Flashcards in Cellular Adaptations 2 Deck (44)
What are characteristics of ischemic injury?
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.
What are characteristics of hypoxic injury?
-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.
T or F. Ischemic and hypoxic changes are reversible – to a point
With hypoxia and ischemia, does most cell death result from necrosis or apoptosis?
What is Ischemic-Reperfusion Injury?
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.
What are some of the mechanisms may account for the exacerbation of cell injury resulting from reperfusion into ischemic tissues?
1) Increased generation of ROS
-Oxygen reintroduced, so more ROS
-Mitochondrial damage leads to incomplete reduction of oxygen
-Antioxidant defenses compromised by ischemia
-Activated leukocytes complement activation
What re the two basic mechanisms of Chemical (toxic) Injury?
Direct action (i.e. many antineoplastic chemotherapeutic drugs)
Conversion to toxic metabolites (i.e. acetaminophen-tylenol)
What is Apoptosis?
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
What are the basic steps of apoptosis?
1. condensation of chromatin and formation of membrane blebs
2. cellular fragmentations and apoptotic body release
3. Phagocytosis of apoptotic bodies
What are some physiologic causes of apoptosis?
• 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
What are some pathologic causes of apoptosis?
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)
What are apoptotic bodies?
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
What is ￼Pyknosis?
the irreversible condensation of chromatin
What is the mechanism of apoptosis?
results from the activation of enzymes called caspases (so named because they are Cysteine proteases that cleave proteins after ASpartic residues)
What two pathways converge on capsize activation?
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.
Describe the mitochondrial (intrinsic) pathway of capsize activation.
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.
Describe the death receptor (extrinsic) pathway of capsize activation.
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
What are some (3) examples of apoptosis that are induced by growth factor deprivation?
• 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 .
How does DNA damage cause apoptosis?
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.
How does protein misfolding lead to apoptosis?
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.
How does protein misfolding lead to CF?
cystic fibrosis transmembrane conductance regulator proteins are misfolded leading to defects in chloride transport
How does protein misfolding lead to familial hypercholesterolemia?
misfolding of LDL receptors lead to elevated cholesterolemia
How does protein misfolding cause Tay-Sachs disease?
protein misfolding of the lysosomal enzyme hexosaminidase-B subunit leads to storage of GM 2 gangliosides in neurons
How does protein misfolding cause alpha-1-antitrypsin deficiency?
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
How does protein misfolding cause Alzheimer disease?
protein misfolding of A-B peptide causes aggregation within neurons and apoptosis
What causes apoptosis of self-reactive lymphocytes?
• 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.
How does cytotoxic T lymphocyte-mediated apoptosis occur?
• 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
What is Autophagy? How does it work?
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.
What are the four pathways of abnormal intracellular accumulations?
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.