Cell injury etiology and pathogenesis

Basic intro, types,etiology and patho

1. Etiology And Pathogenesis CELL INJURY

2. “It is defined as the effect of variety of stresses due to etiologic agents which a cell encounters resulting in changes in its internal and external environment.” The cellular response to stress may vary and depends upon following two variables: Host factors i.e. the type of cell and tissue involved Factors related to injurious agents i.e. extent and type of cell injury Definition

3. Forms of Cellular Responses

4. Hypoxia and ischaemia Physical agents Chemical agents and drugs Microbial agents Immunologic agents Nutritional derangements Ageing Psychogenic Diseases Iatrogenic causes Idiopathic Diseases Etiology of Cell Injury

5. Injury to normal cell by one or more of these etiologic agents may result in state of reversible and irreversible cell injury. Factors pertaining to host cells and etiologic agent determine the outcome of cell injury:- Type, duration and severity of injurious agent: e.g. small dose of toxin or short duration of ischaemia cause reversible cell injury while large dose or persistent ischaemia cause cell death. Type, status and adaptability of target cell: e.g. skeletal muscle can withstand hypoxic injury for long time while cardiac muscle suffers irreversible cell injury after persistent ischaemia Pathogenesis of Cell Injury

6. The interruption of blood supply(ischaemia) and impaired oxygen supply to tissues(hypoxia) are most common form of cell injury in human beings. Although underlying intracellular mechanisms and ultrastructural changes seen in reversible and irreversible cell injury by hypoxia-ischaemia are continuation of the process, these mechanisms are discussed separately. Pathogenesis of Ischaemic and Hypoxic Injury

7. If ischaemia or hypoxia is of short duration the effects may be reversible on rapid restoration of circulation. The sequential and biochemical changes in reversible cell injury are as under: Decreased generation of cellular ATP: Damage by ischaemia from interruption versus hypoxia from other causes REVERSIBLE CELL INJURY

8. 2) Nuclear clumping: Due to intracellular lactic acidosis Hydropic swelling and other membrane changes: Damage to plasma membrane pumps i.e. failure of Na-K Pump and Ca pump Reduced protein synthesis: As due to swelling ribosomes are detached from RER and are dispersed in cytoplasm leading to inactivation of their function

9. Persistence of ischaemia or hypoxia results in irreversible damage to the structure and function of the cell(cell death). The stage at which this irreversibility is reached from reversible cell injury is unclear but the sequence of events is a continuation of reversibly injured cell. In addition, there is further reduction in ATP, continued depletion of proteins, reduced intracellular pH, and leakage of lysosomal enzymes into plasma. IRREVERSIBLE CELL INJURY

10. Effects on ultrastructural component of the cell is as follows: Membrane damage: Increased cytosolic influx of calcium in cell activates endogenous phospholipases . These, in turn, degrade membrane phospholipids which are the main constituent of lipid bilayer membrane. Besides, there is also decreased replacement-synthesis of membrane phospholipids due to reduced ATP.

11. Mitochondrial damage: Excess intracellular calcium collects in mitochondria leading to the formation of vacuoles and deposits of amorphous calcium salts in the matrix. Cytoskeletal damage: Normal cytoskeleton of cell is damaged due to degradation by activated intracellular proteases.

12. Nuclear Damage: DNA or nucleoproteins are damaged by activated lysosomal enzymes such as proteases and endonucleases . Irreversible damage to nucleus can be in 3 forms: Pyknosis – condensation and clumping of nucleus Karyorrhexis – nuclear fragmentation Karyolysis – dissolution of nucleus

13. Lysosomal damage, cell death and phagocytosis: The lysosomal membranes are damaged and results in escape of lysosomal hydrolytic enzymes. These enzymes are activated due to lack of oxygen O 2 in the cell and acidic pH and on activation bring about enzymatic digestion of cellular components and hence cell death. The dead cell is replaced by masses of phospholipids called myelin figures which are phagocytosed by macrophages.

14. Loss of Ca 2+  homeostasis, often in the form of cytoplasmic increases, leads to cell injury. Depending upon cell type and the intensity of Ca 2+ toxicity, the ensuing pathology can be reversible or irreversible. Although multiple destructive processes are activated by Ca 2+ , lethal outcomes are determined largely by Ca 2+ -induced mitochondrial permeability transition. This form of damage is primarily dependent upon mitochondrial Ca 2+  accumulation, which is regulated by the mitochondrial membrane potential. Retention of the mitochondrial membrane potential during Ca 2+  increases favors mitochondrial Ca 2+ uptake and overload, resulting in mitochondrial permeability transition and cell death. In contrast, dissipation of mitochondrial membrane potential reduces mitochondrial Ca 2+  uptake, retards mitochondrial permeability transition, and delays death, even in cells with large Ca 2+ increases. Calcium in C ell Injury and Death

15. Textbook of Pathology…..(Harsh Mohan) -Chapter -2 Google Images https ://en.wikipedia.org/wiki/ Cell _ damage R eference