how will occur cell injury

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

2. TheCell and the Environment
Stimuli
Cell
Adaptation
CellInjury
Reversible
Irreversible (cell death)
apoptosis necrosis
Atrophy
Hypertrophy
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
O2
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 ofATP
• Usuallyin hypoxicandchemicalinjuries.
• Sources : oxidative phosphorylation of ADPin the
mitochondria and Glycolytic pathway using
Glucose.
• The major causes of ATP depletion are
reduced supply of oxygen and nutrients,
mitochondrial damage and the actions of
sometoxins(Cyanide).

9. 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

10. 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.

11. MECHANISM OF CELL INJURY CONT.
SuppliesATP(energy) to the cell.•
• species,Damaged by Calcium influx, reactive oxygen
radiation, oxygen deprivation, toxins and mutations 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 activateRelease of cytochrome c into the cytosol
apoptosis (death).
• Failureof oxidative phosphorylation leadsto ATPdepletion andformation
of reactive oxygenspecies(ROS).

13. 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 ATPdepletion),
-Phospholipases (which cause membrane damage),
- Proteases (which break down both membrane and
cytoskeletal proteins), and
-Endonucleases (which are responsible for DNA and
chromatin fragmentation).

15. MECHANISM OF CELL INJURY CONT.
4. ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS
(OXIDATIVE STRESS)
• Oneof the oxygen derived freeradicals.
• Produced normally in small amounts and
removed by defencemechanisms.
• Once the ROS amount increases this will lead
to what socalled oxidativestress.
• Oxidative stress : cell injury, cancer, aging and
some degenerative diseases like Alzheimer.
Also ROS are produced by leukocytes and
macrophagesin inflammation.

17. • Antioxidants: Vitamin E and A, ascorbic acid
and glutathione in thecytosol.
• Binding proteins.
• Enzymes: Catalase-----H2O2 ----- O2 and H2O,
Superoxidedismutase-(SOD)-----superoxide
anion
H2O2
----H2O2, Glutathione peroxidase----
---H2O or OH------ H2O. Reduced
Glutathione level is important in cellsafety.
Removalof freeradicals

18. 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.

19. 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

21. PATHOGENESIS OF ISCHAEMIC & HYPOXIC
INJURY
Hypoxia/Ishaemia
ATP loss
Decresed PH
( cytosol)
Damaged sodium pump
(membrane)
Decreased Protein synthesis
(RER)
Ultastuctural/functional changes
Reversible cell injury

22. PHYSICAL INJURY
Ionising Radiation
H2O/O2
0H
Proliferating cells
(epithelial cells)
Non proliferating
cells(neurons)
DNAdamage Lipid peroxidation
Cell membrane damage
NECROSIS
Genetic damage
Inhibition of DNA
replication
MUTATIONS
APOPTOSIS