Stages in the cellular response to stress and injurious stimuli
If the adaptive capability is exceeded or if
As cells encounter physiologic stresses or
pathologic stimuli, they can undergo
adaptation to preserve viability and
function. The principal adaptive responses
are hypertrophy, atrophy, hyperplasia,
metaplasia, dysplasia, anaplasia, neoplasia.
There are two types of cell death—necrosis and apoptosis
the external stress is inherently harmful,
cell injury develops. Within certain limits,
injury is reversible, (cells return to a stable
baseline). However, if the stress is severe,
persistent and rapid in onset, it results in
irreversible injury and death of the affected
cells. Cell death is one of the most crucial
events in the evolution of disease in any
tissue or organ.
Causes of Cell Injury
Oxygen Deprivation may occur: locally because of a blocked artery, or systemically because of
respiratory impairment. It leads to Hypoxia (= Oxygen deficiency)
• Chemical Agents (e.g., air pollutants, insecticides, poisons, many therapeutic drugs if used
excessively or inappropriately, Oxygen at sufficiently high partial pressures, even innocuous
substances such as glucose, salt, or even water, if absorbed or administered in excess, can so
derange the osmotic environment)
• Infectious Agents (range from submicroscopic viruses to meter-long tapeworms; in between
are bacteria, fungi, etc.)
• Immunologic Reactions (Examples are autoimmune reactions and allergic reactions)
• Genetic Factors (e.g., Genetic defects → deficiency of functional proteins, such as enzymes in
inborn errors of metabolism, or accumulation of damaged DNA or misfolded proteins → cell
injury)
• Nutritional Imbalances (Protein–calorie insufficiency, specific vitamin deficiencies (because
normal metabolic processes cannot take place))
• Imbalance of fluids or electrolytes
• Physical Agents (Trauma, extremes of temperature, radiation, electric shock, mechanical
pressure, sudden changes in atmospheric pressure, etc)
• Aging (aging leads to alterations in replicative and repair abilities of individual cells and
tissues)

2
Important: ischemia = loss of blood supply in a tissue due to impeded arterial flow or reduced
venous drainage. While ischemia is the most common cause of hypoxia, oxygen deficiency can
also result from inadequate oxygenation of the blood, (as in pneumonia), or from reduction in
the oxygen-carrying capacity of the blood as in blood loss anemia or from ischemia.

3
 Causes of Cell Injury
Example: One mechanism of cell injury caused by Hypoxia
(Oxygen deficiency) as a result of Oxygen Deprivation

A severe oxygen deficit

interferes with energy (ATP) production in the cell

loss of cell function (including loss of

the sodium pump at the cell membrane)

Increase in sodium ions inside the cell At the same time,

Anaerobic metabolism
occurs in the cell,
swelling of the cell leading to a decrease
in pH and further
metabolic impairment.
(Eventually) rupture of the cell membrane.
4
Cellular adaptations are changes in the number, size, phenotype, metabolic activity, or
functions of cells in response to changes in their environment.
The major types of cellular adaptations are hypertrophy, atrophy, hyperplasia, metaplasia,
dysplasia, anaplasia, neoplasia.

The adaptation may be physiological (normal) or pathological (abnormal).

 Physiologic adaptations usually represent responses of cells to normal stimulation by
hormones or endogenous chemical mediators or other non-harmful stimuli.
 Pathologic adaptations are responses to stress that allow cells to modulate their
structure and function and thus escape injury.
Frequently such adaptations are reversible after the stimulus is removed.

Atrophy = a decrease (or shrinkage) in the size of the cell by loss of cell substance (that results
from a combination of decreased protein synthesis and increased protein degradation in cells).
When a sufficient number of cells are involved, the entire tissue or organ diminishes in size,
becoming atrophic .
Although atrophic cells may have diminished function, they are not dead.
Examples of tissue and organs especially susceptible to atrophy: skeletal muscle, cardiac muscle,
and the brain.
5
Common causes of atrophy: Physiologic stimuli [ decrease workload (the shrinkage of skeletal
muscle that occurs when a limb is immobilized in a cast for several weeks), the loss of hormone
stimulation in menopause, aging] or Pathologic stimuli ( loss of innervation, diminished blood
supply, Inadequate nutrition) like Atrophy of the brain is due to aging and reduced blood
supply.
Hypertrophy = an increase in the size of the cell resulting in an enlarged tissue or organ
(hypertrophic).
Hypertrophy involves an increase in intracellular protein rather than cytosol (intracellular fluid).
physiologic hypertrophy is the effect of consistent exercise on skeletal muscle, leading to an
enlarged muscle mass or hormonal stimulation. or pathologic cellular hypertrophy is the
cardiac enlargement that occurs with hypertension.

Hyperplasia = a controlled increase in cell number caused by proliferation of differentiated cells.

Hyperplasia can be physiologic or pathologic; but in both cases cell proliferation is stimulated by
growth factors, then “turned off” by various growth inhibitors.
physiologic hyperplasia: (1) hormonal hyperplasia, e.g. the proliferation of the glandular
epithelium of the female breast at puberty and during pregnancy.
(2) compensatory hyperplasia, in which residual tissue grows after removal or loss of part of an
organ, e.g., hyperlasia after liver resection to restore the liver mass.
pathologic hyperplasia: a disturbed balance between estrogen and progesterone causes
endometrial hyperplasia, which is a common cause of abnormal menstrual bleeding.
6
Important: the hyperplastic process remains controlled; if the signals that initiate it abate, the
hyperplasia disappears.
It is this responsiveness to normal regulatory control mechanisms that distinguishes pathologic
hyperplasias from cancer, in which the growth control mechanisms become dysregulated or
ineffective.
Nevertheless, in many cases, there may be an increased risk of cancer when pathologic
hyperplasia occurs. For example, patients with hyperplasia of the endometrium are at increased
risk of developing endometrial cancer.
In some cases, hypertrophy and hyperplasia occur simultaneously, as in the uterine enlargement th
occurs during pregnancy.
Dysplasia is the term applied to tissue in which the cells vary in size and shape, and the rate of
mitosis is increased.
This situation may result from chronic irritation infection, or it may be a precancerous change.
Anaplasia (dedifferentiation) = reversion of cells to a more primitive or undifferentiated form.
anaplasia is characteristic of cancer and is the basis for grading the aggressiveness of a tumor.
Neoplasm is commonly called a tumor. Tumors are of two types, benign and malignant.
Malignant neoplasms are referred to as cancer.
Note: Benign tumors do not necessarily become malignant.
Benign tumors are usually considered less serious because they do not spread and are not life
threatening unless they are found in certain locations, such as the brain, where they can cause
pressure problems. Benign or malignant tumor of the breast 7
 Metaplasia

 Metaplasia is a reversible change in which one adult cell type

(epithelial or mesenchymal) is replaced by another adult cell type
that is better able to withstand the adverse environment.
Example: Metaplasia (replacement) of ciliated columnar epithelial cells by stratified
squamous epithelium (right) in the trachea and bronchi of smokers
Note: the stress that induces metaplastic change, if persistent, may predispose to
malignant transformation of the epithelium. In fact, squamous metaplasia of the
respiratory epithelium often coexists with lung cancers composed of malignant
squamous cells. It is thought that cigarette smoking initially causes squamous
metaplasia, and cancers arise later in some of these altered foci.
8
Figure 6. Metaplasia of normal columnar (left) to squamous epithelium (right) in a bronchus, shown schematically (A)
and histologically (B). This epithelial metaplasia occurs in the respiratory epithelium of habitual cigarette smokers where
the normal ciliated columnar epithelial cells of the trachea and bronchi are focally or widely replaced by stratified
squamous epithelial cells. The rugged stratified squamous epithelium may be able to survive the noxious chemicals in
cigarette smoke that the more fragile specialized epithelium would not tolerate.
Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost, such
as mucus secretion and ciliary clearance of particulate matter. Epithelial metaplasia is therefore a double-edged sword.