This document discusses etiology and pathogenesis of cell injury. It defines cell injury as changes in a cell's internal and external environment due to various stresses from etiological agents. The cellular response depends on host factors like cell type and extent of injury. Injury can result in reversible or irreversible cell injury depending on factors like agent type/duration and cell adaptability. Common causes of cell injury include hypoxia, ischemia, toxins, microbes, nutrition imbalances, and aging. Ischemia and hypoxia are the most frequent causes of cell injury in humans. Reversible injury involves ATP depletion and membrane changes, while irreversible injury brings further damage including to mitochondria and nuclei, leading to cell death.

1. Etiology
And
Pathogenesis

2.  “It is defined as the effect of variety of
stresses due to etiologic agents which a
cell encounters resulting in changes in its
internal and external environment.”
 The cellular response to stress may vary and depends
upon following two variables:
a) Host factors i.e. the type of cell and tissue involved
b) Factors related to injurious agents i.e. extent and type
of cell injury

3. Normal Cell
Adaptations
Reversible cell
injury
Irreversible cell
injury
Normal cell
restored
Stress removed
Atrophy ,
Hypertrophy ,
Hyperplasia etc.
Repair and
Healing
Stress removed
Degeneration,
Subcellular alterations,
Intracellular
accumulations
Cell Death
Due to severe ,
persistent
stress

4.  Hypoxia and ischaemia
 Physical agents
 Chemical agents and drugs
 Microbial agents
 Immunologic agents
 Nutritional derangements
 Ageing
 Psychogenic Diseases
 Iatrogenic causes
 Idiopathic Diseases

5.  Injury to normal cell by one or more of these etiologic
agents may result in state of reversible and irreversible
cell injury.
 Factors pertaining to host cells and etiologic agent
determine the outcome of cell injury:-
i. Type, duration and severity of injurious agent: e.g.
small dose of toxin or short duration of ischaemia cause
reversible cell injury while large dose or persistent
ischaemia cause cell death.
ii. Type, status and adaptability of target cell: e.g.
skeletal muscle can withstand hypoxic injury for long
time while cardiac muscle suffers irreversible cell injury
after persistent ischaemia

6.  The interruption of blood supply(ischaemia) and
impaired oxygen supply to tissues(hypoxia) are
most common form of cell injury in human
beings.
 Although underlying intracellular mechanisms
and ultrastructural changes seen in reversible and
irreversible cell injury by hypoxia-ischaemia are
continuation of the process, these mechanisms are
discussed separately.

7.  If ischaemia or hypoxia is of short duration the
effects may be reversible on rapid restoration of
circulation.
 The sequential and biochemical changes in
reversible cell injury are as under:
1) Decreased generation of cellular ATP:
Damage by ischaemia from interruption versus
hypoxia from other causes

9. 2) Nuclear clumping:
Due to intracellular lactic acidosis
3) Hydropic swelling and other membrane changes:
Damage to plasma membrane pumps i.e. failure
of Na-K Pump and Ca pump
4) Reduced protein synthesis:
As due to swelling ribosomes are detached from
RER and are dispersed in cytoplasm leading to
inactivation of their function

10.  Persistence of ischaemia or hypoxia results in
irreversible damage to the structure and function of the
cell(cell death).
 The stage at which this irreversibility is reached from
reversible cell injury is unclear but the sequence of
events is a continuation of reversibly injured cell.
 In addition, there is further reduction in ATP,
continued depletion of proteins, reduced intracellular
pH, and leakage of lysosomal enzymes into plasma.

11.  Effects on ultrastructural component of the
cell is as follows:
1) Membrane damage:
Increased cytosolic influx of calcium in cell
activates endogenous phospholipases. These,
in turn, degrade membrane phospholipids
which are the main constituent of lipid
bilayer membrane. Besides, there is also
decreased replacement-synthesis of
membrane phospholipids due to reduced
ATP.

13. 2) Mitochondrial damage:
Excess intracellular calcium collects in
mitochondria leading to the formation of
vacuoles and deposits of amorphous
calcium salts in the matrix.
3) Cytoskeletal damage:
Normal cytoskeleton of cell is damaged
due to degradation by activated
intracellular proteases.

15. 4) Nuclear Damage:
DNA or nucleoproteins are damaged by
activated lysosomal enzymes such as proteases
and endonucleases. Irreversible damage to
nucleus can be in 3 forms:
i. Pyknosis – condensation and clumping of
nucleus
ii. Karyorrhexis – nuclear fragmentation
iii. Karyolysis – dissolution of nucleus

16. 5) Lysosomal damage, cell
death and phagocytosis:
 The lysosomal membranes are damaged and results in
escape of lysosomal hydrolytic enzymes.
 These enzymes are activated due to lack of oxygen O2 in
the cell and acidic pH and on activation bring about
enzymatic digestion of cellular components and hence
cell death.
 The dead cell is replaced by masses of phospholipids
called myelin figures which are phagocytosed by
macrophages.

17.  Loss of Ca2+ homeostasis, often in the form of cytoplasmic
increases, leads to cell injury. Depending upon cell type
and the intensity of Ca2+toxicity, the ensuing pathology can
be reversible or irreversible. Although multiple destructive
processes are activated by Ca2+, lethal outcomes are
determined largely by Ca2+-induced mitochondrial
permeability transition. This form of damage is primarily
dependent upon mitochondrial Ca2+ accumulation, which
is regulated by the mitochondrial membrane potential.
Retention of the mitochondrial membrane potential
during Ca2+ increases favors mitochondrial Ca2+uptake and
overload, resulting in mitochondrial permeability
transition and cell death. In contrast, dissipation of
mitochondrial membrane potential reduces mitochondrial
Ca2+ uptake, retards mitochondrial permeability transition,
and delays death, even in cells with large Ca2+increases.

18. Textbook of Pathology…..(Harsh
Mohan) -Chapter -2
Google Images
https://en.wikipedia.org/wiki/Cell
_damage