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Cellular Adaptations to Stress increased cell and organ size, often in response to increased workload; Hypertrophy induced by growth factors produced in response to mechanical stress or other stimuli; occurs in tissues incapable of cell division...

Cellular Adaptations to Stress increased cell and organ size, often in response to increased workload; Hypertrophy induced by growth factors produced in response to mechanical stress or other stimuli; occurs in tissues incapable of cell division increased cell numbers in response to hormones and other growth Hyperplasia factors; occurs in tissues whose cells are able to divide or contain abundant tissue stem cells decreased cell and organ size, as a result of decreased nutrient supply Atrophy or disuse; associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles change in phenotype of differentiated cells, often in response to chronic irritation, usually induced by altered differentiation pathway of Metaplasia tissue stem cells; may result in reduced functions or increased propensity for malignant transformation  Causes of Cell Injury Oxygen Deprivation Hypoxia is a defciency of oxygen, which causes cell injury by reducing aerobic oxidative respiration. Physical agents capable of causing cell injury include mechanical trauma, extremes of temperature Physical Agents (burns and deep cold), sudden changes in atmospheric pressure, radiation, and electric shock The list of chemicals that may produce cell injury. Simple chemicals such as glucose or salt in hypertonic concentrations may cause cell injury directly or by deranging electrolyte balance in cells. Even oxygen at Chemical Agents and Drugs. high concentrations is toxic. Trace amounts of poisons, such as arsenic, cyanide, or mercuric salts, may damage suffcient numbers of cells within minutes or hours to cause death. These agents range from the submicroscopic viruses to tapeworms several feet in length. Inbetween are Infectious Agents the rickettsiae, bacteria, fungi, and higher forms of parasites. The immune system serves an essential function in defense against infectious pathogens, but immune Immunologic Reactions. reactions may also cause cell injury. Injurious reactions to endogenous self antigens are responsible for several autoimmune diseases may cause cell injury because of deficiency of functional proteins, such as enzyme defects in inborn Genetic defects errors of metabolism, or accumulation of damaged DNA or misfolded proteins, both of which trigger cell death when they are beyond repair Nutritional imbalances continue to be major causes of cell injury. Protein-calorie deficiencies cause an Nutritional Imbalances. appalling number of deaths, chiefly among underprivileged populations Mechanisms of Cell Injury ATP depletion: failure of energy-dependent functions → reversible injury → necrosis Mitochondrial damage: ATP depletion → failure of energydependent cellular functions → ultimately, necrosis; under some conditions, leakage of mitochondrial proteins that cause apoptosis Influx of calcium: activation of enzymes that damage cellular components and may also trigger apoptosis Accumulation of reactive oxygen species: covalent modifcation 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: triggers apoptosis  Cell Death (Role of Mitochondria) ❑ In addition to providing ATP and metabolites that enable the bulk of cellular activity, mitochondria also regulate the balance of cell survival and death. There are two major pathways of cell death : 1. Necrosis: External cellular injury (toxin, ischemia, trauma) can damage mitochondria, inducing the formation of mitochondrial permeability transition pores in the outer membrane. These channels allow the dissipation of the proton potential so that mitochondrial ATP generation fails and the cell dies. 2. Apoptosis: Programmed cell death is a central feature of normal tissue development and turnover and canbe triggered by extrinsic signals (including cytotoxic T cells and inflammatory cytokines), or intrinsic pathways (including DNA damage and intracellular stress) ❑ Mitochondria play a central role in the intrinsic pathway of apoptosis. If mitochondria are damaged (a sign of irreversible cell injury or stress) or the cell cannot synthesize adequate amounts of survival proteins (because of deficient growth signals), mitochondria become leaky. Necrosis The morphologic appearance of necrosis as well as necroptosis is the result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell. Necrotic cells are unable to maintain membrane integrity and their contents often leak out, a process that may elicit inflammation in the surrounding tissue. The enzymes that digest the necrotic cell are derived from the lysosomes of the dying cells themselves and from the lysosomes of leukocytes that are called in as part of the inflamatory reaction. Digestion of cellular contents and the host response may take hours to develop, and so there would be no detectable changes in cells if, for example, a myocardial infarct caused sudden death. Mechanisms of Apoptosis Apoptosis results from the activation of enzymes called caspases (so named because they are cysteine proteases that cleave proteins after aspartic residues) The process of apoptosis may be divided ➔ initiation phase, during which some caspases become catalytically active, and an execution phase, during which other caspases trigger the degradation of critical cellular components. The activation of caspases depends on a fnely tuned balance between production of pro-apoptotic and anti-apoptotic proteins. Two distinct pathways converge on caspase activation: the mitochondrial pathway and the death receptor pathway 1. The Intrinsic (Mitochondrial) Pathway of Apoptosis The mitochondrial pathway is the major mechanism of apoptosis in all mammalian cells. It results from increased permeability of the mitochondrial outer membrane with consequent release of death-inducing (pro-apoptotic) molecules from the mitochondrial intermembrane space into the cytoplasm. Mitochondria are remarkable organelles in that they contain proteins such as cytochrome c that are essential for life, but some of the same proteins, in particular cytochrome c, when released into the cytoplasm (an indication that the cell is not healthy), initiate the suicide program of apoptosis 1. The Intrinsic (Mitochondrial) Pathway of Apoptosis The mitochondrial pathway is the major mechanism of apoptosis in all mammalian cells. It results from increased permeability of the mitochondrial outer membrane with consequent release of death-inducing (pro-apoptotic) molecules from the mitochondrial intermembrane space into the cytoplasm. Mitochondria are remarkable organelles in that they contain proteins such as cytochrome c that are essential for life, but some of the same proteins, in particular cytochrome c, when released into the cytoplasm (an indication that the cell is not healthy), initiate the suicide program of apoptosis The Intrinsic (Mitochondrial) Pathway of Apoptosis ✓ A ➔ Cell viability is maintained by the induction of anti-apoptotic proteins such as BCL2 by survival signals. These proteins maintain the integrity of mitochondrial membranes and prevent leakage of mitochondrial proteins. ✓ B ➔ Loss of survival signals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic proteins and activate the pro-apoptotic proteins BAX and BAK, which form channels in the mitochondrial membrane. The subsequent leakage of cytochrome c (and other proteins, not shown) leads to caspase activation and apoptosis.  The Extrinsic (Death Receptor-Initiated) Pathway of Apoptosis This pathway is initiated by engagement of plasma membrane death receptors on a variety of cells. Death receptors are members of the TNF receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals. The best known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95), but several others have been described. The mechanism of apoptosis induced by these death receptors is well illustrated by Fas, a death receptor expressed on many cell types/ The ligand for Fas is called Fas ligand (FasL). FasL is expressed on T cells that recognize self antigens (and functions to eliminate self-reactive lymphocytes), and on some cytotoxic T lymphocytes (which kill virus-infected and tumor cells). When FasL binds to Fas, three or more molecules of Fas are brought together, and their cytoplasmic death domains form a binding site for an adaptor protein that also contains a death domain and is called FADD (Fas-associated death domain). FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 (and, in humans, caspase-10), again via a death domain. The Execution Phase of Apoptosis The two initiating pathways (intristic /extrinsic) converge to a cascade of caspase activation, which mediates the final phase of apoptosis. The mitochondrial pathway leads to activation of the initiator caspase-9, and the death receptor pathway to the initiator caspases-8 and -10. After an initiator caspase is cleaved to generate its active form, the enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases. For instance, these caspases, once activated, cleave an inhibitor of a cytoplasmic DNase and thus make the DNase enzymatically active; this enzyme induces cleavage of DNA. Caspases also degrade structural components of the nuclear matrix and thus promote fragmentation of nuclei. Some of the steps in apoptosis are not fully defned. For instance, we do not know how the structure of the plasma membrane is changed in apoptotic cells, or how membrane blebs and apoptotic bodies are formed Removal of Dead Cells The formation of apoptotic Bodies breaks cells up into “bite-sized” fragments that are edible for phagocytes. Apoptotic cells and their fragments also undergo several changes in their membranes that actively promote their phagocytosis so they are most often cleared before they undergo secondary necrosis and release their cellular contents (which can result in injurious inflammation). In apoptotic cells this phospholipid “flips” out and is expressed on the outer layer of the membrane, where it is recognized by several macrophage receptors. Cells that are dying by apoptosis secrete soluble factors that recruit phagocytes. Some apoptotic bodies are coated by thrombospondin, an adhesive glycoprotein that is recognized by phagocytes, and macrophages themselves may produce proteins that bind to apoptotic cells (but not to live cells) and thus target the dead cells for engulfment. Apoptotic bodies may also become coated with natural antibodies and proteins of the complement system, notably C1q, which are recognized by phagocytes. Thus, numerous receptors on phagocytes and ligands induced on apoptotic cells serve as “eat me” signals and are involved in the binding and engulfment of these cells. This process of phagocytosis of apoptotic cells is so efficient that dead cells disappear, often within minutes, without leaving a trace, and inflammation is absent even in the face of extensive apoptosis. Necroptosis and Pyroptosis ❑Necroptosis mode of regulated cell death resembles necrosis morphologically and apoptosis mechanistically as a form of programmed cell death. ❑Necroptosis is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses. Necroptosis is caspase-independent but dependent on signaling by the RIP1 and RIP3 complex ➔ reduces mitochondrial ATP generation, causes production of ROS, and permeabilizes lysosomal membranes, thereby causing cellular swelling and membrane damage as occurs in necrosis. ❑Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. ❑Pyroptosis occurs in cells infected by microbes.It involves activation of caspase-1 which cleaves the precursor form of IL-1 to generate biologically active IL-1. Caspase-1 along with closely related caspase-11 ➔ death of the infected cell.