HYPOXIAHYPOXIA

Ischemia ( loss of blood supply ).Ischemia ( loss of blood supply ).

Inadequate oxygenationInadequate oxygenation

( cardiorespiratory failure ).( cardiorespiratory failure ).

Loss of oxygen-carrying capacity of the Loss of oxygen-carrying capacity of the blood ( anemia or CO poisoning ).blood ( anemia or CO poisoning ).

HYPOXIC INJURYHYPOXIC INJURY

• Loss of oxidative phosphorylation and ATP Loss of oxidative phosphorylation and ATP generation by mitochondria.generation by mitochondria.

• Decreased ATP (with increase in AMP): Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, stimulating fructokinase and phosphorylation, resulting in aerobic glycolysis.resulting in aerobic glycolysis.

• Depleted glycogen.Depleted glycogen.• Reduced intracellular pH: Lactic acid and Reduced intracellular pH: Lactic acid and

inorganic phosphate.inorganic phosphate.• Clumping of nuclear chromatin.Clumping of nuclear chromatin.

Four biochemical themesFour biochemical themes

• Oxygen-derived free radicals.Oxygen-derived free radicals.

• Loss of calcium homeostasis and Loss of calcium homeostasis and increased intracellular calcium.increased intracellular calcium.

• ATP depletion.ATP depletion.

• Defects in membrane permeability.Defects in membrane permeability.

PHYSICAL AGENTSPHYSICAL 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 INJURYMECHANISMS OF CHEMICAL INJURY

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

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

MECHANISMS OF CHEMICAL INJURYMECHANISMS OF CHEMICAL INJURY

CClCCl44 in SER of liver cell (P-450) – CCl in SER of liver cell (P-450) – CCl33. . – lipid – lipid

peroxidation and autocatalytic reactions – swelling peroxidation and autocatalytic reactions – swelling

and breakdown of ER, dissociation of ribosome, and breakdown of ER, dissociation of ribosome,

and decreased hepatic protein synthesis ( loss of and decreased hepatic protein synthesis ( loss of

lipid acceptor protein – fatty change of liver cell) – lipid acceptor protein – fatty change of liver cell) –

progressive cellular swelling, plasma membrane progressive cellular swelling, plasma membrane

damage, and cell death.damage, and cell death.

FREE RADICAL INITIATIONFREE 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 Enzymatic conversion of exogenous chemicals

or drugs (CClor drugs (CCl44>CCl>CCl33..))

• Oxygen-derived radicalsOxygen-derived radicals• SuperoxideSuperoxide

Cell injury caused by free radicals throughCell injury caused by free radicals through

• Peroxidation of lipids.Peroxidation of lipids.

• Cross linking proteins by the formation of Cross linking proteins by the formation of disulfide bonds.disulfide bonds.

• Induction of DNA damage that has been Induction of DNA damage that has been implicated both in cell killing and malignant implicated both in cell killing and malignant transformation.transformation.

INFECTIOUS AGENTSINFECTIOUS AGENTS

• VirusesViruses

• RickettsiaeRickettsiae

• BacteriaBacteria

• FungiFungi

• ParasitesParasites

Marfan syndromeMarfan syndromeFibrillin, a scaffolding on which tropoelastinFibrillin, a scaffolding on which tropoelastin

is deposited to form elastic fibers.is deposited to form elastic fibers.FBN1, 15q21, mutations in Marfan FBN1, 15q21, mutations in Marfan

syndrome.syndrome.FBN2, 5q3, mutations in congenital FBN2, 5q3, mutations in congenital

contractual arachnodactyly. contractual arachnodactyly.

Adenomatous polyposis coliAdenomatous polyposis coliAPC loci, 5q21APC loci, 5q21Adenomatous polyposis in colons (in teens).Adenomatous polyposis in colons (in teens).100% malignant transformation ( 100% malignant transformation ( 40ys ). 40ys ).APC protein in the cytoplasm.APC protein in the cytoplasm.Several partners, including Several partners, including -catenin.-catenin. -catenin -catenin entering the nucleusentering the nucleusactivating activating

transcription of growth-promoting genes.transcription of growth-promoting genes.Causing degradation of Causing degradation of -catenin-cateninmaintainingmaintaining low level of low level of -catenin in the cytoplasm.-catenin in the cytoplasm.

CELLS REACT TO ADVERSE CELLS REACT TO ADVERSE INFLUENCESINFLUENCES

• ADAPTINGADAPTING

• SUSTAINING REVERSIBLE INJURYSUSTAINING REVERSIBLE INJURY

• SUFFERING IRREVERSIBLE INJURY SUFFERING IRREVERSIBLE INJURY AND DYINGAND DYING

CELL INJURY AND NECROSISCELL INJURY AND NECROSIS

General mechanisms: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 Preservation of the integrity of the genetic

apparatus.apparatus.