Lecture # 2 Cell injury (alteration). Degeneration. Cellular & extracellular mechanisms of trophics. Causes of development of degenerations. Morphogenetic mechanisms.

Classification. PLAN: 1. 2. 3. 4. 5. 6. Notion about alteration. Main mechanisms of cell injuries. Morphology of cell injury (reversible & irreversible injuries). Regulation of metabolism in the organism. Nature of degenerations. Morphogenesis of degenerations. Classification of degenerations.

Causes of Cell Injury and Necrosis Hypoxia Ischemia Hypoxemia Loss of oxygen carrying capacity Physical agents Chemicals, drugs, toxins Infections Immunologic reactions Genetic abnormalities Nutritional imbalance Free radical damage Cell injury Cell Injury General Mechanisms Four very interrelated cell systems are particularly vulnerable to injury: Membranes (cellular and organellar) Aerobic respiration Protein synthesis (enzymes, structural proteins, etc) Genetic apparatus (e.g., DNA, RNA) Biochemimical reactions which are involved in Cell Injury mechanisms Oxygen and oxygen-derived free radicals Loss of calcium homeostasis ATP depletion Defects in membrane permeability

Mechanism of Free Radical Injury Lipid peroxidation damage to cellular and organellar membranes DNA damage due to reactions of free radicals with thymine Protein cross-linking and fragmentation due to oxidative modification of amino acids and proteins The defensive mechanism of free radicals: a) Intracellular protective enzymes e.g. glutathione peroxidase, catalase, superoxide dismutase. b) Antioxidants e.g. Vit. E, C. Loss of calcium homeostasis Membrane damage and loss of calcium homeostasis are most crucial Some models of cell death suggest that a massive influx of calcium causes cell death Too much cytoplasmic calcium: Denatures proteins Poisons mitochondria Inhibits cellular enzymes Calcium in cell injury KINDS OF CELL INJURY: ISCHEMIC AND HYPOXIC INJURY INJURY DUE TO ACTION OF FREE RADICALS TOXIC INJURY Cause of Hypoxic Injury

Ischemia: Lack of blood supply due to obstruction of arterial blood flow. Decreased oxygen carrying capacity of blood as in anemia and carbon monoxide
poisoning. Decreased oxygenation of blood due to respiratory diseases. Decreased tissue perfusion as in hypotension and shock. Generation of Free Radicals Normal metabolism (oxidation-reduction reactions). Oxygen toxicity. Ionizing radiation (X-ray, ultra violet rays). Drug and chemicals. Cellular aging. Acute inflammation. TOXIC INJURY Direct action of chemicals (cytotoxic action)
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Action of toxic products of metabolism

Reversible Injury -- Morphology Light microscopic changes Cell swelling fatty change Ultrastructural changes Alterations of cell membrane Swelling of and small amorphous deposits in mitochondria Swelling of ER and detachment of ribosomes Irreversible Injury Nuclear Changes Pyknosis Nuclear shrinkage and increased basophilia Karyorrhexis Fragmentation of the pyknotic nucleus Karyolysis Fading of basophilia of chromatin Irreversible Injury -- Morphology Light microscopic changes Increased cytoplasmic eosinophilia (loss of RNA, which is more basophilic) Cytoplasmic vacuolization Nuclear chromatin clumping Ultrastructural changes Breaks in cellular and organellar membranes Larger amorphous densities in mitochondria Nuclear changes Karyolysis & karyorrhexis -- micro Alterations may be present by 2 pathological processes:

Degeneration (dystrophy) Necrosis

Dystrophy (degeneration, accumulation) (from greece dys - disorder & trophe nourish) is pathological process, in the base of which the tissue metabolism disorder lays & it leads to structural changes of tissues. Trophics is the whole of mechanisms defining metabolism and structure of tissue (cell), which need for realization of certain function. Mechanisms of trophics:

Cellular
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Extracellular
Mechanism of degenerations: Disorder of cell autoregulation due to hyperfunction, toxins, radiation, enzyme deficiency etc. Disorder of transport systems of cell, which leads to hypoxia. Disorder of endocrine regulation of trophics (diabetes, hyperthyroidism etc). Degenerations are accumulation of different products of metabolism (proteins, lipids, carbohydrates, minerals, water) in cells or in intercellular substance, which characterized by quantitative & qualitative changes because of disorder of fermentative processes. Morphogenetic mechanisms of degenerations: Infiltration. Decomposition. Unnatural synthesis. Transformation. Infiltration is excessive accumulation of metabolism products in cells or in intercellular substance due to disorder of fermentative systems (infiltration of intima of arteries by lipoproteids in atherosclerosis). Decomposition is decay of ultrastructures of cells & intercellular substance, which leads to disorder of tissue metabolism & accumulation of products of metabolism in tissue (cell) (dystrophy of cardiomyocytes in dyphteria). Unnatural synthesis is synthesis of unusual substances, which are not present in normal cells & tissues) (synthesis of alcoholic hyaline in hepatocytes). Transformation is formation of products of one kind of metabolism from common initial products, which are need for formation of proteins, lipids & carbohydrates (transformation of components of fat & carbohydrate in proteins).

Classification of degenerations: depending of localization of pathological changes Intracellular accumulations Extracellular accumulations Mixed forms. depending of type of metabolism disorder protein accumulations fatty accumulations carbohydrate accumulations mineral accumulations depending of genetic factors Acquired Inherited depending of spreading of process general local