Cellular Responses to Stress & Toxic Insults:

Adaptation, Injury, and Death

Pathology is the study (logos) of disease (pathos).
More specifically, it is the study of
- structural,
- biochemical and
- functional changes
in cells, tissues, and organs that underlie disease by the use of
molecular, microbiologic, immunologic, and morphologic techniques

Study of pathology is divided into :

General pathology : It is concerned with the reactions of cells and

tissues to abnormal stimuli and to inherited defects, which are the
main causes of disease.

Systemic pathology : It is concerned with the alterations in

specialized organs and tissues that are responsible for disorders
that involve these organs.
Morphologic and Molecular Changes:

Morphologic changes refer to the structural alterations in cells

or tissues that are either characteristic of a disease or
diagnostic of an etiologic process.

Disease states can also be analyzed using molecular biologic

and immunologic approaches. Molecular analysis by techniques
such as DNA microarrays can reveal genetic differences that
predict the behavior of the tumors as well as their
responsiveness to different therapies.
Adaptations of Cellular Growth and Differentiation

Adaptations are reversible changes in the size, number, phenotype, metabolic

activity, or functions of cells in response to changes in their environment.
Different forms of adaptations are :
1. HYPERTROPHY : It refers to an increase in the size of cells, resulting in an
increase in the size of the organ.
The increased size of the cells is due to the synthesis of more structural
components of the cells such as the cellular proteins.
Hypertrophy can be physiologic or pathologic and is caused by increased functional
demand or by stimulation by hormones and growth factors.
Physiologic :
The most common stimulus for hypertrophy of muscle is increased workload.
The massive physiologic growth of the uterus during pregnancy is a good example of
hormone-induced increase in the size of an organ that results mainly from
hypertrophy of muscle fibers.

Physiologic hypertrophy of the uterus during pregnancy

Pathologic Hypertrophy :
In the heart, the stimulus for hypertrophy is usually chronic hemodynamic overload,
resulting from either hypertension or faulty valves.

The relationship between normal, adapted, reversibly injured, & dead myocardial cells

Although hypertrophy usually refers to increase in size of cells or tissues, sometimes

a subcellular organelle may undergo selective hypertrophy.
Example. individuals treated with drugs such as barbiturates show hypertrophy of the
smooth endoplamic reticulum (ER) in hepatocytes.
Different forms of adaptations (cont.):
2. HYPERPLASIA : is an increase in the number of cells in an organ or tissue, usually
resulting in increased mass of the organ or tissue. Hyperplasia takes place if the cell population
is capable of dividing, and thus increasing the number of cells.

Hyperplasia can be physiologic or pathologic.

Physiologic :
Physiologic hyperplasia can be divided into:
(1) hormonal hyperplasia: It increases the functional capacity of a tissue when
needed. Example : proliferation of the glandular epithelium of the female breast at
puberty and during pregnancy.
(1I) compensatory hyperplasia: It increases tissue mass after damage .
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.

Pathologic :
Most forms of pathologic hyperplasia are caused by excesses of hormones or growth
factors acting on target cells.
Endometrial hyperplasia is an example of abnormal hormone-induced hyperplasia.
Hyperplasia is a characteristic response to certain viral infections, such as
papillomaviruses,
Different forms of adaptations (cont.) :
3. ATROPHY :
It is reduced size of an organ or tissue resulting from a decrease in cell size
and number. Atrophy results from decreased protein synthesis and increased
protein degradation in cells.
Protein synthesis decreases because of reduced metabolic activity.
Atrophy can be physiologic or pathologic.
Physiologic :
The uterus decreases in size shortly after parturition.
Pathologic :
Pathologic atrophy depends on the underlying cause and can be local or generalized.

A, Normal brain of a young adult.

B, Atrophy of the brain in an 82-year-old male with atherosclerotic cerebrovascular disease,
resulting in reduced blood supply
The common causes of atrophy :
Decreased workload (atrophy of disuse): When a fractured bone is immobilized
in a plaster cast or when a patient is restricted to complete bedrest, skeletal muscle
atrophy rapidly ensues. The initial decrease in cell size is reversible once activity is
resumed.
Loss of innervation (denervation atrophy): The normal metabolism and function
of skeletal muscle are dependent on its nerve supply. Damage to the nerves leads to
atrophy of the muscle fibers supplied by those nerves.
Diminished blood supply: A decrease in blood supply (ischemia) to a tissue as a
result of slowly developing arterial occlusive disease results in atrophy of the tissue.
Inadequate nutrition: Profound protein-calorie malnutrition (marasmus) is
associated with the use of skeletal muscle as a source of energy after other reserves
such as adipose stores have been depleted. This results in marked muscle wasting
(cachexia).
Loss of endocrine stimulation: Many hormone-responsive tissues, such as the
breast and reproductive organs, are dependent on endocrine stimulation for normal
metabolism and function. The loss of estrogen stimulation after menopause results in
physiologic atrophy of the endometrium, vaginal epithelium, and breast.

Pressure: Tissue compression for any length of time can cause atrophy. An enlarging
benign tumor can cause atrophy in the surrounding uninvolved tissues.
Different forms of adaptations (cont.) :

4. METAPLASIA
It is a reversible change in which one differentiated cell type (epithelial or
mesenchymal) is replaced by another cell type.

It may represent an adaptive substitution of cells that are sensitive to stress

by cell types better able to withstand the adverse environment.

Metaplasia of columnar epithelium (left) to squamous epithelium (right)

in a bronchus.
 Overview of Cell Injury and Cell Death
Cell injury results
when cells are stressed so severely that they are no longer able to adapt or
when cells are exposed to inherently damaging agents or suffer from intrinsic
abnormalities.
Injury may progress through a reversible stage and culminate in cell death.

Stages of the cellular response to stress and injurious stimuli

Reversible cell injury
In early stages or mild forms of injury
the functional and morphologic changes are reversible
if the damaging stimulus is removed.

The hallmarks of reversible injury are :

• reduced oxidative phosphorylation with resultant depletion of energy stores
in the form of adenosine triphosphate (ATP)

• cellular swelling caused by changes in ion concentrations and water influx

• various intracellular organelles, such as mitochondria and the cytoskeleton

may also show alterations.

Cell death
With continuing damage the injury becomes irreversible,
at which time the cell cannot recover and it dies.
Two principal types of cell death:
a) Necrosis and b) Apoptosis
which differ in their morphology, mechanisms, and roles in physiology and disease.
 Causes of Cell Injury
Oxygen Deprivation:
Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative
respiration. Hypoxia is an extremely important and common cause of cell injury and cell
death. Causes of hypoxia include
reduced blood flow (celled ischemia)
inadequate oxygenation of the blood due to cardiorespiratory failure
and decreased oxygen-carrying capacity of the blood, as in anemia or carbon monoxide
poisoning
(producing a stable carbon monoxyhemoglobin that blocks oxygen carriage)
or after severe blood loss.
Depending on the severity of the hypoxic state, cells may adapt, undergo injury, or die.
For example, if an artery is narrowed, the tissue supplied by that vessel may initially shrink
in size (atrophy),
whereas more severe or sudden hypoxia induces injury and cell death.

Physical agents:
These are capable of causing cell injury. The agents include mechanical
trauma, extremes of temperature (burns and deep cold), sudden changes
in atmospheric pressure, radiation, and electric shock .
 Causes of Cell Injury

Chemical agents :
Simple chemicals such as glucose or salt in hypertonic concentrations
may cause cell injury directly or by deranging electrolyte balance in
cells.
Even oxygen at high concentrations is toxic.
Trace amounts of poisons, such as arsenic, cyanide, or mercuric salts,
may destroy sufficient numbers of cells within minutes or hours to
cause death.
Other potentially injurious substances are our daily companions:
environmental and air pollutants, insecticides, and herbicides;
industrial and occupational hazards, such as carbon monoxide and
asbestos; recreational drugs such as alcohol; and the ever-increasing
variety of therapeutic drugs.
Infectious agents :
These agents range from the submicroscopic viruses to the large
tapeworms.
In between are the rickettsiae, bacteria, fungi, and higher forms of
parasites.

Nutritional Imbalances:
Protein calorie deficiency.

Immunological reactions :
The immune system serves an essential function in defense against
infectious pathogens
but immune reactions may also cause cell injury.
Injurious reactions to endogenous self-antigens are responsible for
several autoimmune diseases Immune reactions to many external
agents, such as microbes and environmental substances, are also
important causes of cell and tissue injury .