CELL INJURY

MS FATIMA NASIM
LECTURER
UNIVERSITY OF LAHORE , ISLAMABAD CAMPUS
DEFINITION
 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.
 In general, cells of the body have inbuilt mechanism to
deal with changes in environment to an extent. The
cellular response to stress may vary and depends upon
following two variables:
i) Host factors i.e. the type of cell and tissue involved.
ii) 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
1. 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.
2. 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 categorized as under:

1. Hypoxia and ischemia

2. Physical agents
3. Chemical agents and drugs
4. Microbial agents
5. Immunologic agents
6. Nutritional derangements
7. Ageing
8. Psychogenic diseases
9. Iatrogenic factors
10. Idiopathic diseases.
Hypoxia
 Ischaemia
 Local e.g. embolus
 Systemic e.g. cardiac failure
 Hypoxaemia
 Oxygen problems e.g. altitude
 Haemoglobin problems e.g. anaemia
 Oxidative phosphorylation
 E.g. cyanide poisoning
Physical agents
 Direct Physical Effects
 Exposure of tissue to extreme heat or cold results in direct
injury that is often irreversible, resulting in a pattern of
coagulative necrosis .
 Sudden changes in pressure can cause cellular disruption
(e.g. a hammer blow to the thumb).
 Electrical currents can cause direct breakdown of
cellular membranes that may be irreversible.
 mechanical trauma (e.g. road accidents)
 thermal trauma (e.g. by heat and cold);
 Electricity
 radiation (e.g. ultraviolet and ionising); and
 rapid changes in atmospheric pressure.
Chemical agents and drugs
 Many of the common poisons (arsenic, cyanide, mercury)
interfere with cellular metabolism.
 If ATP levels drop below critical levels, affected cells will die.
List of chemical agents:
i)strong acids and alkalis
ii) environmental pollutants
iii) insecticides and pesticides
iv) oxygen at high concentrations
v) hypertonic glucose and salt
vi) alcohol and narcotic drugs

Example: Metabolism of alcohol (a type of drug) to acetaldehyde

Microbial agents
 Fungi, Rickettsiae, Bacteria and Viruses
 E.g.
viruses can take over protein translation
machinery and subvert it entirely to the production of
new virions.
Immunologic agents
 Immunity protects the host against various injurious agents
but it may also turn lethal and cause cell injury e.g.
i) hypersensitivity reactions;
ii) anaphylactic reactions; and
iii) autoimmune diseases.
 Inflammatory mediators such as interferons and
interleukins can alter both gene expression and cellular
metabolism. The effects are designed to help cells
combat an infectious process, but the resulting stress to
the cells can be highly injurious and sometimes deadly.
 Activation of complement can result in direct attack on a
cell's surface membrane.
 Cytotoxic T-cells and NK cells can mediate a direct
attack on a target cells and initiate the self-destruct
cascade within a target cell.
Nutritional Derrangements
 Dietary insufficiency of protein, vitamins and/or
minerals can lead to injury at the cellular level due to
interference in normal metabolic pathways.
 Dietary excess can likewise lead to cellular and tissue
alterations that are detrimental e.g. fat is the biggest
offender, or excess ingestion of "health supplements"
Ageing
 Cellular ageing leads to impaired ability of the cells to
undergo replication and repair, and ultimately lead to
cell death culminating in death of the individual.
Psychogenic diseases
 There are no specific biochemical or morphologic changes in
common acquired mental diseases due to mental stress, strain,
anxiety, overwork and frustration e.g. depression, schizophrenia
 However, problems of drug addiction, alcoholism, and smoking
result in various organic diseases such as liver damage, chronic
bronchitis, lung cancer, peptic ulcer, hypertension, ischaemic
heart disease etc
Iatrogenic causes
 there are some diseases as well as deaths attributed to
iatrogenic causes (owing to physician).
 Examples include occurrence of disease or death due to
error in judgment by the physician and untoward effects
of administered therapy (drugs, radiation).
Idiopathic diseases

 Idiopathic means “of unknown cause” .

 Finally, although so much is known about the etiology
of diseases, there still remain many diseases for which
exact cause is undetermined. For example, most
common form of hypertension (90%) is idiopathic
hypertension.
 Similarly, exact etiology of many cancers is still
incompletely known.
Principle structural targets for cell
damage
 Cell membranes
 Plasmamembrane
 Organelle membranes
 DNA
 Proteins
 Structural
 Enzymes
 Mitochondria
 oxidative phosphorylation
General Pathogenesis of Cell injury
 Following common scheme applies to most forms of cell
injury by various agents:
 Factors pertaining to etiologic agent and host
 Common underlying mechanisms
 Usual morphologic changes
 Functional implications and disease outcome
1. Factors pertaining to etiologic
agent and host
 i) Type, duration and severity of injurious agent
 small dose of chemical toxin or short duration of
ischaemia cause reversible cell injury while large dose of
the same chemical agent or persistent ischaemia cause
cell death.
ii) Type, status and adaptability of target cell
 Skeletal muscle can withstand hypoxic injury for long-
time while cardiac muscle suffers irreversible cell injury
after persistent ischaemia due to total coronary
occlusion >20 minutes.
2. Common underlying
mechanisms
 Irrespective of other factors, following essential
intracellular biochemical phenomena underlie all forms
of cell injury:

i) Cell membrane damage disturbing the metabolic and

trans-membrane exchanges.
ii) Release of toxic free radicals.
3. Usual morphologic changes
 Biochemical and molecular changes underlying cell
injury from various agents become apparent first, and
are associated with appearance of ultrastructural
changes in the injured cell.
 However, eventually, gross and light microscopic
changes in morphology of organ and cells appear.
 The morphologic changes of reversible 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
 cell injury affects cellular function
 clinical features in the form of symptoms and signs would
appear.
 Further course or prognosis will depend upon the
response to treatment versus the biologic behaviour of
disease.
 The interruption of blood supply (i.e. ischaemia) and
impaired oxygen supply to the tissues (i.e. hypoxia) are
most common form of cell injury in human beings.
PATHOGENESIS OF HYPOXIA
A) 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.
1. Decreased generation of cellular ATP:
Damage by ischaemia from interruption
versus hypoxia from other causes
 ATP is 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 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.
 Early fall in intracellular pH (i.e. intracellular lactic acidosis)
results in clumping of nuclear chromatin.
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 as
under:
i) Failure of sodium-potassium pump Normally, the
energy (ATP)-dependent sodium pump (also called Na+-
K+ ATPase) operating at the plasma membrane allows
active transport of sodium out of the cell and diffusion of
potassium into the cell.
 Lowered ATP in the cell lowers the activity of sodium
pump and consequently interferes with this membrane-
regulated process. This results in intracellular accumulation
of sodium and diffusion of potassium out of the cell.
 The accumulation of sodium in the cell leads to increase
in intracellular water to maintain iso-osmotic conditions
ii) Failure of calcium pump Membrane damage causes
disturbance in the calcium ion exchange across the cell
membrane.
 Excess of calcium moves into the cell (i.e. calcium influx),
particularly in the mitochondria, causing its swelling
and deposition of phospholipid-rich amorphous densities.
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.
 Ultra structural 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; these are derived from
membranes (plasma or organellar) enclosing water and
dissociated lipoproteins between the lamellae of injured
membranes.
 Up to this point, withdrawal of acute stress that resulted
in reversible cell injury can restore the cell to normal
state.
PATHOGENESIS OF HYPOXIA
Irreversible
 Massiveintra-cytoplasmic calcium accumulation
 Enzyme activation
IRREVERSIBLE CELL INJURY
 Persistence of ischaemia or hypoxia results in irreversible
damage to the structure and function of the cell (cell death).
 the sequence of events is a continuation of reversibly injured
cell.
 Two essential phenomena always distinguish irreversible from
reversible cell injury.
 Inability of the cell to reverse mitochondrial dysfunction on
reperfusion or reoxygenation
 Disturbance in cell membrane function
In addition, there is further reduction in ATP, continued
depletion of proteins, reduced intracellular pH, and leakage
of lysosomal enzymes into the plasma.
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.
 Excess intracellular calcium collects in the mitochondria
disabling its function. Morphological changes are in the
form of vacuoles in the mitochondria and deposits of
amorphous calcium salts in the mitochondrial matrix.
2. Activated phospholipases: Membrane
damage
 Damage to plasma membrane in particular, is the most
important event in irreversible cell injury.
 Increased cytosolic influx of calcium in the cell activates
endogenous phospholipases. These, in turn, degrade
membrane phospholipids progressively which are the
main constituent of the lipid bilayer membrane.
 Besides, there is also decreased replacement-synthesis
of membrane phospholipids due to reduced ATP. Other
lytic enzyme which is activated is ATPase which causes
further depletion of ATP.
3. Intracellular proteases: Cytoskeletal
damage
 The normal cytoskeleton of the cell (microfilaments,
micro tubules 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 of nucleus which

becomes dark basophilic.
ii) Karyorrhexis: Nuclear fragmentation in to small bits
dispersed in the cytoplasm.
iii) Karyolysis: Dissolution of the nucleus.

 Damaged DNA activates proapoptotic proteins leading

the cell to death.
5. Lysosomal hydrolytic enzymes: Lysosomal
damage, cell death and phagocytosis
 The lysosomal membranes are damaged and result in escape of
lysosomal hydrolytic enzymes.
These enzymes are activated due to lack of oxygen in the cell
and acidic pH.
 These hydrolytic enzymes: (e.g. hydrolase, RNAase,
DNAase, protease, glycosidase, phosphatase, lipase, amylase,
etc) on activation bring about enzymatic digestion of cellular
components and hence cell death.
 The dead cell is eventually replaced by masses of phospholipids
called myelin figures which are either phagocytosed by
macrophages or there may be formation of calcium soaps.
 Liberated enzymes just mentioned leak across the
abnormally permeable cell membrane into the serum, the
estimation of which may be used as clinical parameters of cell
death.
 For example, in myocardial infarction, estimation of
elevated serum glutamic oxaloacetic transaminase (SGOT),
lactic dehydrogenase (LDH), isoenzyme of creatine kinase
(CK-MB), and cardiac troponins (are useful guides for
death of heart muscle.
 While cell damage from oxygen deprivation by above
mechanisms develops slowly, taking several minutes to hours,
the cell injury may become prominent after restoration of blood
supply and subsequent events termed ischaemic-reperfusion
injury and liberation of toxic free radicals (or reactive oxygen
species.