Cellular responses Flashcards
adaptations
reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment
hypertrophy
increase in the size of cells, that results in an increase in the size of the affected organ
Hyperplasia
an increase in the number of cells in an organ or tissue in response to a stimulus
Physiologic hyperplasia
Physiologic hyperplasia due to the action of hormones or growth factors occurs in several circumstances: when there is a need to increase functional capacity of hormone sensitive organs; when there is need for compensatory increase after damage or resection
pathologic hyperplasia
Most forms of pathologic hyperplasia are caused by excessive or inappropriate actions of hormones or growth factors acting on target cells
Atrophy
as a reduction in the size of an organ or tissue due to a decrease in cell size and number
Pathologic atrophy
Decreased workload (atrophy of disuse) Loss of innervation (denervation atrophy)
Diminished blood supply
Inadequate nutrition
This results in marked muscle wasting (cachexia)
Loss of endocrine stimulation
Pressure
Metaplasia
is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type
Overview of Cell Injury and Cell Death
Historically, two principal types of cell death, necrosis and apoptosis, which differ in their morphology, mechanisms, and roles in physiology and disease
Whereas necrosis is always a pathologic process, apoptosis serves many normal functions and is not necessarily associated with cell injury
Causes of cell injury
oxygen deprivation chemical agents and drugs immunologic reactions nutritional imbalances physical agents infectious agents genetic derangement
cherry red skin sign of
carbon monoxide poisoning
brown spots on the hands sign of
chronic arsenic poisoning
cyanide poisoning shuts down
oxidative phosphorylation/ krebs cycle
apoptosis vs necrosis
apoptosis means “fade away,” without inflammation; compare this to necrosis, coming in all loud and annoying. Inflammation is present in necrosis
reversible injury: two features that can be seen, and types of cells usually seen in
Two features of reversible cell injury can be recognized under the light microscope: cellular swelling and fatty change
It is seen mainly in cells involved in and dependent on fat metabolism, such as hepatocytes and myocardial cells
patterns of tissue necrosis
coagulative necrosis gangrenous necrosis fat necrosis liquefactive necrosis caseous necrosis fibrinoid necrosis
man drinker, high lipase
acute pancreatitis. Saponification called fat necrosis
kidney?
coagulative necrosis!
brain leaking out?
liquification necrosis!
artery with pink stuff?
fibrinoid necrosis
pancreas with white chalky deposits and calcium soap formation
fat necrosis
number one problem with cell injuries?
screwing up the ATP with mitochondria problems –> cell swelling
Depletion of ATP
Reduction in ATP levels is fundamental cause of necrotic cell death
The major causes of ATP depletion are reduced supply of oxygen and nutrients, mitochondrial damage, and the actions of some toxins (e.g., cyanide)
mahogony tumor with central scar loaded with pink cells on histology?
benign renal tumor
Influx of Calcium and Loss of Calcium Homeostasis
The accumulation of Ca2+ in mitochondria results in opening of the mitochondrial permeability transition pore and, as described earlier, failure of ATP generation.
Increased cytosolic Ca2+ activates a number of enzymes with potentially deleterious effects on cells. These enzymes include phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin fragmentation), and ATPases (thereby hastening ATP depletion).
Increased intracellular Ca2+ levels also result in the induction of apoptosis, by direct activation of caspases and by increasing mitochondrial permeability.
major aspect of mitochondria’s job
clean up ROS
Removal of Free Radicals
Antioxidants either block the initiation of free radical formation or inactivate (e.g., scavenge) free radicals. Examples are the lipid-soluble vitamins E and A as well as ascorbic acid and glutathione in the cytosol
toxicity of iron and copper
Iron and copper can catalyze the formation of ROS. The levels of these reactive metals are minimized by binding of the ions to storage and transport proteins (e.g., transferrin, ferritin, lactoferrin, and ceruloplasmin), thereby minimizing the formation of ROS.
Enzymes that act as free radical-scavenging systems and break down H202 and superoxide
These enzymes are located near the sites of generation of the oxidants and include the following:
1.Catalase, present in peroxisomes, decomposes H2O2.
2.Superoxide dismutases (SODs) are found in many cell types and convert superoxideto H2O2. This group includes both manganese–SOD, which is localized in mitochondria, and copper-zinc–SOD, which is found in the cytosol.
3.Glutathione peroxidase also protects against injury by catalyzing free radical breakdown The intracellular ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) is a reflection of the oxidative state of the cell and is an important indicator of the cell’s ability to detoxify ROS.
young kid sore throat with ear infection. start antibiotic, comes back with jaundice–> blood smear with anemia. Cells with chunk taken out (bite cells). What’s up?
G6P deficiency
membrane unstable, so bites taken out of the red blood cells
Damage to DNA and Proteins
Cells have mechanisms that repair damage to DNA, but if DNA damage is too severe to be corrected (e.g., after exposure to DNA damaging drugs, radiation, or oxidative stress), the cell initiates a suicide program that results in death by apoptosis
Two phenomena consistently characterize irreversibility—the inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury, and profound disturbances in membrane function
Leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific cellular injury and necrosis using blood serum samples
Ischemia
Ischemia is the most common type of cell injury in clinical medicine and it results from hypoxia induced by reduced blood flow, most commonly due to a mechanical arterial obstruction
Ischemia-Reperfusion Injury
Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured, but can also paradoxically exacerbate the injury and cause cell death
Oxidative stress.
New damage may be initiated during reoxygenation by increased generation of reactive oxygen and nitrogen species.
Intracellular calcium overload.
Calcium overload favors opening of the mitochondrial permeability transition pore with resultant depletion of ATP. This in turn causes further cell injury.
Inflammation.
Ischemic injury is associated with inflammation as a result of “dangers signals” released from dead cells, cytokines secreted by resident immune cells such as macrophages, and increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells, all of which act to recruit circulating neutrophils to reperfused tissue.
Activation of the complement system may contribute to ischemia-reperfusion injury.
Some IgM antibodies have a propensity to deposit in ischemic tissues, for unknown reasons, and when blood flow is resumed, complement proteins bind to the deposited antibodies, are activated, and cause more cell injury and inflammation
Mercuric chloride poisoning
poisoning, mercury binds to the sulfhydryl groups of cell membrane proteins, causing increased membrane permeability and inhibition of ion transport. In such instances, the greatest damage is usually to the cells that use, absorb, excrete, or concentrate the chemicals—in the case of mercuric chloride, the cells of the gastrointestinal tract and kidney
Cyanide poisons
mitochondrial cytochrome oxidase and thus inhibits oxidative phosphorylation.
Direct toxicity
mercuric chloride, cyanide.
Many antineoplastic chemotherapeutic agents and antibiotics also induce cell damage by direct cytotoxic effects.
CCl4,
which was once widely used in the dry cleaning industry, is converted by cytochrome P-450 to the highly reactive free radical ˙CCl3, which causes lipid peroxidation and damages many cellular structures.
Acetaminophen
an analgesic drug, is also converted to a toxic product during detoxification in the liver, leading to cell injury
Apoptosis
is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins
Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed, and to maintain a steady number of various cell populations in tissues
Apoptosis in Physiologic Situations
The destruction of cells during embryogenesis, including implantation, organogenesis, developmental involution, and metamorphosis
Involution of hormone-dependent tissues upon hormone withdrawal, such as endometrial cell breakdown during the menstrual cycle, ovarian follicular atresia in menopause, the regression of the lactating breast after weaning, and prostatic atrophy after castration
Cell loss in proliferating cell populations, such as immature lymphocytes in the bone marrow and thymus and B lymphocytes in germinal centers that fail to express useful antigen receptors and epithelial cells in intestinal crypts, so as to maintain a constant number (homeostasis)
Elimination of potentially harmful self-reactive lymphocytes, either before or after they have completed their maturation, so as to prevent reactions against one’s own tissues
Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response.
Apoptosis in pathologic conditions: DNA damage
Radiation, cytotoxic anticancer drugs, and hypoxia can damage DNA, either directly or via production of free radicals. If repair mechanisms cannot cope with the injury, the cell triggers intrinsic mechanisms that induce apoptosis. In these situations elimination of the cell may be a better alternative than risking mutations in the damaged DNA, which may result in malignant transformation.
Apoptosis in pathologic conditions: 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.
Accumulation in the ER –> ER stress–> apoptotic cell death.
the basis of several degenerative diseases of the central nervous system and other organs.
Apoptosis in pathologic conditions: Cell death in certain infections
Particularly viral infections, in which loss of infected cells is largely due to apoptosis that may be induced by the virus (as in adenovirus and HIV infections) or by the host immune response (as in viral hepatitis). An important host response to viruses consists of cytotoxic T lymphocytes specific for viral proteins, which induce apoptosis of infected cells in an attempt to eliminate reservoirs of infection. During this process there can be significant tissue damage. The same T-cell–mediated mechanism is responsible for cell death in tumors and cellular rejection of transplants.
caspases
Apoptosis results from the activation of enzymes called caspases (so named because they are cysteine proteases that cleave proteins after aspartic residues)
Two distinct pathways converge on caspase activation:
the mitochondrial pathway and the death receptor pathway
The Intrinsic Pathway of Apoptosis
The mitochondrial pathway is the major mechanism of apoptosis in all mammalian cells
Cell viability maintained by induction of anti-apoptotic proteins such as BCL2 (GOOD THING) by survival signals. Loss of survival signals/ DNA damage/ etc. –> sensors that antagonize the anti-apoptotic proteins–> activate the pro-apoptotic proteins BAX and BAK–> channels in mitochondrial membrane–> leakage of cytochrome c –> caspase activation and apoptosis.
Extrinsic pathway of apoptosis
This pathway is initiated by engagement of plasma membrane death receptors on a variety of cells
death receptor intiated pathway of apoptosis: Fas engagement, FAAD (Fas-associated death domain), FasL, Fas ligand. –> pro caspase-8, active caspase 8, executioner caspases.
Execution phase of apoptosis
The two initiating pathways converge to a cascade of caspase activation, which mediates the final phase of apoptosis
Removal of dead cells.
Disorders Associated with Dysregulated Apoptosis
–>increased cell survival.
may permit the survival of abnormal cells,
- cells that carry mutations in TP53 are susceptible to the accumulation of mutations because of defective DNA repair–> cancer.
The importance of apoptosis in preventing cancer development is emphasized by the fact that mutation of TP53 is the most common genetic abnormality found in human cancers.
3 examples of disorders associated with increased apoptosis and cell death
These diseases are characterized by a loss of cells and include
Neurodegenerative diseases, manifested by loss of specific sets of neurons, in which apoptosis is caused by mutations and misfolded proteins;
Ischemic injury, as in myocardial infarction and stroke; and
Death of virus-infected cells in many viral infections
autophagy
is a process in which a cell eats its own contents (Greek: auto, self; phagy, eating)
Chaperone-mediated
Microautophagy
macroautophagy
Chaperone-mediated autophagy
direct translocation across the lysosomal membrane by chaperone proteins
Microautophagy
inward invagination of lysosomal membrane for delivery
Macroautophagy
(hereafter referred to as autophagy), the major form of autophagy involving the sequestration and transportation of portions of cytosol in a double-membrane bound autophagic vacuole (autophagosome)
Intracellular Accumulations
Inadequate removal of a normal substance secondary to defects in mechanisms of packaging and transport, as in fatty change (steatosis) in the liver
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 α1-antitrypsin
Failure to degrade a metabolite due to inherited enzyme deficiencies. The resulting disorders are called storage diseases
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
Steatosis (Fatty Change)
The terms steatosis and fatty change describe abnormal accumulations of triglycerides within parenchymal cells
The causes of steatosis include toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia. In developed nations, the most common causes of significant fatty change in the liver (fatty liver) are alcohol abuse and nonalcoholic fatty liver disease, which is often associated with diabetes and obesity.
what is NAFL associated with
non alcoholic fatty liver disease : diabetes and/or high BMI
Atherosclerosis
In atherosclerotic plaques, smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are made up of cholesterol and cholesterol esters. Such cells have a foamy appearance (foam cells), and aggregates of them in the intima produce the yellow cholesterol-laden atheromas characteristic of this serious disorder. Some of these fat-laden cells may rupture, releasing lipids into the extracellular space. The extracellular cholesterol esters may crystallize in the shape of long needles, producing quite distinctive clefts in tissue sections.
Cholesterolosis
This refers to the focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder. The mechanism of accumulation is unknown.
Xanthomas
Intracellular accumulation of cholesterol within macrophages is also characteristic of acquired and hereditary hyperlipidemic states. Clusters of foamy cells are found in the subepithelial connective tissue of the skin and in tendons, producing tumorous masses known as xanthomas.
Niemann-Pick disease
This lysosomal storage disease is caused by mutations affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs
how do proteins usually look?
Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm
Reabsorption droplets in proximal renal tubules
are seen in renal diseases associated with protein loss in the urine (proteinuria). In the kidney small amounts of protein filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal tubule. In disorders with heavy protein leakage across the glomerular filter there is increased reabsorption of the protein into vesicles, and the protein appears as pink hyaline droplets within the cytoplasm of the tubular cell. The process is reversible; if the proteinuria diminishes, the protein droplets are metabolized and disappear.
nephritic vs nephrotic
nephritic- blood in urine
nephrotic- protein in urine
Russell bodies
The proteins that accumulate may be normal secreted proteins that are produced in excessive amounts, as occurs in certain plasma cells engaged in active synthesis of immunoglobulins. The ER becomes hugely distended, producing large, homogeneous eosinophilic inclusions called Russell bodies.
Defective intracellular transport and secretion of critical proteins.
In alpha 1-antitrypsin deficiency, mutations in the protein significantly slow folding, resulting in the buildup of partially folded intermediates, which aggregate in the ER of the liver and are not secreted. The resultant deficiency of the circulating enzyme causes emphysema. In many of these diseases the pathology results not only from loss of protein function but also ER stress caused by the misfolded proteins, culminating in apoptotic death of cells.
Accumulation of cytoskeletal proteins
Accumulations of keratin filaments and neurofilaments are associated with certain types of cell injury. Alcoholic hyaline is an eosinophilic cytoplasmic inclusion in liver cells that is characteristic of alcoholic liver disease, and is composed predominantly of keratin intermediate filaments. The neurofibrillary tangle found in the brain in Alzheimer disease contains neurofilaments and other proteins
Aggregation of abnormal proteins
Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions. The deposits can be intracellular, extracellular, or both, and the aggregates may either directly or indirectly cause the pathologic changes. Certain forms of amyloidosis fall in this category of diseases.
hyaline change
The term hyaline usually refers to an alteration within cells or in the extracellular space that gives a homogeneous, glassy, pink appearance in routine histologic sections stained with hematoxylin and eosin
glycogen
Glycogen is a readily available energy source stored in the cytoplasm of healthy cells. Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism
lipofuscin
an insoluble pigment, also known as lipochrome or wear-and-tear pigment
Hemosiderin
A hemoglobin-derived, golden yellow-to-brown, granular or crystalline pigment is one of the major storage forms of iron
When there is a local or systemic excess of iron, ferritin forms hemosiderin granules, which are easily seen with the light microscope
Hemosiderosis
When there is systemic overload of iron hemosiderin may be deposited in many organs and tissues, a condition called hemosiderosis.
The main causes of hemosiderosis are
Increased absorption of dietary iron due to an inborn error of metabolism called hemochromatosis,
Hemolytic anemias, in which premature lysis of red cells leads to release of abnormal quantities of iron, and
Repeated blood transfusions, because transfused red cells constitute an exogenous load of iron
Pathologic Calcification
Pathologic calcification is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts
When the deposition occurs locally in dying tissues it is known as dystrophic calcification; it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism.
In contrast, the deposition of calcium salts in otherwise normal tissues is known as metastatic calcification, and it almost always results from hypercalcemia secondary to some disturbance in calcium metabolism
psammoma bodies
dystrophic calcifications seen particularly in tumors
Metastatic calcification
Metastatic calcification may occur in normal tissues whenever there is hypercalcemia.
- Increased secretion of parathyroid hormone (PTH) with subsequent bone resorption, as in hyperparathyroidism due to parathyroid tumors, and ectopic secretion of PTH-related protein by malignant tumors
- Resorption of bone tissue, secondary to primary tumors of bone marrow (e.g., multiple myeloma, leukemia) or diffuse skeletal metastasis (e.g., breast cancer), accelerated bone turnover (e.g., Paget disease), or immobilization
- Vitamin D–related disorders, including vitamin D intoxication, sarcoidosis (in which macrophages activate a vitamin D precursor), and idiopathic hypercalcemia of infancy (Williams syndrome), characterized by abnormal sensitivity to vitamin D
- Renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism
Normal calcium, phosphorus in serum
- 5-10.6 mg/dl for calcium
2. 5-4.5 mg/dl for phosphorus
locations for metastatic calcification
may occur widely throughout the body but principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins.
Cellular Aging
Cellular aging is the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences
Werner syndrome
Patients with Werner syndrome show premature aging, and the defective gene product is a DNA helicase, a protein involved in DNA replication and repair and other functions requiring DNA unwinding
cellular senescence
All normal cells have a limited capacity for replication, and after a fixed number of divisions cells become arrested in a terminally nondividing state, known as replicative senescence
Telomere attrition
One mechanism of replicative senescence involves progressive shortening of telomeres, which ultimately results in cell cycle arrest
Defective Protein Homeostasis
Protein homeostasis involves two mechanisms: those that maintain proteins in there correctly folded conformations (mediated by chaperones) and others that degrade misfolded proteins by the autophagy-lysosome system and ubiquitin-proteasome system
longevity
It is thought that caloric restriction increases longevity both by reducing the signaling intensity of the IGF-1 pathway and by increasing sirtuins
