Irreversible cell injury
Contents
Irreversible cell injury
• Pathogenesis
• Morphology
Objectives
At the end of this PDF, student will be able to
• Explain the sequence of changes occurring
during irreversible cell injury
• Explain the morphology of irreversible cell injury
• Describe the pathogenesis of irreversible
cell injury due to hypoxia and ischemia
Irreversible cell injury
Pathogenesis of irreversible cell injury
• Ischemia
& hypoxia persists for long time, results in irreversible changes in
structure & function of cell
Irreversible cell injury differs from reversible cell injury
• Inability
of cell to reverse the mitochondrial changes
• Disturbance
in cell membrane structure &
function
Sequence of events in irreversible cell injury
Mitochondrial dysfunction
• Continued
hypoxia
• Large
influx of Ca2+ - taken up by mitochondria - mitochondrial dysfunction
• Formation of vacuole
• Deposition
of amorphous Ca2+ in
mitochondrial matrix
Membrane damage
• O2
deprivation - Ca2+ from mitochndria & ER shifts to cytosole
• ↑
Ca2+ activates phospholipases & proteases
• Phospholipases
- breakdown phospholipids in cell
membrane
• Accumulation
of lipid break down product - Injury to cell
• Leakage
of proteins, co-enzymes, RNA and other vital cell constituents
• Free
radicals of O2 - superoxide,
hydrogen peroxide & hydroxyl
• Injury
- lipid peroxidation, DNA, RNA
destruction
Liberation of hydrolytic enzymes
• Damage
to lysosomal membranes- liberates
hydrolytic
• enzymes
– digestion of cellular components
• Nuclear
changes – cell death
• Cellular
contents digested by lysosome hydrolases
• Dead
cells replaced by myelin figues (large phospholipid masses)
Serum estimation of liberated intracellular enzymes
• Liberated
enzymes leak across the abnormally permeable cell membrane in to serum
• Estimation
of these enzyme levels in serum - extent of cell death
E.g. In MI, serum estimation of SGOT, LDH, Creatinine kinase
and cardiac troponins – guides for assessing extent of death of cardiac muscles
Morphology of irreversible cell injury
Cell death occurs as local or focal changes
• Autolysis
• Necrosis
• Apoptosis
and changes that follow like gangrene
and pathological calcification
Autolysis
• Self
digestion
• Disintegration
of cell by its own hydrolytic enzyme
• Rapid
in tissues rich in hydrolytic enzymes -
pancreas, gastric mucosa
• Intermediate
in liver, kidney and heart
• Slow
in fibrous tissues
• May
or may not be associated with inflammation
Necrosis
• Focal
death of living tissue
• Progressive
degeneration by various enzymes
• Often
associated with inflammation
• Result
of 2 concurrent process
– Cell
digestion by lytic enzymes
– Denaturation
of proteins
Types of necrosis
• Coagulative
necrosis – Most commom, due to sudden cessation of blood supply
• Liquefaction
necrosis – follows ischemic injury, bacterial or fungal infection; Common in
brain
• Caseous
necrosis - combination of coagulative & liquefaction
necrosis ; in centre of tuberculous infection
• Fat
necrosis – focal area associated with fat destruction
• Fibrinoid
necrosis – appearance of fibrin like materials; in peptic ulcer &
immunologic injury
Gangrene
• Form
of coagulative necrosis
• Characterized
by inflammation
• Provoked
by virulent bacteria resulting in massive tissue necrosis
3 types of gangrene
Ø Wet
gangrene
Ø Dry
gangrene
Ø Gas
gangrene
Dry gangrene
• Usually occur in limbs
• Originates from toe or fingers
• Affected by improper blood supply due to
ischemia
• Microbial contamination follows
• Spreads from origin upward until it reaches
the point of blood supply
Wet gangrene
• Occurs in moist tissues and organs as mouth, bowel,
lungs, cervix, etc.,
• Occur during vein blockage rather than
arterial blockage
Gas gangrene
• Special
form of wet gangrene
• Formed
by gas forming clostridia - G +ve
bacteria
• Gains
entry into open wounds
• Produces
toxins that causes necrosis and edema
Pathological calcification
• Deposition
of calcium in tissues other than bone and enamel
e.g. Kidney
stones
Two types
- Dystrophic
calcification- Deposition of calcium in dead and degenerated tissue
- Metastatic
calcification - In normal living tissues with deranged calcium metabolism
Apoptosis
• Co-ordinated,
internally programmed cell death
• Physiological
process - unwanted cells are eliminated
Changes occurring during apoptosis
– Shrinkage
of cells
– Formation
of membrane bound apoptotic body
– Condensation
of chromatin
– Phagocytosis
of apoptotic bodies by macrophages
– Proteolysis
of cytoskeleto proteins
Necrosis vs. Apoptosis
|
Necrosis |
Apoptosis |
|
Evoked by non-physiological disturbances (immune reaction, microbes,
hypoxia, ischemia & other poisons) |
Non physiological process Induced by stimuli like lack of growth factor, change in hormonal
environment |
|
Significant inflammatory response |
No inflammatory response |
|
Affects group of cells |
Affects individual cells |
|
Loss of membrane integrity |
Membrane blebbing, no loss of integrity |
|
Begins with swelling of cytoplasm & mitochondria |
Begins with shrinking of cytoplasm & condensation of nucleus |
|
Ends with total cell lysis |
Ends with fragmentation of cells in to smaller bodies |
|
No vesicle formation, complete lysis |
Formation of membrane bound vesicles, apoptotic body |
|
Disintegration |
Mitochondria becomes leaky due to pore formation |
|
Passive process, no requirement of ATP |
Energy dependent active process |
|
Post lytic DNA process |
Prelytic DNA fragmentation |
Summary
• Hypoxia
and ischemia causes cell injury
• If
hypoxia and ischemia persists for a long time, it results in irreversible cell
injury
• It
is associated with mitochondrial dysfunction, membrane damage, liberation of
hydrolytic enzymes
• Irreversible
cell injury brings about certain morphological changes like autolysis,
gangrene, necrosis, apoptosis
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