The Pathogenesis and molecular changes in cell injury and necrosis:
There are several biochemical and molecular changes evident in cell injury & necrosis. To properly understand these changes let’s discuss the patterns of cell injury and necrosis:
Reduced ATP production from hypoxia decreases oxidative phosphorylation of ADP. Inefficient Na+/K+ pump drives Na+, water into the cell, & K+ out of the cell. Swelling causes rough endoplasmic reticulum to distend. Ribosomes detach from ER resulting in reduced protein synthesis.
Anaerobic Glycolysis causes build up of lactic acid which reduces PH level. The reduction of enzyme activity takes place , with clumping of nuclear chromatin. This is part of the molecular changes.
Mitochondrial damage from cytosolic calcium, hypoxia, and toxins increase permeability of mitochondria. This reduces oxidative phosphorylation and ATP that leads to cell injury.
Increased cytosolic calcium from ischemia activates intracellular enzymes and increases mitochondria membrane permeability. Enzymes like endonucleases, proteases, phospholipases destroy the cell. Mitochondria membrane damage decreases ATP synthesis as part of the molecular changes.
Generation of free radicals cause oxidation of free metallic ions & molecular compounds like carbohydrates & proteins. This oxidation damages protein synthesis, DNA, and plasma membrane. Common free radicals include superoxide; hydrogen peroxide & hydroxyl ion, Nitrogen dioxide, trichloromethyl. Free radicals are produced in mitochondria, peroxisomes, lysosymes and by radioactive agents. Antioxidants like vitamin A, E, C, and superoxidase dismutase and catalase prevent oxidative stress from occurring.
Increased membrane permeability in mitochondria, lysosymes, & cell from injurious stimuli causes extensive damages. Mitochondria ATP depletion and death from hypoxia; digestion of RNA, DNA, glycogen, protein by lysosymes; plasma cell swelling and death.
In necrosis, nuclear membrane is damaged in this forward pattern: Pyknosis (condensation of chromatin)- Karyorrhexis (fragmentation of nucleus)- Karyolysis (digestion of chromatin).
Clinically important causes of cell injury:
In medical practice, we may encounter cases of hypoxic-ischemic cell injury, chemical intoxication, & ischemia-reperfusion injury. Common causes as these, disrupt cell membrane intergrity by producing free radicals.
In ischemia-reperfusion injury, parenchymal and endothelial cells release reactive oxygen and nitrogen molecules.
Cytochrome P-450 enzyme converts drugs to highly reactive metabolites in chemical intoxication.
Apoptosis and its molecular changes
Apoptosis is the irreversible death of cells from misfolded proteins, DNA damage, & hormone withdrawals. Examples: Endometrial cell breakdown in menstruation; ovarian follicular atresia in menopause; programmed cell death in embryogenesis; viral infections; death of inflammatory cells.
The hallmark of apoptosis: Intact plasma cell & nuclear membrane; Cell shrinkage; chromatin condensation & digestion; plasma membrane blebs and apoptotic bodies formation; phagocytosis.
Pathogenesis of apoptosis:
The most common pathway is the mitochondrial intrinsic pathway. Growth factors withdrawal, DNA damage, & misfolded proteins activate Bcl-family sensors that activate pro-apoptotic Bcl-family and inhibit anti-apoptotic BCL-family. The prop-apoptotic Bcl-family attaches to mitochondria membrane to create pores. Cytochrome c is released which activates cytosolic caspase-3 that causes indirect chromatin fragmentation and plasma bleb formation.
Intracellular accumulation of molecular substances:
Molecular compounds like, lipids, carbohydrates, proteins, iron remain in the cell vacuoles. Slow metabolism, defective enzymes to transport them or excess amount of them are found to be the cause.
Fatty change (steatosis), causes excessive triglyceride to build up in the vacuoles of liver or heart due to defective metabolism. They appear as orange-red color on With Sudan-IV stain.
In atherosclerosis, cholesterol accumulates in vacuoles of macrophages and smooth muscles of large arteries. They appear as yellow-cholesterol laden atheromas in the cytoplasm.
The accumulation of intracellular protein takes place in the proximal renal tubule. In vesicles, they appear as rounded eosinophilic or pink droplets within the cytoplasm.
Lipofuscin is an insoluble pigment, derived from undigested debris within the cytoplasm. It gives a yellow-brown granular color on H&E stain. Seen among aging nutrient deficient population.
The carbon pigment is an exogenous pigment, formed from the inhalation of coal dust. It produces a black pigment in lung tissue as in the case of anthracosis.
Hemosiderin pigment is derived from hemoglobin & it is a storge form of iron. It produces a golden yellow-brown granular pigment on H&E stain. On a Prussian blue histochemical reaction, it creates a blue-black color.
Dystrophic Calcification is the calcification of tissues after necrosis. Macroscopically, it appears as fine, white granules. Microscopically, creates a basophilic amorphous granule on H&E stain.
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