2. Learning objectives:
General principles of cell injury
Concept of reversible & irreversible damage
Ischemic and chemical injury models
Discuss the point of no return, i.e. cell death
3. Summary !
• All human disease occur because of cell / tissue injury,
Virchow’s concept of cellular pathology
• Both plasma and mitochondrial membranes are key targets
• Many early steps are reversible
• Cell death seems to follow a point of no return
(i.e. irreversible injury) with drop in pH, rise in Ca2+
4. • Causes of cell injury range from gross mechanical external
causes such as trauma to subtle endogenous causes as
genetic lack of enzymes etc.
Epidural bleeding (hematoma) Subdural bleeding (hematoma)
5. • Under normal conditions, the cells are in:
homeostastatic steady state, (homeostasis)
• Normal cell is confined to relatively narrow range of functions
and structure by its genetic programme to handle normal
physiologic demands,
• Virtually all forms of tissue injuries start with molecular or
structural alterations in cells
7. Ischemia & hypoxia
• Hypoxia denotes decrease of oxygen supply and is the most common
cause of cell injury. It occurs usually as a result of ischemia (loss of blood
supply),
• Most common cause of ischemic hypoxia is narrowing of muscular arteries
due to atherosclerosis and/or thrombosis,
• Hypoxia in cardiorespiratory failure is due to inadequate oxygenation
• In anemia, methemoglobinemia or in carbon monoxide (CO) poisoning
there is decreased oxygen carrying capacity of the blood so that less
oxygen is delivered to the tissues
8. Genetic defects
• Genetic injury may result in severe defects and congenital
malformations (e.g. Down syndrome) or derangements and
errors of metabolism (lack of a distinctive enzyme ), etc.
The congenital form of methemoglobinemia
has an autosomal recessive pattern of inheritance.
Down syndrome (DS) or Down's syndrome, also known as
trisomy 21, is a genetic disorder caused by the presence of all
or part of an excess (third) copy of chromosome 21
9. Epidural bleeding (hematoma) Subdural bleeding (hematoma)
Many forms of physical energy may give rise to cell and tissue injury, such
as mechanical trauma, extremes of temperature, sudden changes in
atmosphere pressure, electromagnetic energy, radiation and electric shock
The most important and frequent in clinical practice are result of
mechanical forces, i.e. trauma (e.g. traffic accidents)
Physical agents
10. Physical agents
• Changes in atmosphere pressure and hypotermia are relatively
uncommon causes of injury, but hypertermia (burns) are more
commonly seen
• Radiation injury has also assumed importance as potential causes of
widespread destruction
11. Chemical agents
The list of chemicals that may cause cell injury is wide,
*Alcohol and narcotics
*Poisons and toxic chemicals,
*e.g. arsenic, cyanide, mercuric salts,etc
*Air pollutants, insecticides and herbicides
*Various therapeutic & illicit drugs, and even oxygen
12. Nutritional imbalances
• Protein-calorie deficiencies chiefly among underprivileged
populations besides deficiencies of specific vitamins and
nutrients such as vitamins A, B, C, D, iodine
• Nutritional excesses have become important in cell injury
among populations (excess in lipids predispose to
atherosclerosis, cause obesity and metabolic syndrome
along with diabetes mellitus)
13. Immunologically mediated
• Immune system defends against biologic agents however
immune reactions may cause cell injury
• Hypersensitivity reactions such as anaphylaxis due to a
foreign proteins or chemicals.
• Autoimmune diseases result from reactions to endogenous
self-antigens
14.
15.
16. Microbiologic (infectious)agents
• These agents range from the viruses, rickettsiae to bacteria,
fungi and higher forms of parasites
• Besides harming the host cells these agents also initiate
several inflammatory reactions
21. General principles of cell injury
Cell response to injurious stimuli depends on:
1. Type of injury, its duration, and its severity
2. Type, status, adaptability, metabolic demand & genetic
features of the injured cell
3. Nutritional (or hormonal) status of the cell :
e.g., a cell rich in glycogen will tolerate ischemia
better than that has less energy storage
22. 4 weak points of the cell
Cell membrane integrity is critical to cellular ionic and
osmotic homeostasis
ATP energy synthesis; largely through mitochondrial
aerobic respiration
Protein synthesis through RER
Integrity of the genetic apparatus (nucleus)
23. Basic mechanisms of cell damage
• Mitochondrial damage, depletion of ATP
• Influx of intracellular calcium, loss of Ca2+ homeostasis
• Accumulation of oxygen-derived free radicals
• (oxidative stress)
• Defects in membrane permeability
24.
25. The structural and biochemical components of a cell are so
integrally connected that regardless of the initial locus of
injury, multiple secondary effects occur
(Ripple effect)
26.
27. Cell Injury
Loss of cell functions e.g. myocardial cells lose power of contraction after 1-2
minutes of injury
Death of cells e.g. myocardial cells die after 20 to 30 minutes of ischemia
Ultrastructural (electron microscopic ) changes in the dead myocardium
become visible 2-3 hrs after ischemic injury
Light microscopic changes in the dead myocardium become visible 6-12 hrs
Time lag between
different events
after cell injury
Gross (naked-eye) changes occur after another few hours
28. Morphology of Cell Injury
and Necrosis
• Cell injury – Reversible
– Irreversible
• Cell death – Necrosis
– Apoptosis
29. Reversible Injury
• Gross Findings
• Pallor, increased turgor, and increased in weight.
At the light microscopic level Critical changes are limited mainly
to the cytoplasm cell swelling (hydrophic change) or vacuolar
degeneration develops due to decreased function of ATP
dependant pumps
Later there is accumulation of lipid vacuoles in the cytoplasm:
fatty change
30. Hydrophic change (vacuolar degeneration)
• This is the first manifestation of almost all forms of reversible
cell injury. Increasing hydration of the cell due to alteration in ion
transport at cell membrane may be due to various causes such
as infections, physico-chemical injury (toxic) or ischemia.
• Hydropic change or vacuolar degereration appears whenever
cells are incapable of maintaining ionic and fluid homeostasis.
31. •organ swollen with rounded edges.
•cut surface: tissue bulges and wet / heavy.
Hydrophic change (vacuolar degeneration)
Normal kidney
35. Ischemia vs Hypoxia
• Loss of blood supply resulting in
reduced O2 as well as reduced
delivery of other nutrients
• Reduced removal of toxic waste
products of the cells so there is
accumulation of toxic substances, e.g
lactic acid
• Quicker and more severe injury than
with just lack of oxygen (hypoxia)
• Lack of Oxygen in tissues
• Maybe due to ischemia or due
to other causes like due to less
RBCs in the blood, or less
oxygen in the atmosphere etc.
• Less severe injury than with
Ischemia
37. • Reversible hypoxic / ischemic injury
Loss of ATP generation by mitochondria initially results in
reversible events:
o Na+/K+ ATPase membrane pump leads to a loss of ionic
o and osmotic gradient ( increased Ca2+ Na+, decreased K+ and
osmotic gain of water) resulting cell swelling & ER dilatation)
o Reduced anaerobic glycolysis results in glycogen depletion
o and lactic acid accumulation (decrease in pH),
o Reduced protein synthesis due to ribosome detachment from
o the RER
38. Irreversible hypoxic / ischemic injury
• These changes are reversible if O2 and flow are reinstated, the
transition to irreversible injury depends on the extent of ATP
depletion and membrane dysfunction especially of mitochondria.
• ATP depletion results in Mitochondrial Permeability Transition (MPT)
with loss of the H+ gradient
• ATP depletion releases cytochrome c that can induce apoptosis
39. Irreversible hypoxic/ ischemic injury
• Increased Ca2+ activates membrane phospholipases with
resulting membrane damage
• Membrane phospholipid degradation products that accumulate
are directly toxic to the cell
• Activated intracellular proteases lead to cytoskeletal degradation
40.
41.
42. Effects of excess
calcium in the cytosol
Where is the cut-off
point between reversible
and irreversible (lethal)
injury, i.e. cell death ?
53. Irreversible cell injury leads to cell death
resulting in two final events:
•Necrosis
•Apoptosis
54. • Irreversible injury (necrosis)
o Two basic processes underlie the morphologic
changes of necrosis
*Denaturation of proteins
*Enzymatic digestion of cell components