Types of Cellular Injury

Reversible

ATP depletion

Main mechanism of cellular injury

Causing damage to:

Integrity of Cell Membranes

Reduced activity of Na+/K+ pumps

Net gain of solute

Cell swelling and dilation of ER

Aerobic Respiration

Cellular metabolism altered

Increased rate of anaerobic glycolysis

Accumulation of lactic acid and inorganic phosphorus

Reduction of intracellular pH

Protein Synthesis and Function

Disruption of protein synthesis

Detachment of ribosomes from ER

Dissociation of polysomes to monosomes

Irreversible

Persistence of ischemia leads to further deterioration

Characterised by:

1) Inability to reverse mitochondrial dysfunction

Marked reduction of ATP production

Membrane Permeability transition

2) Profound disturbances in membrane function

Loss of membrane phospholipds

Loss of intracellular amino acids

Generation of free radicals

Ischemia / Reperfusion Injury

New cell damage that occurs after blood flow is restored

Mechanisms

Increased generation of ROS

Inability to neutralize ROS due to injury

Production of cytokines and adhesion molecules

Additional injury due to inflamation

Free Radical Removal Mechanisms

Antioxidants

Block initiation/activation of Free Radicals

Examples

Vitamin E

Ascorbic Acid

Glutathione

Protein Binding

Transferrin

Ferritin

Lactoferrin

Scavenging Systems

Catalase

Superoxide Dismutase

Glutathione Peroxidase

Free Radicals Generated by:

Free radicles produces by Ox-Phos in the mitochondria

Radiant Energy

UV light

X-Rays

Enzymatic metabolism of exogenous chemicals/drugs

Oxidation/Reduction of transition metals

Nitric Oxide

Mechanism Of Injury

Integrity of Cell Membranes

Peroxidation of Membrane lipids

FR reacts with unsaturated fatty acids

More FR generated causing autocatalytic chain rxn propagation

Protein Synth and Function

Oxidative Metab of Enzymes

Formation of Protein-Protein Cross Links

Disrupts enzyme activity

Degredation of enzymes by proteasome complex

Integrity of Genetic Apparatus

DNA damage

Reaction with thymine causes single stranded breaks

Induce Cell injury by 2 mechanisms

1) Directly by combining with critical molecular component or organelle

2) Not biologically active but can be converted into toxic metabolites

Carbon Tetrachloride

Converted by Cyt P450 to highly reactive Free radical

Paracetamol

Converted by Cyt P450 to highly toxic Metabolite