HYPOXIA Ischemia ( loss of blood supply ). Inadequate oxygenation ( cardiorespiratory failure ). ( cardiorespiratory failure ). Loss of oxygen-carrying capacity of the blood ( anemia or CO poisoning ).

HYPOXIC INJURY Loss of oxidative phosphorylation and ATP generation by mitochondria.Loss of oxidative phosphorylation and ATP generation by mitochondria. Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, resulting in aerobic glycolysis.Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, resulting in aerobic glycolysis. Depleted glycogen.Depleted glycogen. Reduced intracellular pH: Lactic acid and inorganic phosphate.Reduced intracellular pH: Lactic acid and inorganic phosphate. Clumping of nuclear chromatin.Clumping of nuclear chromatin.

Four biochemical themes Oxygen-derived free radicals.Oxygen-derived free radicals. Loss of calcium homeostasis and increased intracellular calcium.Loss of calcium homeostasis and increased intracellular calcium. ATP depletion.ATP depletion. Defects in membrane permeability.Defects in membrane permeability.

PHYSICAL AGENTS TraumaTrauma HeatHeat ColdCold RadiationRadiation Electric shockElectric shock

CHEMICAL AGENTS AND DRUGS Endogenous products: urea Exogenous agents: Therapeutic drugs: hormones Nontherapeutic agents: lead or alcohol

MECHANISMS OF CHEMICAL INJURY Directly: Mercury of mercuric chloride binds to SH groups of cell membrane proteins, causing increased permeability and inhibition of ATPase-dependent transport.Directly: Mercury of mercuric chloride binds to SH groups of cell membrane proteins, causing increased permeability and inhibition of ATPase-dependent transport.

By conversion to reactive toxic metabolites which in turn cause cell injury either by direct covalent binding to membrane protein and lipid, or more commonly by the formation of free radicals.By conversion to reactive toxic metabolites which in turn cause cell injury either by direct covalent binding to membrane protein and lipid, or more commonly by the formation of free radicals. MECHANISMS OF CHEMICAL INJURY

CCl 4 in SER of liver cell (P-450) – CCl 3. – lipid peroxidation and autocatalytic reactions – swelling and breakdown of ER, dissociation of ribosome, and decreased hepatic protein synthesis ( loss of lipid acceptor protein – fatty change of liver cell) – progressive cellular swelling, plasma membrane damage, and cell death.

FREE RADICAL INITIATION Absorption of energy (UV light and x-rays)Absorption of energy (UV light and x-rays) Oxidative metabolic reactionsOxidative metabolic reactions Enzymatic conversion of exogenous chemicals or drugs (CCl 4 >CCl 3. )Enzymatic conversion of exogenous chemicals or drugs (CCl 4 >CCl 3. ) Oxygen-derived radicalsOxygen-derived radicals SuperoxideSuperoxide

Cell injury caused by free radicals through Peroxidation of lipids.Peroxidation of lipids. Cross linking proteins by the formation of disulfide bonds.Cross linking proteins by the formation of disulfide bonds. Induction of DNA damage that has been implicated both in cell killing and malignant transformation.Induction of DNA damage that has been implicated both in cell killing and malignant transformation.

INFECTIOUS AGENTS VirusesViruses RickettsiaeRickettsiae BacteriaBacteria FungiFungi ParasitesParasites

Marfan syndrome Fibrillin, a scaffolding on which tropoelastin is deposited to form elastic fibers. FBN1, 15q21, mutations in Marfan syndrome. FBN2, 5q3, mutations in congenital contractual arachnodactyly.

Adenomatous polyposis coli APC loci, 5q21 Adenomatous polyposis in colons (in teens). 100% malignant transformation (  40ys ). APC protein in the cytoplasm. Several partners, including  -catenin.  -catenin  entering the nucleus  activating transcription of growth-promoting genes.  -catenin  entering the nucleus  activating transcription of growth-promoting genes. Causing degradation of  -catenin  maintaining low level of  -catenin in the cytoplasm. low level of  -catenin in the cytoplasm.

CELLS REACT TO ADVERSE INFLUENCES ADAPTINGADAPTING SUSTAINING REVERSIBLE INJURYSUSTAINING REVERSIBLE INJURY SUFFERING IRREVERSIBLE INJURY AND DYINGSUFFERING IRREVERSIBLE INJURY AND DYING

CELL INJURY AND NECROSIS General mechanisms: Maintenance of the integrity of cell membranes.Maintenance of the integrity of cell membranes. Aerobic respiration and production of ATP.Aerobic respiration and production of ATP. Synthesis of enzymes and structure proteins.Synthesis of enzymes and structure proteins. Preservation of the integrity of the genetic apparatus.Preservation of the integrity of the genetic apparatus.