Lecture # 21
CELL INJURY & RESPONSE-4
Dr. Iram Sohail
Assistant Professor
Pathology
College Of Medicine
Majmaah University
OBJECTIVES
• Discuss ischemic and hypoxic injury
• Discuss ischemic - reperfusion injury
• Discuss chemical injury
1. ISCHEMIA & HYPOXIC INJURY
• Ischemia (decrease blood flow) is the most
common cause of cell injury.
• The main abnormality in hypoxia is the
reduced generation of ATPs because of
decrease supply of oxygen.
• Loss of ATPs results in failure of energy
dependent systems of cells like,
1. Failure of ion pump
• Leads to swelling of cell
• Calcium influx
2. Depletion of glycogen stores
3. Accumulation of lactic acid
4. Decrease protein synthesis
Also
• Bleb formation
• Loss of microvilli
• Swelling of cells & its organelles
(mitochondria, ER)
• If oxygen is restored then all of the above
mentioned abnormalities will be reversed
(reversible injury)
• If the ischemia persists, irreversible injury &
necrosis (death) will occur.
• The main features of irreversible injury are
– Severe damage to cell membrane
– Extensive mitochondrial damage
– Swelling of lysosomes
• Death is mainly by necrosis.
• Finally the dead cell will be degraded and
phagocytosed by WBCs.
2. ISCHEMIA – REPERFUSION INJURY
• If the injury is reversible, restoration of blood
flow can result in recovery.
But,
• Sometimes restoration of blood flow to the
ischemic tissue leads to further damage to
cell.
• This is called ischemic – reperfusion injury.
• It mostly occurs in heart & brain.
Mechanism
• Restoration of blood ----- influx of ROS (from
parenchymal cells, endothelial cells &
leukocytes) ----- increased consumption of
antioxidants by ROS ----- increased free radicle
accumulation ------ damage to cell.
Also,
• Ischemia is associated with inflammation ----increased numbers of WBCs (leukocytes) and
plasma protein are present at site of ischemia
– reperfusion ------ will cause further damage.
Also
• Activation of complement system also causes
ischemia – reperfusion injury.
3. CHEMICAL (TOXIC) INJURY
• Chemicals cause injury by one of 2
mechanisms.
1. Direct
2. Indirect
1. Some chemicals are active and directly binds
with cell organelles.
Examples
• In mercuric chloride poisoning, mercury
directly binds with cell membrane and causes
its damage.
• Many anti-neoplastic (anti-cancer) drugs
directly damage the cells.
2. Many other chemicals are initially inactive, so
first converted to reactive (active) toxic
metabolite which then act on target cell.
• This conversion occurs in liver by help of an
enzyme called P-450.
• The most important mechanism in this type of
injury is free radicle injury.
Example
• CCL4 (carbon tetra chloride) is converted to
toxic free radicle CCL3 in liver ----- CCL3 causes
rapid damage to cell membrane, mitochondria
and ER ------ cell swelling & calcium influx ----death of the cell.