Lecture_4.pdf

Cell Injury and Cell Death PART-2 Cell Death By the end of this session students should be able to: ◦ Recognize types of cell death as a result of irreversible injury. Session’s Objectives Part 2 ◦ Identify necrosis (definition, morphology, types and fate). ◦ Identify apoptosis(definition, causes, t...

Cell Injury and Cell Death PART-2 Cell Death By the end of this session students should be able to: ◦ Recognize types of cell death as a result of irreversible injury. Session’s Objectives Part 2 ◦ Identify necrosis (definition, morphology, types and fate). ◦ Identify apoptosis(definition, causes, types, biochemical and molecular mechanism, and morphology). ◦ Differentiate between apoptosis and necrosis. ◦ Recognize aging and its mechanism ◦ Define and classify pathologic calcification Irreversible Injury means CELL DEATH Apoptosis Necrosis Controlled cell death Uncontrolled cell death ◦ Necrosis is type of cell death associated with loss of membrane integrity and leakage of cellular contents resulting from degradative action of enzymes. Cell Death: Necrosis ◦ The morphologic appearance of necrosis is the result of two concurrent processes: ◦ Inability to reverse mitochondrial dysfunction. ◦ Profound disturbances in membrane function leading to disruption of cell membrane or lysosomal membrane which induce ◦ Denaturation of proteins causing lethal damage ◦ Enzymatic digestion of this lethally damaged cell ◦ It is always pathological! ◦ Cell membrane rupture, so cell contents are leaked out and inflammatory response is seen in surrounding tissue. Necrosis ◦ Cell digestion is result of enzymes from dying cells lysosomes and lysosomes of inflammatory leucocytes ◦ Clinical significance: ◦ Leakage of proteins into circulation is a mode of detecting tissue specific cell injury, e.g. Troponins and CK-MB in myocardial infarction. Morphology of Necrosis Necrotic cell show: ◦ Increased eosinophilia i.e. pink staining (due to loss of RNA & denatured proteins) and glassy appearance (due to loss of glycogen) ◦ Dead cells replaced by myelin figures (whorled phospholipids masses) and calcification ◦ Breakdown of plasma membrane and organelles ◦ Mitochondrial dilatation ◦ Nuclear changes: ◦ Karyolysis: Fading of the basophilia of the chromatin, due to lysis of DNA by endonucleases. ◦ Pyknosis: Nuclear shrinkage and increased nuclear basophilia. The DNA condenses into a solid, shrunken basophilic mass. ◦ Karyorrhexis: The pyknotic nucleus undergoes fragmentation. ◦ Finally: The nucleus totally disappears Nuclear changes of cell death Morphological Types of Necrosis Pattern of tissue necrosis 1. Coagulative necrosis 2. Liquefactive necrosis Coagulative necrosis ◦ It implies preservation of the basic outline of the necrotic cells for several days. ◦ Cell components are dead but basic tissue architecture is preserved and firm ◦ This is due to denaturation of structural and enzymatic proteins, so proteolysis of the cells are blocked ◦ Ischemia leads to coagulative necrosis ◦ Everywhere except in brain where its Liquefactive necrosis ◦ Infarct: areas of ischemic necrosis in all solid organs Coagulative necrosis in myocardial infarction 1- Gangrenous necrosis ◦ It is usually applied to a limb, generally the lower leg, that has lost its blood supply and has undergone coagulative necrosis (dry gangrene). ◦ When bacterial infection is superimposed, coagulative necrosis is modified by the liquefactive action of the bacteria and the attracted leukocytes (wet gangrene). 2- Caseous necrosis ◦ This a distinctive form of coagulative necrosis, seen in tuberculous infection. ◦ The term caseous is derived from friable yellow white appearance of necrotic tissue. ◦ Unlike coagulative necrosis, the tissue architecture is completely obliterated, No cellular outlines, enclosed within distinct inflammatory border (granuloma) Liquefactive necrosis Necrosis characterized by liquefactive process resulting in complete digestion of the dead cells. ◦ Examples: ◦ Focal bacterial and fungal infections: accumulation of phagocytes and enzymes of leukocytes that digest tissue ( abscess) ◦ Infarct/Hypoxia in brain leads to liquefactive necrosis Other Types of Necrosis Fat necrosis: Focal area of fat destruction appears as white chalky areas with basophilic calcium deposits Example: after acute pancreatitis due to action of pancreatic lipases. Fate of Necrotic Tissue ◦ Ultimately, in the living patient, most necrotic cells disappear by a combined process of enzymatic digestion and fragmentation, with phagocytosis by leukocytes. ◦ If necrotic cells are not completely destroyed and reabsorbed, they attract calcium salts become calcified. This is called dystrophic calcification ◦ Definition: Cell death: Apoptosis ◦ Self suicide or programmed cell death in which cell activate the enzymes to degrade cell’s own nuclear and cytoplasmic proteins. Fragments of apoptotic cells break off, (literally means “Falling away”) ◦ Plasma membrane of apoptotic cell and its fragments remain intact ◦ It can be physiologic and pathologic Physiologic apoptosis: Eliminates cells that are no longer needed: ◦ Embryogenesis Causes of Apoptosis ◦ Hormonal “Involution”endometrial cell breakdown during the menstrual cycle, ovarian follicular atresia in the menopause, the regression of lactating breast after weaning, and prostatic atrophy after castration ◦ Cell loss in proliferating epithelium ◦ Removal of neutrophils & lymphocytes after inflammatory or immune response ◦ Elimination of potentially harmful self-reactive lymphocytes ◦ Cell death of virus infected cells by Cytotoxic T cells Pathologic apoptosis: Elimination of cells that are genetically altered or injured beyond repair without eliciting host inflammatory response. Causes of Apoptosis ◦ DNA damage by drugs, radiation, hypoxia, or ROS. If repair is not successful then cell dies by apoptosis ◦ Cell injury in certain infections, e.g. viral hepatitis, HIV ◦ Tumor cells death by chemotherapy ◦ Pathological atrophy of glands after duct obstruction Apoptosis of an Epidermal cell, which is shrunken, has intensely eosinophilic cytoplasm, and condensed nucleus. MORPHOLOGY OF APOPTOSIS programmed cell death Chromatin condensation followed by karryorhexis Cell shrinks rapidly, form cytoplasmic buds and fragment into Apoptotic bodies, these are phagocytosed quickly without eliciting inflammation On microscopy apoptotic cells appear as round eosinophilic masses ◦ Apoptosis is an active enzyme process in which nucleoproteins are broken down by activation of caspases and cell is fragmented. Mechanism of Apoptosis Two distinct pathways activate caspases: 1-Mitochondrial (intrinsic ) pathway of apoptosis: Signalling pathways that initiate apoptosis. signals such as ◦ Lack of growth hormones ◦ Damage to DNA e.g. radiation Activate the sensor, Bcl2 family (Bax & Bak) which increase mitochondrial membrane permeability release cytochrome c, that activates caspases. 2-Death receptor (extrinsic ) pathway of apoptosis: Cell surface receptors (TNF family, Fas ) called death receptors that trigger apoptosis by direct transmission of signals to activate caspases result in protein cleavage Removal of dead cells is by phagocytosis Mechanism of Apoptosis Necrosis vs Apoptosis Robbins Pathology 10th edition Necrosis vs Apoptosis Apoptosis Programmed cell death Cell suicide Physiological. mostly Pathological Vs Necrosis Definition Uncontrolled Cell Death Causes Always Pathological Single cell Cell membrane intact Morphology Multiple cell Damaged cell membrane No inflammation Host response Inflammation Features of necrosis and apoptosis Features Necrosis Apoptosis Definition Uncontrolled cell death Programmed cell death Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis, karyorrhexis, karyolysis Pyknosis, karyorrhexis Plasma membrane Disrupted Intact Cellular contents Enzymatic digestion, leak out of cells Intact in apoptotic bodies Adjacent inflammation Frequent No Physiologic or pathologic role Pathologic (irreversible cell injury) Often physiologic May be pathologic Robbins, page 7, table 1-1 Progressive decline in cell’s Aging process of getting old / aged ◦ Proliferating capacity (Replicative senescence) ◦ Life span of cells Several mechanisms are responsible for cellular aging: increasing DNA damage With cell aging, decreased cellular replication (Replicative senescence) by decreasing telomerase & progressive shortening of chromosomal end (telomere) metabolic damage Intrinsic Molecular Programs of Aging ◦ All normal cells have limited capacity of replication, after fixed number of divisions cells become arrested in terminally nondividing state known as replicative senescence associated with aging ◦ Telomere are segments of DNA present on chromosomal ends to ensure complete replication ◦ When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened. ◦ As shortened telomeres chromosome show signs of DNA damage and have cell cycle arrest ◦ So cell aging, telomeres become shorter and exit cell cycle and inability to generate new cells ◦ Conversely in cancer, cells telomerase (enzyme that maintained telomere lengths) is reactivated, and telomeres are not shortened Mechanism of Cellular Aging Pathologic calcification means abnormal deposition of calcium salts into the tissues. ◦ There are two forms of pathologic calcification: ◦ Dystrophic calcification: Deposition occurs in nonviable or dying tissues, and it occurs with normal serum levels of calcium Pathologic calcification ◦ Metastatic calcification: Deposition of calcium salts in vital tissues, and it almost always associated with hypercalcemia. Examples: ◦ High PTH level ◦ Vitamin D intoxication ◦ Renal failure ◦ Malignancy ◦ Myeloma, leukemia Summary