Cell Injury and Death

Pathological processes are initially manifested at the cellular level. Thus, cell survival depends on the maintenance of homeostasis. When this homeostatic state is disrupted, the cell attempts to adapt to the change. If the cell is unable to fully adapt, cell injury ensures. Injury at first causes reversible changes but may progress ultimately to irreversible injury and cell death. The ability of the cell or organ to tolerate injury depends on the severity, duration, and type of insult, as well as the adaptive capacity of the tissue. There are many causes of cell injury and death and these include: Hypoxia: lack of oxygen leads to the inability of the cell to synthesize sufficient ATP Toxins: can produce injury locally or systemically Thermal injury (heat, or cold): coagulation of proteins and thereby disrupts the structure and function of cells Trauma: disrupts cells and denatures proteins; local vascular thrombosis with subsequent ischaemia and infarction Radiation: damages DNA irreversibly Microorganisms: many processes but includes membrane disruption and

inflammatory reaction Immune mechanisms: causes local tissue damage

Cellular appearances following injury: Membrane damage

plays a central role in the pathogenesis of irreversible injury the membrane can be damaged from the loss of membrane phospholipids, breakdown of the cytoskeleton, production of toxic oxygen intermediates, and the production of lipid products, which by themselves can have the detergent like effect on the plasma membrane.

Hydropic change

cytoplasm becomes pale and swollen due to accumulation of fluid.

Fatty change

abnormal accumulation of fat in the parenchymal cells, not the stroma. occurs in the liver, myocardium, and the kidney. causes of fatty liver: alcohol, obesity, diabetes mellitus, protein malnutrition, and hepatotoxins
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Intracellular accumulations

lipids proteins glycogen in complex carbohydrates pigments (exogenous and endogenous)

Calcification

calcification of tissues often occurs after damage dystrophic calcification: scars, site of infection, heart valves if serum calcium is abnormally high, tissue calcification occurs but not at the site of cell damage (in kidney, lung, and skin)

Cellular events associated with necrosis Necrosis is death of cells or tissues in a living organisms, irrespective of the cause. It involves a pathological process following cellular injury and several types are recognized and distinguished by the type of tissue that it affects and the causative agent. Coagulative necrosis is the most common form of necrosis in cells without large numbers of lysosomes. The cells converted into a homogeneous, eosinophilic mass with the loss of nucleus but preservation of cellular shape. Coagulative necrosis typically occurs after sudden ischemia, or toxin injury. The heart is the most common example of an organic undergoing coagulative necrosis following an injury. Liquefaction (Colliquative) necrosis results from cellular destruction by hydrolytic enzymes involved in autolysis and heterolysis. Typically, liquefaction necrosis occurs in brain infarcts and pancreatic necrosis. Liquefaction by leukocytic enzymes is called suppuration, and the resultant fluid is called pus. Caseous necrosis is a combination of coagulation and liquefaction necrosis, which produces tissue that is grossly soft, friable, and "cheese-like." It produces a pattern of necrosis in which the dead tissue lacks any structure. Histological staining shows an amorphous eosinophilic area stippled by haematoxyphilic nuclear debris. Caseous necrosis is characteristic of tuberculosis, some granulomas and fungal infections, and the center of certain malignancies. Gangrene is necrosis with the putrefaction of the tissues, sometimes as the result of the action of certain bacteria (e.g. clostridia). The affected tissues appear black dueto the depostiion of iron sulphide from degraded haemoglobin. o 'dry' gangrene sterile; 'wet' gangrene - with bacterial putrefaction.
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Enzymatic fats necrosis is caused by the action of lipases on fatty tissue. Following trauma to the adipose tissue, the release of intracellular fat elicits a brisk inflammatory response, with polymorphs and macrophages phagocytosing the fat proceding eventually to fibrosis. It is characteristic of tissues adjacent to pancreatic necrosis.

Gummatous necrosis is seen in the late stage of syphilis; grossly, it differs from coagulative and liquefactive necrosis by its gelatinous appearance.

Cellular events associated with apoptosis Apoptosis differs significantly from necrosis. It is an energy dependent physiological process involved in removing unwanted individual cells and is a specialized form of programmed cell death that is characterized by: o chromatin condensation and formation of cytoplasmic membrane blebs (cell surface deformities caused by a cytoskeleton disruption) o breakdown of DNA into nucleosome-sized fragments o RNA and protein synthesis o a minimal inflammatory response It has a central role in morphogenesis, maintaining organ size, and atrophy. Apoptosis can also occur in the removal of defective cells. Factors controlling apoptosis include: inducers: loss of matrix attachment, glucocorticosteroids, free radicals, ionising radiation inhibitors: growth factors, cell matrix, sex steroids Apoptosis begins with the activation of endogenous proteases and endonucleases in the presence of inducers or the absence of inhibitors. This results in the degradation of the cytoskeletal structure, fragmentation of DNA and loss of mitochondrial function. The cell shrinks, retaining its plasma membrane, however, if the plasma membrane is altered, phagocytosis occurs. Cells not phagocytosed break into smaller membrane-bound fragments called apoptotic bodies. These is no inflammatory reaction to these bodies.

Apoptosis vs. Necrosis Feature Induction Affects Biochemical events Morphology Inflammatory response Fate of dead cells Necrosis Invariably due to pathological injury Cell groups Impairment or cessation of homeostasis Lysosomes leak lytic enyzmes Cell swelling and lysis Common Apoptosis May be induced by physiological or pathological stimuli Single cells ion Energy-dependent fragmentation of DNA by endogenous endonucleases Lysosomes intact Cell shrinkage and fragmentation to form apoptotic bodies with dense chromatin None

Phagocytosed by neutrophil Phagocytosed by neighbouring cells polymorphs and macrophages