Dr. Temur Ahsan Khan
Cells and tissues undergo a number of
responses according to intensity and
duration of pathological conditions and
injuries
1.
Cellular adaptations-----hypertrophy,
atrophy, hyperplasia, metaplasia etc
2.
Regressive changes (degeneration)---swelling (hydropic degeneration) and
steatosis (fatty Change)
3.
Cell death (necrosis) and apoptosis
(programmed cell death)
1.
2.
3.
4.
Coagulative
Liquefactive or lytic
Caseous
Fat necrosis



1.
2.
3.
Same as general causes of disease.
A very common cause of cell injury is hypoxia and
anoxia (ischemia)
Combination of hypoxia /anoxia are:
Anoxic anoxia---inadequate oxygen in the
presence of circulation for example in anaemia,
pneumonia, liver necrosis, congestion etc.
Ischemic anoxia---due to decrease or stoppage
of arterial blood flow as in embolism, thrombism
and infarction.
Cytoxic anoxia---there is interference with O2
utilization as seen in cyanide poisoning.
Sensitivity to anoxia varies in different tissues,
for example following loss of blood supply
neurons die within 3-5 minutes, myocardium,
hepatocytes and several epithelial cells
between 30 minutes to two hours and
fibroblasts, epidermis and skeletal muscles
survive for several hours.
1.
2.
3.
4.
Plasma membranes---cause leakage
Mitochondria---depletion of ATP
Synthesis of proteins in rough endoplasmic
reticulum is stopped.
Preservation of integrity of genetic
apparatus is compromised.
ATP depletion
(a) All energy requiring functions stop, H2O,
Na+ and Ca2+ go inside the cell and K+
comes out.
(b) Energy is derived through anaerobic
glycolysis which causes accumulation of
lactic acid and lowering of pH.
1.
2.Generation of oxygen derived free radicals

Supereoxide anion, hydroxyl radical,
hydrogen peroxide, nitric oxide, carbon
tetrachloride.

Volatile and tissue destructive.

Important mechanism in radiation injury,
killing of bacteria by leucocytes etc.

Generated during metabolism of oxygen
and mitochondrial electron transport.



Free radicals oxidize proteins, membranes,
genetic material and unsaturated fatty acidsperoxidation of fat—autocatalysis
Antioxidants– superoxide dismutase,
hydrogen peroxide, catalase, glutathione
peroxidase, selenium and vitamin E
Oxidative stress: imbalance between free
radical generation and their removal /
inactivation.
3. Loss of calcium homeostasis: accumulation of
calcium in cytosol has the following serious
consequences and eventually causes cell death:
 (a) uncoupling of gap junctions, isolation and
dissociation of injured cells
 (b) depolymerization of cytoskeleton i.e.
micrifilaments and microtubules. Cytoskeleton
disappears from the periphery of the cell. The
cell cannot perform its function of movement,
phagocytosis and secretion and it looses shape
(become rounded)
 (c) activation of endogenous phospholipases
which cause breakdown of cell membranes.
4. defects in membrane permeability
 Caused directly by bacterial toxins, viral
proteins, complement components and
cytoxic lymphocytes etc.
 Caused indirectly by loss of ATP and enzymes
activated by Ca2+ like phospholipases
5. mitochondrial damage
Several mechanisms
 Increased cytosolic Ca2+ and oxidative stress
 Formation of high conductance channels
As the injured cell die, proteins and other large
molecules present in the cell escape into the
interstitium and then into the blood circulation.
Necrosis in the following tissues releases specific
enzymes into the blood and these can be
assayed to determine the extent of damage:
 Heart---creatine kinase (CK)
 Skeletal muscle---asparatate aminotransferase
(AST) and CK isoform
 Liver ---alanine aminotransferase (ALT) and
AST
 Pancreas---pancreatic specific lipase.
General
Pathology
(PATH 303)
Lecture # 4

Common Biochemical Mechanisms
of Cell Injury
(Contd.)
1. Mechanisms of injury caused by free
radicals:
Lipid peroxidation of plasma and cell membranes
 Attack double bond in unsaturated fatty acids
 Autocatalytic chain reaction
Cross-linking of proteins
 Inactivate sulphydryl enzymes
 Form disulphide bonds
DNA fragmentation
 React on thymine in DNA
 Cause mutation and fragmentation
2. Loss of calcium homeostasis

Increase in cytosolic Ca
o
o





Influx from outside
Release from mitochondria
Activates phospholipase, protease,
ATPase, endonuclease
Depolymerization of cytoskeleton
Inhibits cell movement
Inhibits phagocytosis
Inhibits secretion
3. Defects in membrane permeability

Directly damaged by:
o
Bacterial toxins
Viral proteins
Complement component
Cytotoxic lymphocytes etc.

Indirectly damaged by:
o
o
o


Loss of ATP synthesis
Activation of phospholipase by Ca
4. Mitochondrial damage

Irreparable damage to mitochondria causes
cell death.

By increased cytosolic Ca, oxidative stress,
breakdown of phospholipids.


Formation of high conductive channels
Leakage of proteins and cytochrome C
5. Lysosomes, heterophagy and autophagy





Primary lysosomes contain hydrolytic enzymes
Fuse with phagosomes to produce phagolysosomes
and cause break down of ingested material
Heterophagy --- endocytosis of particulate matter
from outside e.g. bacteria; --- pinocytosis – uptake
of soluble macromolecules.
Autophagy: Removal of damaged or senescent
organelles by autophagic vacuoles formed from RER.
Fuse to form autophagolysosomes.
6. Cellular swelling

Disturbance of cellular metabolism leads to cellular
swelling.

Causes: Toxins, temperature, metabolic diseases, poisons,
hypoxia

Gross appearance: Organ enlarged, increased weight, edges
become rounded, cut surface bulges, capsule retracts.

Microscopic appearance: Seen in cells of liver, kidney,
cardiac and skeletal muscles. Cells are larger in size.
Cytoplasm stains darker and appears granular.

Significance: Reversible caused by mild injury--disappears when the cause is removed.
7. Hydropic degeneration

Similar to but more severe than acute cellular swelling.
Water enters the cells and dilutes cytoplasm. Protease
clears the cytoplasm.

Causes: Mechanical (rubbing) injuries, thermal injuries,
chemical agents; infectious agents - some neoplasm.

Grossly: Blisters are circumscribed, raised area, fluctuating,
filled with fluid

Microscopic: Water accumulates in endoplasmic reticulum
forming clear vacuoles, ballooning degeneration - Fuse and
rupture to form bullae and vesicles.

Significance: If uncomplicated, it heals quickly without scar
formation.

Secondary infections cause abscessation.