Types of Cellular Injury

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Types of Cellular Injury

Chemical Injury

Paracetamol

Converted by Cyt P450 to highly toxic Metabolite

Carbon Tetrachloride

Converted by Cyt P450 to highly reactive Free radical

Induce Cell injury by 2 mechanisms

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

1) Directly by combining with critical molecular component or organelle

Free Radical Induced

Mechanism Of Injury

Integrity of Genetic Apparatus

DNA damage

Reaction with thymine causes single stranded breaks

Protein Synth and Function

Oxidative Metab of Enzymes

Degredation of enzymes by proteasome complex

Disrupts enzyme activity

Formation of Protein-Protein Cross Links

Peroxidation of Membrane lipids

More FR generated causing autocatalytic chain rxn propagation

FR reacts with unsaturated fatty acids

Free Radicals Generated by:

Nitric Oxide

Oxidation/Reduction of transition metals

Enzymatic metabolism of exogenous chemicals/drugs

Radiant Energy

X-Rays

UV light

Free radicles produces by Ox-Phos in the mitochondria

Free Radical Removal Mechanisms

Scavenging Systems

Glutathione Peroxidase

Superoxide Dismutase

Catalase

Protein Binding

Lactoferrin

Ferritin

Transferrin

Antioxidants

Examples

Glutathione

Ascorbic Acid

Vitamin E

Block initiation/activation of Free Radicals

Hypoxic / Ischemic Injury

Ischemia / Reperfusion Injury

Mechanisms

Production of cytokines and adhesion molecules

Additional injury due to inflamation

Increased generation of ROS

Inability to neutralize ROS due to injury

New cell damage that occurs after blood flow is restored

Irreversible

Characterised by:

2) Profound disturbances in membrane function

Generation of free radicals

Loss of intracellular amino acids

Loss of membrane phospholipds

1) Inability to reverse mitochondrial dysfunction

Membrane Permeability transition

Marked reduction of ATP production

Persistence of ischemia leads to further deterioration

Reversible

ATP depletion

Causing damage to:

Protein Synthesis and Function

Disruption of protein synthesis

Dissociation of polysomes to monosomes

Detachment of ribosomes from ER

Aerobic Respiration

Cellular metabolism altered

Reduction of intracellular pH

Accumulation of lactic acid and inorganic phosphorus

Increased rate of anaerobic glycolysis

Integrity of Cell Membranes

Reduced activity of Na+/K+ pumps

Cell swelling and dilation of ER

Net gain of solute

Main mechanism of cellular injury