Robbins Ch 2 - Cellular Response to Stress and Toxic Insults Flashcards
Define adaptation
reversible changes in size, number, phenotype, metabolic activity, or functions of cells in response to charges in their environment
_ are defined as structural alterations in cells or tissues that are either characteristic of a disease or diagnostic of an etiologic process
morphologic changes
Hypertrophy is a result of _.
Increased in cells due to synthesis and assembly of additional intracellular structural components.
Some cells are able to undergo both hypertrophy and hyperplasia simultaneously, while some can only undergo one or the other. Give an example of types of cell for each.
Cells capable of division may respond to stress by undergoing both hyperplasia and hypertrophy, whereas nondividing cells can only increase tissue mass via hypertrophy like cardiomyocytes.
What are some causes of physiological hypertrophy?
increased functional demand or stimulation by hormones and growth factors. Increased workload.
Give an example of workload induce hypertrophy and a hormone induced hypertrophy.
Workload induced hypertrophy: cardiomyocytes
Hormone induced hypertrophy: uterus during pregnancy
Explain the molecular pathogenesis of cardiac hypertrophy
- integrated actions of mechanical sensors, growth factors (TGF-beta IGF1, FGF), vasoactive agents (a-adrenergic agonists, endothelin-1, angiotensin II). These signals originating in cell membrane activate a complex web is signal transduction pathways (PI3K/AKT pathway) and signaing downstream of G-protein. These signaling pathways activate a set of TF such as GATA4, NFAT, MEF2. these TF work coordinately to increase the synthesis of muscle proteins that are responsible for hypertrophy.
cardiac hypertrophy is associated with switching of it’s contractile proteins to what kind of contractile proteins?
From adult to fetal or neonatal forms. this is cuz the beta isoform of myosin in neonates is more energetically economical.
To prevent the continued hypertrophy of the cardiac myocytes, which of the following can be blocked pharmacologically? A. NFAT B. GATA4 C. MEF2 D. All of the above
D. all of the above.
The hormonally induced changes as seen in the glandular epithelium of the female breast at puberty and during pregnancy results in what adaptive change?
Hyperplasia
The glandular epithelial cells of the breasts and uterus are an example of what kind of adaptation?
hypertrophy
After partial hepatectomy, the liver undergoes what kind of adaptation?
Hyperplasia.
What is the most common causes of pathologic hyperplasia?
1 excessive or inappropriate actions of hormones or growth factors acting on target cells.
The prostate is a common structure that undergoes pathologic _ in responses to hormonal stimulation by androgens.
Hyperplasia
Papillomaviruses have known to cause _ as a characterisitic response to it’s infection.
hyperplasia
Give an example of atrophy of disuse.
when a fractured bone is immobilized in a plaster cast or if a patient is restricted to complete bed rest.
What are some causes of pathologic atrophy?
- Decreased workload
- Loss of innervation
- Diminished blood supply due to atherosclerosis or other other factors
- Inadequate nutrition.
- Loss of endocrine stimulation
- Pressure
Explain how inadequate nutrition can cause pathologic atrophy.
Profound protein-calorie malnutrition (marasmus) is associated with utilization of skeletal muscle proteins as a source of energy after other reserves have been depleted. this results in muscle wasting (cachexia, which is also seen in patients with CI and cancer)
Explain the mechanism of atrophy.
Atrophy results from decreased protein synthesis (due to decreased metabolic activity) and increased protein degradation in cells.
The degradation of cellular proteins as seen in atrophy is mainly by _ pathway.
ubiquitin-proeosome pathway.
Marked increase of autophagic vacuole in a tissue is characteristic of a tissue that is undergoing: A. hypertorphy B. Hyperplasia C. Metaplasia D. Atrophy
D. atrophy
Presence of lipofuscin granules in membrane-bound residual bodies in a tissue is indicative of a tissue that is undergoing: A. hypertrophy B. Hyperplasia C. metaplasia D. Atrophy
D. Atrophy
Explain the metaplasia that is seen in a smoker’s respiratory tract.
Normal ciliated colunar epithelial cells are replaced by stratified squamous epithelial cells.
Explain the metaplasia seen in a patient with chronic GERD
Stratified squamous to simple columnar.
A deficiency of vitamin A can cause what kind of adaptation in the respiraotry tract lining?
Metaplasia. Normal respiratory epithelium is changed to stratified squamous
What kind of metaplasia is seen in myositis ossificans?
Connective tissue metaplasia where the normal tissue is changed to cartilage or bone.
what is the mechanism of metaplasia?
Reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue.
Explain the hallmark signs of reversible cell injury.
reduced oxidative phosphorylation with resultant depletion of energy stores in the form of ATP, and cellular swelling and caused by changes in ion concentration and water influx.
How does oxygen deprivation cause cell injury?
Hypoxia causes cell injury by reducing aerobic oxidative respiration.
pyknosis leading to karyorrhexis leading to karyolysis is seen in what kind of cell death?
Necrosis
What are characteristics of reversible injury?
- generalized swelling of cell and its organelles
- blebbing of plasma membrane
- detached ribosomes from ER
- clumping of nuclear chromatin
Under the microscope what two characteristics of reversible cell injury are noticeable?
- cellular swelling
2. Fatty acid changes
What is the cause of cellular swelling as seen in reversible cell injury?
cells incapable of maintaining ionic and fluid homeostasis and is the result of failure of energy-dependent ion pumps in the plasma membrane.
In reversible injury, fatty changes with appearance of lipid vacuoles are most prominent in what cell type?
cells that are involved in fat metabolism like hepatocytes and myocardial cells.
Hydropic changes or vacuolar degeneration is characteristic of what kind of cell damage?
nonlethal injury associated with reversible cell injury.
The appearance of increased eosinophilia as seen in necrotic cells is likely due to _.
loss of cytoplasmaic RNA (which binds the blue dye, hematoxylin) and in part denatured cytoplasmic proteins (which bind red dye siosin.
what are myelin figures and where are they commonly found?
In necrotic cells, dead cells may be replaced by large, whorled phospholipid masses referred to as myelin figures that are derived from damaged cell membranes.. they can further degrade into fatty acids; calcification of such fatty acid residues results in calcium soup generation.
Discontinuities in plasma organelle membranes, marked dilation of mitochondria with appearance of large amorphous densities, intracytoplasmic myelin figures, amorphous debris, and aggregates of fluffy material are seen in what kind of tissue damage?
Necrotic cells.
What are some general patterns of tissue necrosis?
- Coagulative necrosis
- Liquefactive necrosis
- Gangrenous necrosis
- Caseous necrosis
- Fat necrosis
- Fibrinoid necrosis
Explain some characteristics of coagulative necrosis and what kind of scenarios you’d most likely see this type of necrosis.
- architecture of dead tissues is preserved for a span of time.
- exhibits firm texture which can be cuz the injury denatured the enzymes needed to proteolysis
- eosinophilic, anucleate cells may persist for days or weeks
- ultimately necrotic cells are removed phagocytes and shows filtration of leukocytes.
Can be seen in localized tissue damaged due to infarct!
Explain characteristics of liquefactive necrosis and where it’s commonly seen.
Characterized by digestion of dead cells, resulting in transformation of the tissue into a liquid viscous masses.
- seen in focal bacterial or fungal infections cuz dmicrobes stimulate accumulation of leukocytes and liberation of enzymes.
- usually creamy yellow cuz of pus
- Usually seen in necrosis of CNS
Explain characteristics of gangrenous necrosis and where its commonly seen
usually applied to limb, generally the lower leg that has lost is blood supply and has undergone necrosis (typically coagulative necrosis) and superimposed by bacterial infection to more liquefactive necrosis. together gives the appearance of wet gangrene.
What are some characteristics of Caseous necrosis and where is it commonly seen?
- often in foci of tuberculous infection
- cheese like
- appears structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border;
- focus of inflammation known as granuloma
What are some characteristics of fat necrosis and where is it commonly seen?
- focal areas of fat destruction, typically resulting from activated pancreatic lipases into substance of pancreas and the peritoneal cavity.
- seen as a result of acute pancreatitis where enzymes leak out and liquefy the membranes of fat cells int he peritoneum
- chalky-white areas (fat aponification) is due to split of triglyceride which combine with calcium
What are some characteristics of fibrinoid necrosis and where is it commonly seen?
- usually seen in immune reactions involving blood vessels
- occurs with complexes of Ag-Ab deposits on walls of arteries
- Ab-Ag comlexes along with fibrin that leaked out of vessels results in bright pink and amorphous apperance - fibrinoid
Explain what can happen if necrotic cells are not removed by enzymatic digestion and phagocytosis.
It provide a nidus for deposition of calcium salts and other minerals and thus tend to become calcified. this is known as dystrophic calcification
What are some major causes of ATP depletion?
- reduced supply of oxygen and nutrients,
- mt damage
- action of some toxins (cyanide)
What are some general mechanisms of cell injury?
- Depletion of ATP
- Mitochondrial damage
- Influx of Calcium and loss of calcium hemeostasis
- Accumulation of oxygen-derived free radicals (Oxidative stress)
- Defects in membrane permeability
- Damage to DNA and proteins
A reduction of ATP to what percentage can have widespread effects on many cirtical cellular system?
5-10%
What are some consequences of ATP depletion?
- Activity of plasma membrane energy-dependent Na pump (ouabain-sensitive, Na, K-ATPase) is reduced. Causues Na to enter cell, K to leak out and causes isosmotic gain of water, and cause cell swelling and dilation of ER
- Cellular energy metabolism is altered. Wit oxidative phosphorylation, ADP builds up and this stimulates glycolytic pathway which builds up lactic acid which then decreases pH
- Failure of Ca pump leading to influx of Ca
- Structural disruption of protein synthetic apparaus, detachment of ribosome, leads to reduction in protein synthesis.
- Leads to misfolding of protein which can accumulate in ER and lead to unfolded protein response
- Mitochondrial damage
What are some causes of mitochondrial damage?
- increased cytosolic Ca
- ROS
- Oxygen deprivation
What are three major consequence of mitochondrial damage?
- formation of mitochondiral permeability transition pore which leads to loss of mt membrane potential thus resulting in failure of oxidative phosphorylation and progresive depletion of ATP.
- abnromal oxidative phosphorylation leading to formation of ROS
- Activation of apoptosis due to release of cytochrome c
What protein on mitochondrial permeability transition pore is targeted by immunosuppressive drug cyclospoine which is used to prevent graft rejection?
Cyclophilin D
Explain three ways, increased intracellular Ca can cause tissue damage.
- Accumulation of Ca in mitochondria results in opening of mitochondrial permeability transition pore and leads to failure of ATP
- increased Ca activates number of enzymes with potentially deleterous effects on cells. these enzymes include phospholipases, protease, endonuclease, ATPase etc
- Induce of apoptosis by directly activating caspases.
What are some ways free radicals can be generated?
- reduction-oxidation reaction that occur during normal metabolic process . Produces superoxide anion, hydrogen peroxide, hydroxyl ion
- absorption of radiant energy - hydroize water into hydroxyl radical and hydrogen free radicals.
- Rapid burst of ROS produced in activated leukocyte during inflammation. Xanthine oxidation generates superoxide
- eznymatic metabolism of exogenous chemicals or drugs, similar to ROS and includes tetrachloride radical.
- Transition metal like Fe and Cu. catalyze free radical as seen in Fenton reaction. this creates hydroxyl radical and superoxide anion.
- NO makes ONOO- and NO2 and NO3-
superoxide is so unstable tha when it combines with _ it froms O2 and H2O2 via the enzyme_.
water.
dismutase.d
What are some antioxidants that normally works int eh body to block free radical formation or inactivate free radicals?
- vitamins E, A, and C
- glutathione
Catalase is one of the enzyme involved in removal free radical. Where are catalase found and what does it decompose?
Found in peroxisomes and decomposes H202 to make O2 and water.
superoxide can be converted to H202 via what enzyme?
Superoxidase dismutases
Intracellular ration of oxidized _ to reduced _ is a reflection of the oxidative state of the cell and is an important indicator of the cell’s ability to detoxify ROS
glutathione (GSSE)
glutathione (GSH)
What are three common pathologic effects of free radicals?
- Lipid peroxidation in membranes
- Oxidative modification or proteins
- Lesions in DNA
In lipid peroxidation in membranes, the most reponsible free radical is _
hydroxyl radical which attacks the double bonds in unsaturated fatty acids of membrane lipids.
What are some ways cell membranes can get damaged?
- ROS
- decreased phospholipid synthesis - could be due to defective mitochondrial function or hypoxia
- increased phospholipid breakdown: could be due to activaton of Ca-dependent phosphoipases by increased levels of cytosolic and mitochondiral Ca.
- cytoskeletal abnormalities
For each of the following, state what the significance of that the membrane damage is:
A. mitochondrial membrane damage
B. plasma membrane damage
C. Injury to lysosomal membrane
A. opens up mitochondrial permeability transition pore leading to decreased ATP generation
B. loss of osmotic balance
C. leakage of enzymes into cytoplasm and activation of acid hydrolases
What two phenomena consistently characterize irreversibility in most cells?
- inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and TP generation)
- profound disturbances in membrane function
Explain why ischemia tends to cause more rapid and severe cell and tissue injury than does hypoxia in the absence of ischemia.
During hypoxia, energy production by anaerobic glycolysis can continue, but ischemia compromises the delivery of substrate for glycolysis. Thus, in ischemic tissue not only is aerobic metaboism compromised but anerobic energy generation also stops after glycolytic substrates are exhausted, or glycolysis is inhibited by accumulation of metabolites that would otherwise be washed out by flowing blood
What is the significance of HIF-1 during hypoxic stress?
It serves as a protective response to deal with hypoxic stress where HIF-1, a TF, promotes new blood vessel formation, stimulates cell survival pathways, and enhances anaerobic glycolysis.
Explain some ways how reperfusion cause injury?
- Oxidative stress. Free radical may be produced in reperfused tissue as a resuslt of incomplete reduction of oxygen by dmaged nitochondria or cuz of action of oxidases in leukocytes, endothelal cells, or parenchymal cells. And cellular antioxidant defense is likely lost cuz of the ischemia.
- Intraclelular Ca overload
- Inflammation - ischemic injury is associated with inflammation as result of danger signals released from dead cells and other resident cells. with reperfusion all the activated immune cells can now recruit circulating neutrophils to reperfused tissue
- Activation of complement system - some Ig like IgM has the propensity to accumulate in ischemic tissue and tissue is reperfused, those complex can deposit to the reperfused tissue and cause cell injury and inflammation
what are two modes by which chemicals can induce cell injury
- direct toxicity, where the chemical binds directly to the cell and cause damage. e.g. mercuric chloride poisoning, mercury binds to sulfhydryl groups of cell membrane and cause increased membrane permeability and inhibition of ion transport
- Conversion to toxic metabolites
In apoptotic cells, what is the integrity of the plasma membrane?
Intact, but structure is altered.
The release of mitochondrial pro-apoptotic proteins is tightly controlled by _ family of proteins
BCL2
what are the anti-apoptotic proteins?
BCL2, BCL-XL, MCL1 - all with 4 BH domain
What are the pro-apoptotic proteins?
BAX and BAK - all with four BH domain
What are the sensors proteins involved in apoptosis
BAD, BIM, BID, PUMA and NOXA. all with one BH domain.
Explain the pathway going from when cells are deprived of survival signals or their DNA is damaged.
- BH3-only proteins senses damage and are activated.
- BAX and BAK are activated which form oligomers that insert into the mitochondrial membrane and allow proteins from inner mitochondrial embrane to leak out. BH3-only can also block BCL2 and BCLXL. and formation of new BCL2 and BCLXL can also blocked.
3 Apoptotic proteins are released into the cytoplasma namely cytochrome c. - Cytochorme c binds to APAF-1 which forms a apoptosome. this complex binds to caspase 9.
- series of cleavage and activation of other pro-caspase. all work to mediate the activation of execution
Which caspase is deemed the critical initiator caspase of the mitochondrial pathway?
caspase 9
What is the normal function of IAP?
to block the activation of caspases, including executioners like caspase 3, and keep cells alive.
What mitochondrial proteins enter the cytoplasm to bind and neutralize cytoplasmic proteins that function as physiologic inhibitors of apoptosis (IAPs)
Smac/Diablo
In the death receptor-initiated pathway, death recepors are members of what receptor family?
TNF receptor family that has a cytoplasmic domain involved in protein-protein interaction that is called death domain because it is essential for delivering apoptotic signals.
Explain the pathway for the death receptor-initiated pathway of apoptosis
When FasL binds to Fas, three or more molecules of Fas are brought togeterh, and their cytoplasmci death domains form a binding site for an adaptor protein that also contains a death domainand is called FADD.
- FADD that is attached to death reeptor in turn binds an inactive form of caspase 8 (in humans its caspase 10) again via death domain.
- Multiple procaspase 8 molecules are thurs brought into proximity and they cleave one another to generate active caspase 8.
- The rest of the events are same as the mitochondrial pathwway
Some viruses and normal cells produce _ , which is able to inhibit the extrinsic apoptotic pathway, and protect themselves from Fas-mediated apoptosis.
FLIP
What are the executioner caspses?
Caspase 3 and 6.
During apoptosis, cytoplasmic DNase can become active by _
Capase 3 and 6 which cleave an inhibitor of DNase thus making DNase active.
In an apoptotic cell, what are some changes that take place, which signals that cells to be eaten by phagocytes?
- phosphatydlserine is flipped
- secrete soluble factors that recruit phagocytes
- some are coated by thrombospondin, an adhesive glycoproteins that is recognized by phagocytes
- May become coated with natural antibodies and proteins of complement system notably C1q.
of the following examples of apoptosis, state whether it’s via intrinsic or extrinsic pathway.
A. hormone -sensitive cell deprived of the relevant hormone
B. lymphocytes that are not stimulated by antigens and cytokines
C. Neurons deprived of nerve growth factor
All are via intrinsic pathway
Explain the mechanism by which CTL kills cells.
- CTL recognize foreign antigens presented on the surface and is activated.
- Once activated they secrete perforin which promotes entry of CTL granule serine proteases granzyme which cleave proteins at aspartate residues and thus activate a variety of cellular caspases.
- In this way CTL kills target cells by directly inducing the effector phase of apoptosis.
The process of necroptosis starts in a manner similar to which apoptotic pathway?
Extrinsic pathway, that is by ligamation of receptor by its ligand, e.g. ligation of TNFR1
In the necroptosis pathway, once TNFR1 is ligated what proteins are recruited into a multiprotein complex that also contains caspase-8?
RIP 1 and RIP 3.
What are the terminal events of necroptosis pathway?
Similar to necrosis: permeabilization of ysosomal membranes, generation of ROS, damage to mt, reduction of ATP and etc.
what physiological process requires necroptosis?
mammalian bone growth plate formation
What pathologic condition leads to necroptosis?
-cell death in steatohepatitis, acute pancreattiis, reperfusion injury, neurodengeratie disease like PD.
The host cell protects itself from infection from CMV via which cell death pathway (necrosis, apoptosis (intrinsic/extrinsic), necroptosis)
Necroptosis, cuz CMV has caspase inhibitors.
In pyroptosis, what is the purpose of inflammasome?
to activate caspase 1 (aka IL1beta converting enzyme which cleaves to form IL-1)
what are the three general categories of autophagy?
- Chaperone-mediated autophagy - direct translocation across the lysosomal membrane by chaperone proteins
- Microautophagy (inward invagination of lysosomal membrane for delivery)
- Macroautophagy - major form of autophagy - involving sequestration and transportation of proteins of cytosol in a double membrane bound autophagic cavule (autophagosome)
What are the general steps involved in autophagy?
- formation of an isolation membrane, aka phagophore, and its nucleation; the isolation membrane is believed to be derived from the ER
- Elongation of the vesicle
- Maturation of the autophagosome, its fusion with lysosomes, and eventual degrdadation of contents
what protein can be used as a marker to identify cells that are undergoing autophagy?
LC3
Explain the mechanism via which autophagy leads to degradation
Environmental cues or depletion of GF activate an initiation complex of four proteins that stimulate the assembly of a nucleation complex. this then promotes the nucleation of autophagosomal membrane. The autophagosomal membrane elongates surrounds and captures its cytosolic cargo and closes to form autophagosome. this action requires microtubule-associated protein light chain 3 (LC3) The formed autophagosome fuses with endosomes and then with lysosomes to form a autophagolysosome.
What protein is responsible for targeting protein aggregates and effete organelles during the loading of cargo step into autophagosome?
LC3
Steatosis and fatty change is associated with abnormal accumulations of _ within parenchymal cells
triglycerides
What are some major causes of steatosis?
Toxins, proteins malnutrition, DM, obesity, and anorexia.
What organ is steatosis usually seen in?
Mainly the liver, but can also be seen in heart, muscle, and kidney
Inn atherosclerosis, cholesterol and cholesterol esters build up in which cells and what is a characteristic appearance of these cells?
In smooth muscle cells and macrophages and appears foamy (foam cells).
In xanthomas, intracellular accumulation of cholesterol within macrophages is seen in what tissues?
In subepithelial connective tissue of skin and in tendons.
In cholesterolosis, accumulation of cholesterol-laden macrophages are found in _ of gallbladder.
lamina propria
In Niemann pick disease, cholesterol accumulation in multple organ is due to_
mutation affecting an enzyme involved in cholesterol trafficking
rounded, eosinpholic droplets, cavuoles, or aggregates in the cytoplasm which under microscope can appear amorphous, fibrillar, or crystalline are characteristic of accumulation of _
proteins
Russell bodies are seen in accumulation of _
Normal proteins produced in access amount. in this ER becomes hugely distended, producing large, homogenous eiosinpholic includes called russell bodies
In a1-antitrypsin deficiency, defective intracellular transport and secretion of critical proteins is due to _
mutations in protein significantly slow folding resulting in build up partically folded intermediates which aggregates in the ER of liver and are not secreted.
Lipofuscin is not injurious to the cell, but its a telltale sign of _
free radical injury and lipid peroxidation.
The main cause of metastatic calcification is _
hypercalcemia secondary to some disturbance in calcium metabolism
Where is dystrophic calcification usually found?
around areas of necrosis
what are psammoma bodies?
The progression of mineral deposition (Ca++) acquisition on outer layers of tisues which create lamellated configurations and resembles grains of salt.
Dystrophic calcification often causes organ dysfunction and the major pathology it is associated with in the heart is _.
calcific valvular disease and atherosclerosis.
what is Werner’s syndrome?
Disease associated with defective DNA helicase which causes rapid accumulation of chromosomal damage that may mimic the injury that normally accumulates during cellular aging. It has been associated with premature aging.
In bloom’s syndrome and in ataxiatelangiectasia, patient present with increased rate of aging due to _
the mutated genes encode a proteins involved in repairing double strand breaks in DNA
Activation of tumor suppressor genes in _ locus has shown to be involved in controlling replicative senescence.
CDKN2A
CDKN2A locus encode two tumor suppressor proteins know as _ and _ and is correlated with chronologic age in virtually all human tissue.
p16 and INK4a
IGF1 related to nutrient sensing that which play a role in aging has two relevent downstream kinases. What are they?
- AKT
2. mTOR
Sirtuins are a family of _ deacetylases that which promote the expression of genes whose products increase longevity.
NAD
What two ways does caloric restriction increase longevity?
- reducing the signaling intensity of IGF1 pathway
2. Increase sirtuins
