumulate in the ER because of inherited mutations or environmental perturbations, they induce a protective cellular response that is called the unfolded protein response. 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.

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 inducing cell injury. Cell death as a result of protein misfolding is now recognized as a feature of a number of neurodegenerative diseases, including Alzheimer, Huntington, and Parkinson diseases, and possibly type 2 diabetes. Deprivation of glucose and oxygen and stresses such as infections also result in protein misfolding, culminating in cell injury and death.

Question 21

How does protein misfolding lead to CF?

Answer 21

cystic fibrosis transmembrane conductance regulator proteins are misfolded leading to defects in chloride transport

Question 22

How does protein misfolding lead to familial hypercholesterolemia?

Answer 22

misfolding of LDL receptors lead to elevated cholesterolemia

Question 23

How does protein misfolding cause Tay-Sachs disease?

Answer 23

protein misfolding of the lysosomal enzyme hexosaminidase-B subunit leads to storage of GM 2 gangliosides in neurons

Question 24

How does protein misfolding cause alpha-1-antitrypsin deficiency?

Answer 24

Storage of nonfunctional protein in hepatocytes causes apoptosis; absence of enzymatic activity in lungs causes destruction of elastic tissue giving rise to emphysema

normal amounts of alpha-a-antitrypsin in the liver but they can’t leave so lungs are deficient

Question 25

How does protein misfolding cause Alzheimer disease?

Answer 25

protein misfolding of A-B peptide causes aggregation within neurons and apoptosis

Question 26

What causes apoptosis of self-reactive lymphocytes?

Answer 26

• Lymphocytes capable of recognizing self antigens are normally 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 are activated

Failure of apoptosis of self-reactive lymphocytes is one of the causes of autoimmune diseases.

Question 27

How does cytotoxic T lymphocyte-mediated apoptosis occur?

Answer 27

• CTLs recognize foreign antigens presented on the surface of infected host cells and tumor cells.
• On activation, CTL granule proteases called granzymes enter the target cells.
• Granzymes cleave proteins at aspartate residues and are able to activate cellular caspases.
• CTL kills target cells by directly inducing the effector phase of apoptosis, without engaging mitochondria or death receptors

• CTLs also express FasLigand on their surface and may kill cells by ligation of Fas receptors on target cells


Question 28

What is Autophagy? How does it work?

Answer 28

self-eating. Lysosomal digestion of the cells own components encased in VACUOLES

In this process, intracellular organelles and portions of cytosol are first sequestered within an autophagic vacuole, which is postulated 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. 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 devouring itself; at this stage, autophagy may also signal cell death by apoptosis.

Question 29

What are the four pathways of abnormal intracellular accumulations?

Answer 29

Under some circumstances cells may accumulate abnormal amounts of various substances, which may be harmless or associated with varying degrees of injury. The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus, and it may be synthe- sized by the affected cells or may be produced elsewhere

1. Inadequate removal of a normal substance secondary to defects in mechanisms of packaging and transport, as in fatty change in the liver
2. Accumulation of an abnormal endogenous substance as a result of genetic or acquired defects in its folding, packaging, transport, or secretion, as with certain mutated forms of α 1 -antitrypsin
3. Failure to degrade a metabolite due to inherited enzyme deficiencies. The resulting disorders are called storage diseases.
4. Deposition and accumulation of an abnormal exogenous substance (i.e. breast implants) 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.

Question 30

What are Russell bodies?

Answer 30

the marked accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic cells

Question 31

Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either glucose or glycogen.

Examples?

Answer 31

diabetes mellitus - glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans.

Glycogen also accumulates within cells in a group of closely related genetic disorders collectively referred to as glycogen storage diseases, or glycogenosis.

Question 32

How are apoptotic cells cleared?

Answer 32

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 phagocytosis of the apoptotic cells. 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).

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 engulfment. Numerous macrophage receptors have been shown to be involved in the binding and engulfment of apoptotic cells. This process of phagocytosis of apoptotic cells is so efficient that dead cells disappear without leaving a trace, and inflammation is virtually absent.

Question 33

ATP deficiency would typically lead to ____.

Answer 33

necrosis

Question 34

DNA damage would typically lead to ____.

Answer 34

apoptosis

Question 35

What is Steatosis?

Answer 35

Fatty change refers to any abnormal accumulation of triglycerides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabolism, 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 36

What is the most common exogenous pigment?

Answer 36

carbon (an example is coal dust), a ubiquitous air pollutant of urban life. When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes. Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis)

Question 37

What is Lipofuscin?

Answer 37

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, when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.

not really a bad thing to have it

Question 38

What is dystrophic calcification?

Answer 38

the deposition of calcium occurring in dead or dying tissues

it occurs in the absence of derangements in calcium metabolism (i.e., with normal serum levels of calcium)

Question 39

What is metastatic calcification?

Answer 39

The deposition of calcium salts in normal tissues; is almost always se 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 40

Where is dystrophic calcification typically found?

Answer 40

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

Although dystrophic calcification may be an incidental finding indicating insignificant 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

Question 41

Metastatic calcification can occur in normal tissues when- ever there is hypercalcemia. The major causes of hypercalcemia are:

Answer 41

(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 accelerated turnover (e.g., Paget disease), immobilization, or tumors (increased bone catabolism associated with multiple myeloma, leukemia, or diffuse skeletal metastases);
(3) vitamin D–related disorders including vitamin D intoxication and sarcoidosis (in which macrophages activate a vitamin D precursor); and
(4) renal failure, in which phosphate retention leads to secondary hyperparathyroidism.

Question 42

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, such as:

Answer 42

• DNA damage. A variety of metabolic insults that accumulate over time may result in damage to nuclear and mitochondrial DNA.
• 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 non-dividing state, known as replicative senescence. In human cells, the mechanism of replicative senescence involves progressive shortening of telomeres, which ultimately results in cell cycle arrest. When somatic cells replicate, 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
• 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 43

Telomere length is maintained by nucleotide addition mediated by an enzyme called ____.

Answer 43

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.

Question 44

What happens to telomerase in cancer cells?

Answer 44

Conversely, in immortalized cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells to proliferate indefinitely.