CELL INJURY
Cell injury is defined as the effect of a variety of stresses due to etiologic
agents 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:-
- Host factors i.e. the type of cell and tissue involved.
- Factors pertaining to injurious agent i.e. extent and type of cell injury.
Various forms of cellular responses to cell injury may be as follows:-
- When there is increased functional demand, the cell may adapt to the
changes which are expressed morphologically, which then revert back to
normal after the stress is removed (cellular adaptations).
- When the stress is mild to moderate, the injured cell may recover
(reversible cell injury), while persistent and severe form of cell injury may
cause cell death (irreversible cell injury).
3. The residual effects of reversible cell injury may persist in the cell
as evidence of cell injury at subcellular level (subcellular changes), or
metabolites may accumulate within the cell (intracellular accumulations).
ETIOLOGY OF CELL INJURY:-
The cells may be broadly injured by two major ways:
A. Genetic causes
B. Acquired causes
The acquired causes of disease comprise vast majority of common
diseases afflicting mankind. Based on underlying agent, the acquired causes
of cell injury can be further categorised as under:
1. Hypoxia and ischaemia.
2. Physical agent.
3. Chemical agents and drugs.
4. Microbial agent.
5. Immunologic agents.
6. Nutritional derangements.
7. Ageing.
8. Psychogenic diseases.
9. Iatrogenic factors.
10. Idiopathic diseases.
PATHOGENESIS OF CELL INJURY:-
The underlying alterations in biochemical systems of cells for reversible and irreversible cell injury by various agents are complex and varied. However, in
general, irrespective of the type, following common scheme applies to most
forms of cell injury by various agents.
1.Factors pertaining to etiological agent and host (A)Type duration and severity of injurious agents; (B) Type, status and adaptability of target cell.
2.Common underlying mechanisms Irrespective of other factors,
following essential intracellular biochemical phenomena underlie all forms of
cell injury: (A) Mitochondrial damage causing ATP depletion. (B) Cell membrane damage disturbing the metabolic and trans-membrane
exchanges. (C) Release of toxic free radicals.
3. Usual morphologic changes The morphologic changes of rever
-
sible cell injury (e.g. hydropic swelling) appear earlier while later morphologic
alterations of cell death are seen (e.g. in myocardial infarction).
4. Functional implications and disease outcome Eventually, cell
injury affects cellular function adversely which has bearing on the body. Consequently, clinical features in the form of symptoms and signs would
appear.
PATHOGENESIS OF ISCHAEMIC AND HYPOXIC INJURY
Ischaemia and hypoxia are the most common forms of cell injury. Although
underlying intracellular mechanisms and ultrastructural changes seen
in reversible and irreversible cell injury by hypoxia-ischaemia (depending
upon extent of hypoxia and type of cells involved) are a continuation of the
process, these mechanisms are discussed separately below.
REVERSIBLE CELL INJURY :- If the ischaemia or hypoxia is of short
duration, the effects may be reversible on rapid restoration of circulation
e.g. in coronary artery occlusion, myocardial contractility, metabolism
and ultrastructure are reversed if the circulation is quickly restored. The
sequential biochemical and ultrastructural changes in reversible cell injury
are as under.
1. Decreased generation of cellular ATP: Damage by ischaemia from
interruption versus hypoxia from other causes All living cells require
continuous supply of oxygen to produce ATP which is essentially required for
a variety of cellular functions (e.g. membrane transport, protein synthesis,
lipid synthesis and phospholipid metabolism). ATP in human cell is derived
from 2 sources:
” Firstly, by aerobic respiration or oxidative phosphorylation (which
requires oxygen) in the mitochondria.
” Secondly, cells may subsequently switch over to anaerobic glycolytic
oxidation to maintain constant supply of ATP (in which ATP is generated from
glucose/glycogen in the absence of oxygen).
Ischaemia due to interruption in blood supply as well as hypoxia from
other causes limit the supply of oxygen to the cells, thus causing decreased
ATP generation from ADP:
” In ischaemia from interruption of blood supply, aerobic respiration
as well as glucose availability are both compromised resulting in more
severe and faster effects of cell injury. Ischaemic cell injury also causes
accumulation of metabolic waste products in the cells.
” On the other hand, in hypoxia from other causes (RBC disorders, heart
disease, lung disease), anaerobic glycolytic ATP generation continues, and
thus cell injury is less severe.
However, highly specialised cells such as myocardium, proximal tubular
cells of the kidney, and neurons of the CNS are dependent solely on aerobic
respiration for ATP generation and thus these tissues suffer from ill-effects of
ischaemia more severely and rapidly.
2. Intracellular lactic acidosis: Nuclear clumping Due to low oxygen
supply to the cell, aerobic respiration by mitochondria fails first. This is
followed by switch to anaerobic glycolytic pathway for the requirement of
energy (i.e. ATP). This results in rapid depletion of glycogen and accumulation of lactic acid lowering the intracellular pH.
3. Damage to plasma membrane pumps: Hydropic swelling and
other membrane changes Lack of ATP interferes in generation of
phospholipids from the cellular fatty acids which are required for continuous
repair of membranes. This results in damage to membrane pumps operating
for regulation of sodium-potassium and calcium.
4. Reduced protein synthesis: Dispersed ribosomes As a result
of continued hypoxia, membranes of endoplasmic reticulum and Golgi
apparatus swell up. Ribosomes are detached from granular (rough)
endoplasmic reticulum and polysomes are degraded to monosomes, thus
dispersing ribosomes in the cytoplasm and inactivating their function. Similar
reduced protein synthesis occurs in Golgi apparatus.
Ultrastructural evidence of reversible cell membrane damage is seen in
the form of loss of microvilli, intramembranous particles and focal projections
of the cytoplasm (blebs). Myelin figures may be seen lying in the cytoplasm
or present outside the cell.
Up to this point, withdrawal of acute stress that resulted in reversible
cell injury can restore the cell to normal state.
IRREVERSIBLE CELL INJURY :- Persistence of ischaemia or hypoxia
results in irreversible damage to the structure and function of the cell (cell
death). Two essential phenomena always distinguish irreversible from rever
-
sible cell injury
.
” Inability of the cell to reverse mitochondrial dysfunction on reperfusion
or reoxygenation. ” Disturbance in cell membrane function in general, and in plasma
membrane in particular.
In addition, there is further reduction in ATP, continued depletion of
proteins, reduced intracellular pH, and leakage of lysosomal enzymes into
the plasma. These biochemical changes have effects on the ultrastructural
components of the cell.
1. Calcium influx: Mitochondrial damage As a result of continued hypoxia , a large cytosolic influx of calcium ions occurs, especially after reperfusion of irreversibly injured cell.
2. Activated phospholipases: Membrane damage Damage to
membrane function in general, and plasma membrane in particular, is the
most important event in irreversible cell injury. Increased cytosolic influx of calcium in the call activates endogenous phospholipases. These , in turn, degrade membrane phospholipids progressively which are the main constituents of the lipid bilayer membrane.
3. Intracellur proteases: cytoskeletan damage the normal cytoskeleton of the cell (microfilaments , microtubules and intermediate filaments) which anchors the cell membrane is damaged due to degradation by activated intracellular proteases or by physical effect of cell swelling producing irreversible cell membrane injury.
4. Activated endonucleases: Nuclear damage DNA or nucleoproteins
are damaged by the activated lysosomal enzymes such as proteases and
endonucleases. Irreversible damage to the nucleus can be in three forms:
i) Pyknosis: Condensation and clumping
ii) Karyorrhexis: Fragmentation
iii) Karyolysis: Dissolution.
5. Lysosomal hydrolytic enzymes: Lysosomal damage, cell death
and phagocytosis The lysosomal membranes are damaged and result
in escape of lysosomal hydrolytic enzymes. The dead cell is eventually rep
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laced by masses of phospholipids called myelin figures which are either
phagocytosed by macrophages or there may be formation of calcium soaps.
Liberated enzymes leak across the abnormally permeable cell
membrane into the serum, the estimation of which may be used as clinical
parameters of cell death.
