Cell Injury

Download as pdf or txt
Download as pdf or txt
You are on page 1of 8

1

Basic principles of Cell injury and Adaptation

DEFINITION OF PATHOLOGY
The word ‘Pathology’ is derived from two Greek words—pathos meaning
suffering, and logos meaning study. Pathology is, thus, scientific study of
structure and function of the body in disease; or in other words, pathology
consists of the abnormalities that occur in normal anatomy (including
histology) and physiology owing to disease.
Another commonly used term with reference to study of diseases is
‘pathophysiology’ comprised by two words: patho=suffering;
physiology=study of normal function. Pathophysiology, thus, includes
study of disordered function or breakdown of homeostasis in diseases.

Cell injury is defined as a variety of stresses a cell encounters as a result of


changes in its internal and external environment.
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 the
following variables:
1. The type of cell and tissue involved.
2. 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 and then revert back to
normal after the stress is removed (Cellular adaptation)
2. When the stress is mild to moderate, the injured cell may recover
(reversible cell injury), while when the injury is persistent cell death
may occur (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)
2

ETIOLOGY OF CELL INJURY


The cells may be broadly injured by two major ways:
 By genetic causes
 By acquired causes
GENETIC CAUSES
 Developmental defects: Errors in morphogenesis
 Cytogenetic (Karyotypic) defects: chromosomal abnormalities.
 Single-gene defects: Mendelian disorders
 Multifactorial inheritance disorders
ACQUIRED CAUSES
 Hypoxia and ischaemia
 Physical agents.
 Chemical agents and drugs
 Microbial agents
 Immunologic agents
 Nutritional derangements
 Aging
 Psychogenic diseases
 Iatrogenic factors
 Idiopathic diseases.
HYPOXIA AND ISCHAEMIA.
Hypoxia is the most common cause of cell injury. Hypoxia may result from
the following
3

 The most common mechanism of hypoxic cell injury is by reduced


supply of blood to cells due to interruption i.e. ischaemia.
 Hypoxia may result from other causes as well e.g. disorders of oxygen-
carrying RBCs (e.g. anaemia, carbon monoxide poisoning), heart
diseases, lung diseases and increased demand of tissues.
PHYSICAL AGENTS
 Mechanical trauma (e.g. road accidents);
 Thermal trauma (e.g. by heat and cold);
 Electricity;
 Radiation (e.g. ultraviolet and ionising);
 Rapid changes in atmospheric pressure.
CHEMICALS AND DRUGS.
Chemical agents and drugs may cause cell injury are
 Chemical poisons such as cyanide, arsenic, mercury;
 Strong acids and alkalis;
 Environmental pollutants;
 Insecticides and pesticides;
 Oxygen at high concentrations;
 Hypertonic glucose and salt;
 Social agents such as alcohol and narcotic drugs
 Therapeutic administration of drugs.
MICROBIAL AGENTS
Injuries by microbes include infections caused by bacteria, rickettsiae,
viruses, fungi, protozoa, metazoa, and other parasites.
IMMUNOLOGIC AGENTS
Immunity is a ‘double edged sword’—it protects the host against various
injurious agents but it may also turn lethal and cause cell injury
e.g. hypersensitivity reactions; anaphylactic reactions; and autoimmune
diseases.
NUTRITIONAL DERANGEMENTS
A deficiency or an excess of nutrients may result in nutritional imbalances.
 Nutritional deficiency diseases may be due to overall deficiency of
nutrients (e.g. starvation), of protein calorie (e.g. marasmus,
kwashiorkor), of minerals (e.g. anaemia), or of trace elements.
 Nutritional excess is a problem of affluent societies resulting in obesity,
atherosclerosis, heart disease and hypertension.
4

AGING.
Cellular aging or senescence 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.
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.
Occurrence of disease or death due to error in judgment by the physician and
untoward effects of administered therapy.
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 (or essential) hypertension. Similarly, exact
etiology of many cancers is still incompletely known.

PATHOGENESIS OF CELL INJURY


The following principles apply in pathogenesis of most forms of cell injury by
various agents
1. Type, duration and severity of injurious agent
2. Type, status and adaptability of target cell
3. Underlying intracellular phenomena
PATHOGENESIS OF ISCHAEMIC AND HYPOXIC INJURY
The intracellular mechanisms and ultrastructural changes involved in
reversible and irreversible cell injury by hypoxia and ischaemia depending
upon extent of hypoxia and type of cells are involved are a continuation of the
process.
REVERSIBLE CELL INJURY
The sequential biochemical and ultrastructural changes in reversible cell
injury are
1. Decreased generation of cellular ATP: Damage by ischaemia versus
hypoxia from other causes
5

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, 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.

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 and calcium as under:

 Failure of sodium-potassium pump


The energy (ATP)-dependent sodium pump (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 and consequent increased ATPase activity
interfere with this membrane-regulated process. This results in
intracellular accumulation of sodium and diffusion of potassium
out of cell. The accumulation of sodium in the cell leads to
increase in intracellular water to maintain isoosmotic condition

 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
6

The membranes of endoplasmic reticulum and Golgi apparatus swell


up. Ribosomes are detached from granular endoplasmic reticulum and
polysomes are degraded to monosomes, thus dispersing ribosomes in
the cytoplasm and inactivating their function.

The 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). The stage at which this point of
no return or irreversibility is reached from reversible cell injury is unclear but
the sequence of events is a continuation of reversibly injured cell.
 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
There is further reduction in ATP, continued depletion of proteins, reduced
intracellular pH, and leakage of lysosomal enzymes into the cytoplasm. These
biochemical changes have effects on the ultrastructural components of the
cell.
7

1. Calcium influx: Mitochondrial damage.


As a result of continued hypoxia, a large cytosolic influx of calcium ions
occurs. Excess intracellular calcium collects in the mitochondria
disabling its function. Morphologically, mitochondrial changes are
vacuoles in the mitochondria and deposits of amorphous calcium salts
in the mitochondrial matrix.

2. Activated phospholipases: Membrane damage.


As a result of sustained ischaemia, there is increased cytosolic influx of
calcium in the cell. Increased calcium 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, 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.


The nucleoproteins are damaged by the activated lysosomal enzymes such
as proteases and endonucleases. Irreversible damage to the nucleus can
be in three forms:
 Pyknosis: Condensation and clumping of nucleus which becomes
dark basophilic.
 Karyorrhexis: Nuclear fragmentation in to small bits dispersed in
the cytoplasm. iii) Karyolysis: Dissolution of the nucleus.
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 include:
hydrolase, RNAase, DNAase, protease, glycosidase, phosphatase,
lipase, amylase, cathepsin etc) which 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
8

You might also like