Pathogenesis of cell injury

how will occur cell injury

1. PRESENTATION ON: Pathogenesis of cell injury Presented by : Mohammad Muztaba Asst. Professor Department of Pharmacology

2. The Cell and the Environment Stimuli C e ll Adaptation Cell Injury Reversible Irreversible (cell death) apoptosis necrosis Atrophy Hy p e r t r op hy Hyperplasia metaplasia Reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletion water influx ---Cellular swelling

3. PATHOGENESIS OF CELL INJURY The following principles apply in pathogenesis of most forms of cell injury by various agents : 1.Type,duration & severity of injurious agent Type……means living/non living Duration…… how much time it contact to the cell Severity…how much injurious agent is severity the extent of injury depend upon type ,duration & severity of stimulus agents Ex .. Small dose of chemical toxin or short duration of ischemia causes cell injury ….whereas a large dose of same chemical persistent ischemia causes cell death

4. Type of nutrition Resist/capacity/ adoptation 2.Type,status & adaptability of target cell O 2 Cardiac Tissue Skeletal muscle Irreversible Cell injury Reversible Cell injury CELL DEATH NORMAL Example:- Skeletal muscle withstand (resist) hypoxic injury for long time while cardiac muscle suffers irreversible cell injury after 30-60 minutes of continuous Ischemia.

5. 3. Underlying intracellular phenomenom (Biochemical reactions which are common in all form of cell injury) Ex- The mitochondrial dysfunction of cells caused by reperfusion or re-oxygenation cannot be reversed. 4. Morphologic consequences: The biochemical changes caused by cell injury are expressed in the form of morphological alterations (ultra structure can be change) . Ex- Myocardial infraction

6. MECHANISM OF CELL INJURY 1.DEPLETION OF ATP 2.MITOCHONDRIAL DAMAGE 3.INFLUX OF INTRACELLULAR CALCIUM & LOSS OF CALCIUM HOMEOSTASIS 4.ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS) 5. DEFECTS IN MEMBRANE PERMEABILITY

7. Depletion of ATP Usually in hypoxic and chemical injuries. Sources : oxidative phosphorylation of ADP in the mitochondria and Glycolytic pathway using Glucose. The major causes o f A T P dep l eti o n a r e r edu ce d suppl y of oxygen and nutrients, mitochondrial damage a n d t h e a ct i o n s of some toxins (Cyanide).

8. MECHANISM OF CELL INJURY CONT . 2- Mitochondrial Damage: Mitochondria are important targets for all types of injury, including hypoxia and toxins . Mitochondrial changes are seen as vacuoles (membrane bound organelle) in the mitochondria and deposit of amorphous calcium salts in mitochondrial matrix

9. MECHANISM OF CELL INJURY CONT . Mitochondria can be damaged by : A- Increases of cytosolic Ca2 + B- Oxidative stress C- Breakdown of phospholipids D- Lipid breakdown products.

10. MECHANISM OF CELL INJURY CONT. Supplies ATP (energy) to the cell. • • species, D am age d b y Ca l c iu m i n f lux , r e ac t i v e o x y g e n radiation, oxygen deprivation, toxins and m ut a t i o n s in mitochondrial genes. • Consequences of mitochondrial damage : Formation of mitochondrial permeability transition pore which leads to loss of membrane potential, failure of phosphorylation and ATP depletion and then necrosis. • that activate R e l e ase o f c y t o c h r o m e c int o t h e c y t o s o l apoptosis ( death ). Failure of oxidative phosphorylation leads to ATP depletion and formation of reactive oxygen species(ROS).

11. MECHANISM OF CELL INJURY CONT . 3.INFLUX OF INTRACELLULAR CALCIUM & LOSS OF CALCIUM HOMEOSTASIS . . Ischemia causes an increase in cytosolic calcium concentration. Increased Ca2+ in turn activates a number of enzymes, e.g . - ATPases (thereby hastening ATP depletion), -P hospholipases (which cause membrane damage), - Proteases (which break down both membrane and cytoskeletal proteins), and -E ndonucleases (which are responsible for DNA and chromatin fragmentation).

12. MECHANISM OF CELL INJURY CONT . 4. ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS) One of the oxygen derived free radicals. Produced normally in small amounts and removed by defence mechanisms. Once the ROS amount increases this will lead to what so called oxidative stress. Oxidative stress : cell injury, cancer, aging and some degenerative diseases like Alzheimer. Also ROS are produced by leukocytes and macrophages in inflammation.

13. An t i oxi d a nt s : V i t a m i n E a n d A , a s c o r b i c a c i d and glutathione in the cytosol. Binding proteins. E nz y m es : Ca t a l a s e -- - - - H 2 O 2 - - - - - O 2 a n d H 2 O, Superoxide dismutase-(SOD) ----- superoxide a n i on H 2 O 2 - - -- H 2 O 2 , G l uta th i o n e p e r ox i da s e - - -- -- - H 2 O o r O H -- - - - - H 2 O . R edu ced Glutathione level is important in cell safety. Removal of free radicals

14. MECHANISM OF CELL INJURY CONT . 5. Defects In Membrane Permeability : In ischemic cells, membrane damage may be the result of ATP depletion and calcium-modulated activation of phospholipases. It can also be damaged directly by certain bacterial toxins, viral proteins etc.

15. MECHANISM OF CELL INJURY CONT . The biochemical mechanisms which contribute to membrane damage are: Accelerated degradation of membrane phosholipid Mitochondrial dysfunction Cytoskeletal abnormalities Reactive oxygen species Lipid breakdown products

16. P ATHOGENESIS OF ISCHAEMIC & HYPOXIC INJU R Y Hypoxia/Ishaemia ATP loss Decresed PH ( cytosol) Damaged sodium pump (membrane) Decreased Protein synthesis (RER) Ultastuctural/functional changes Reversible cell injury

17. PHYSICAL INJURY Ionising Radiation H 2 O/O 2 0H Proliferating cells (epithelial cells) Non proliferating cells(neurons) DNA damage Lipid peroxidation Cell membrane damage NECROSIS Genetic damage Inhibition of DNA replication MUTATIONS APOPTOSIS