HYPOXIA
Ischemia ( loss of blood supply ).
Inadequate oxygenation
( 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.
• Decreased ATP (with increase in AMP):
stimulating fructokinase and phosphorylation,
resulting in aerobic glycolysis.
• Depleted glycogen.
• Reduced intracellular pH: Lactic acid and
inorganic phosphate.
• Clumping of nuclear chromatin.
Four biochemical themes
• Oxygen-derived free radicals.
• Loss of calcium homeostasis and
increased intracellular calcium.
• ATP depletion.
• Defects in membrane permeability.
PHYSICAL AGENTS
• Trauma
• Heat
• Cold
• Radiation
• Electric 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.
MECHANISMS OF CHEMICAL INJURY
• 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.
CCl4 in SER of liver cell (P-450) – CCl3. – 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)
• Oxidative metabolic reactions
• Enzymatic conversion of exogenous chemicals
or drugs (CCl4>CCl3.)
• Oxygen-derived radicals
• Superoxide
Cell injury caused by free radicals through
• Peroxidation of lipids.
• Cross linking proteins by the formation of
disulfide bonds.
• Induction of DNA damage that has been
implicated both in cell killing and malignant
transformation.
INFECTIOUS AGENTS
•
•
•
•
•
Viruses
Rickettsiae
Bacteria
Fungi
Parasites
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.
Causing degradation of -cateninmaintaining
low level of -catenin in the cytoplasm.
CELLS REACT TO ADVERSE
INFLUENCES
• ADAPTING
• SUSTAINING REVERSIBLE INJURY
• SUFFERING IRREVERSIBLE INJURY
AND DYING
CELL INJURY AND NECROSIS
General mechanisms:
• Maintenance of the integrity of cell membranes.
• Aerobic respiration and production of ATP.
• Synthesis of enzymes and structure proteins.
• Preservation of the integrity of the genetic
apparatus.