General Pathology

Cellular responses to cell injury

Dr. Hersh A. Ham-Karim

PhD Molecular Pathology
 Cell injury
Cells are the basic units of tissues, which form organs and systems in the human body. In health, the
cells remain in accord with each other. In 1859, Virchow first published cellular theory of disease,
bringing in the concept that diseases occur due to abnormalities at the level of cells. Since then,
study of abnormalities in structure and function of cells in disease has remained the focus of
attention in understanding of diseases.
Thus, most forms of diseases begin with cell
injury followed by consequent loss of
cellular function. Cell injury is defined as a
variety of stresses a cell encounters as a
result of changes in its internal and external
environment.
 Causes of cell injury
The causes of cell injury span a range from gross physical trauma, such as after a motor vehicle
accident, to a single gene defect that results in a nonfunctional enzyme in a specific metabolic disease.
Most injurious stimuli can be grouped into the following categories.
Hypoxia and ischemia. Hypoxia, which
refers to oxygen deficiency, and ischemia,
which means reduced blood supply, are
among the most common causes of cell
injury. Both deprive tissues of oxygen, and
ischemia, in addition, results in a
deficiency of essential nutrients and a build
up of toxic metabolites.
The most common cause of hypoxia is ischemia resulting from an arterial obstruction,
but oxygen deficiency also can result from inadequate oxygenation of the blood, as in a
variety of diseases affecting the lung, or from reduction in the oxygen-carrying
capacity of the blood, as with anemia of any cause, and carbon monoxide (CO)
poisoning.
a. The neurons are highly susceptible to ischemic damage. They undergo irreversible
damage when deprived of oxygen (by ischemia) for 3 to 4 minutes.
b. Myocardial cells and hepatocytes are of intermediate susceptibility to ischemic
damage (20-30 minutes).
c. Skeletal muscles, the epidermis of the skin and fibroblasts are of low susceptibility
to ischemia (many hours).
Toxins. Potentially toxic agents are encountered daily in
the environment; these include air pollutants,
insecticides, CO, asbestos, cigarette smoke, ethanol, and
drugs. Many drugs in therapeutic doses can cause cell or
tissue injury in a susceptible patient or in many
individuals if used excessively or inappropriately. Even
innocuous substances, such as glucose, salt, water and
oxygen, can be toxic.

Infectious agents. All types of disease-causing

pathogens, including viruses, bacteria, fungi, and
protozoans, injure cells.
Nutritional imbalances. Protein–calorie insufficiency
among impoverished populations remains a major cause of
cell injury, and specific vitamin deficiencies are not
uncommon even in developed countries with high
standards of living. Ironically, excessive dietary intake may
result in obesity and also is an important underlying factor
in many diseases, such as type 2 diabetes mellitus and
atherosclerosis.

Aging. Cellular senescence results in a diminished ability

of cells to respond to stress and, eventually, the death of
cells and of the organism.
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.

Genetic abnormalities Genetic aberrations can result in

pathologic changes as conspicuous as the congenital
malformations associated with Down syndrome or as subtle as
the single amino acid substitution in hemoglobin giving rise to
sickle cell anemia. Genetic defects may cause cell injury as a
consequence of deficiency of functional proteins, such as
enzymes in inborn errors of metabolism, or accumulation of
damaged DNA or misfolded proteins, both of which trigger cell
death when they are beyond repair.
 Cellular responses to cell injury

Cells actively interact with their environment, constantly adjusting their structure and
function to accommodate changing demands and extracellular stresses. The intracellular
milieu of cells is normally tightly regulated such that it remains fairly constant, a state
referred to as homeostasis. As cells encounter physiologic stresses (such as increased
workload in the heart) or potentially injurious conditions (such as nutrient deprivation), they
can undergo adaptation, achieving a new steady state and preserving viability and function.
If the adaptive capability is exceeded or if the external stress is inherently harmful or
excessive, cell injury develops
Cellular responses to cell injury
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 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:
a. 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 adaptations).
b. 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).
 Cellular adaptation

 Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or
functions of cells in response to changes in their environment.
 Cells must constantly adapt, even under normal conditions, to changes in their
environment.
 These physiological adaptations usually represent responses of cells to normal stimulation
by hormones or endogenous chemical substances.
• For example, as the enlargement of the breast and induction of lactation by pregnancy.
 Pathologic adaptation may share the same underlying mechanisms, but they provide the
cells with the ability to survive in their environment and perhaps escape injury.
 Examples of adaptations
1. Hypertrophy: Hypertrophy refers to an increase in the size of cells, that results in an
increase in the size of the affected organ.
The increased size of the cells is due to the synthesis and assembly of additional
intracellular structural components.
2. Hyperplasia is defined as an increase in the number of cells in an organ or tissue in
response to a stimulus
a. Physiologic
Female breast during pregnancy (epithelium)
Liver - In individuals who donate one lobe of the liver for transplantation, the remaining
cells proliferate so that the organ soon grows back to its original size
b. Pathologic
Endometrium – in response to hormones
Hyperplasia of prostate in old age
3. Atrophy: is defined as a reduction in the size of an organ or tissue due to a decrease in cell
size and number.
a. Physiologic
• Post partum uterus
b. Pathologic
• Disuse atrophy
• Alzheimer`s
Metaplasia: is a reversible change in which one adult cell type (epithelial or mesenchymal)
is replaced by another adult cell type.
It may represent and adaptive substitution of cells that are sensitive to stress by cell types
better able to withstand the adverse environment.
• Stones in the excretory ducts of the salivary
glands, pancreas or bile ducts may cause
replacement of the normal secretory columnar
epithelium by nonfunctioning stratified squamous
epithelium.
• In the habitual cigarette smoker, the normal
ciliated columnar epithelial cells of the trachea
and bronchi are often replaced focally or widely
by stratified squamous epithelial cells.
 Pathogenesis of cell injury
Injury to the normal cell may result in a state of reversible or irreversible cell injury. The underlying
alterations in biochemical systems of cells for reversible and irreversible cell injury by various
agents is complex and varied.
1. The cellular response to injurious stimuli depends on the type, duration, and severity of
injurious agent. Thus, low doses of toxins or a brief period of ischemia may lead to reversible
cell injury, whereas larger toxin doses or longer ischemic times may result in irreversible injury
and cell death.
2. The consequences of an injurious stimulus also depend on the type, status, adaptability,
and genetic makeup of the injured cell. The same injury has vastly different outcomes
depending on the cell type. For instance, striated skeletal muscle in the leg tolerates complete
ischemia for 2 to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20
to 30 minutes of ischemia.
 The nutritional (or hormonal) status also can be important; understandably, a glycogen-
replete hepatocyte will survive ischemia better than one that has just burned its last glucose
molecule. Genetically determined diversity in metabolic pathways can contribute to
differences in responses to injurious stimuli. For instance, when exposed to the same dose
of a toxin, individuals who inherit variants in genes encoding cytochrome P-450 may
catabolize the toxin at different rates, leading to different outcomes. Much effort is now
directed toward understanding the role of genetic polymorphisms in responses to drugs and
toxins, a field of study called pharmacogenomics. In fact, genetic variations influence
susceptibility to many complex diseases as well as responsiveness to various therapeutic
agents. Using the genetic makeup of the individual patient to guide therapy is one example
of “precision medicine.”
3. Cell injury usually results from functional and biochemical abnormalities in one or
more of a limited number of essential cellular components. Different external insults
and endogenous perturbations typically affect different cellular organelles and
biochemical pathways. For instance, deprivation of oxygen and nutrients (as in hypoxia
and ischemia) primarily impairs energy dependent cellular functions, culminating in
necrosis, whereas damage to proteins and DNA triggers apoptosis. However, it should be
emphasized that the very same injurious agent may trigger multiple and overlapping
biochemical pathways. Not surprisingly, therefore, it has proved difficult to prevent cell
injury by targeting an individual pathway.
 Pathogenesis of ischemic and hypoxic injury

Ischemia and hypoxia are the most

common forms of cell injury. Although
underlying intracellular mechanisms and
ultrastructural changes involved in
reversible and irreversible cell injury by
hypoxia and ischemia depending upon
extent of hypoxia and type of cells are
involved are a continuation of the process.
The sequential biochemical and ultrastructural changes in reversible cell injury are as
1. Decreased generation of cellular ATP: Damage by ischaemia versus hypoxia from
other causes. 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.
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:

a. Failure of sodium-potassium pump. Normally, 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 isosmotic conditions
(i.e. hydropic swelling occurs).
b. 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.
Morphology of reversible cell injury
In conventional description of morphologic changes, the term degeneration has been used to
denote morphology of reversible cell injury. However, now it is realized that this term does not
provide any information on the nature of underlying changes and thus currently more acceptable
terms of retrogressive changes or simply reversible cell injury are applied to non-lethal cell
injury.

The reversible (sub-lethal) cell injuries include the

following patterns of morphological changes:
 Accumulation
 Pigmentation
 Accumulation
Under some circumstances, cells may accumulate abnormal amounts of various substances,
which may be harmless or may cause varying degrees of injury. The substance may be located in
the cytoplasm, within organelles (typically lysosomes), or in the nucleus, and it may be
synthesized by the affected cells or it may be produced elsewhere.
The main pathways of abnormal intracellular accumulations are inadequate removal and
degradation or excessive production of an endogenous substance, or deposition of an abnormal
exogenous material
The accumulation includes:
1. Hydropic Change
Hydropic change means accumulation of water within the cytoplasm of the cell. Other synonyms used
are cloudy swelling (for gross appearance of the affected organ) and vacuolar degeneration (due to
cytoplasmic vacuolation).
 Cloudy swelling results from impaired regulation of sodium and potassium at the level of
cell membrane. This results in intracellular accumulation of sodium and escape of potassium.
This, in turn, leads to rapid flow of water into the cell to maintain iso-osmotic conditions and
hence cellular swelling occurs. In addition, influx of calcium too occurs. Hydropic swelling
is an entirely reversible change upon removal of the injurious agent.

2. Fatty change (steatosis)

Fatty change, steatosis or fatty metamorphosis is the intracellular accumulation of neutral fat
within parenchymal cells. The deposit is in the cytosol and represents an absolute increase in the
intracellular lipids. It is especially common in the liver but may occur in other non-fatty tissues
like the heart, skeletal muscle, kidneys (lipoid nephrosis or minimum change disease) and other
organs.
Fatty Liver
Liver is the commonest site for accumulation of fat because it plays central role in fat
metabolism. In the liver, fatty change may be secondary to alcoholism, diabetes mellitus,
malnutrition, obesity, or poisonings.
3. Hyaline Change
The term “hyalin” usually refers to an alteration within cells or in the extracellular space, which
gives a homogeneous, glassy, pink appearance in routine stained histological sections. Hyaline
change is almost always associated with the accumulation of a protein in the tissue either
intracellularly (intracellular hyalin) or exracellularly (extracellular hyalin).
Examples of intracellular hyaline

a. Re-absorption protein droplets (tubular epithelial hyaline droplets) seen within the
cytoplasm of the lining epithelial cells of the renal tubules in cases of protein losing
nephropathies such as the nephrotic syndrome. In such conditions, the lining epithelial cells
of the renal tubules try to re-absorb the excessive quantities of the proteins that had leaked
through the glomerular filtrate.
b. Mallory’s hyaline (Alcoholic hyaline or
Mallory body) represents aggregates of
intermediate filaments in the hepatocytes in
alcoholic liver cell injury with a
characteristic twisted-rope appearance found
in the cytoplasm of liver cells.
Examples of extracellular hyaline

1. Collagenous fibrous tissue in old scars may appear hyalinized (give a homogeneous,
glassy, pink appearance in H and E stained histological sections), but the physiochemical
mechanism underlying this change is not clear.
2. In long-standing hypertension and diabetes mellitus, the walls of arterioles, especially in
the kidney, become hyalinized, due to deposition of extravasated plasma protein.