Cell Injury

Causes of Cell (Tissue) Injury

The structural and functional changes produced by pathology start with

injury to the cells that make up

the tissues. Mild injury produced by stressors leads to sublethal alterations

of the affected cells that may

be reversible, whereas moderate or severe injury leads to lethal alterations

that are likely irreversible,

and can lead to cell death. We start by discussing the most common
causes of cellular injury.

Cells may be damaged by a variety of factors. The most important causes

are:

• Ischemia (lack of blood supply)

• Infectious agents

• Immune reactions

• Genetic factors

• Nutritional factors

• Physical factors

• Chemical factors

Cell injury may be reversible or irreversible. Whether the injury is reversible

is dependent on the cell’s

ability to withstand the derangement of homeostatic mechanisms and its

adaptability (i.e., ability to
return to a state of homeostasis). Reversing the injury and achieving
homeostasis are determined by a

combination of factors including the mechanism of injury, length of time

the injury is present without

intervention, and the severity of the injury.

Figure 1 Cellular response to stress and injurious stimuli

Infectious Agents

Infectious agents, such as bacteria, viruses, mycoplasmas, fungi,

rickettsiae, protozoa, prions, and

helminths, may also cause cell injury or death. Bacterial and viral agents
are responsible for the vast

majority of infections.

Bacterial infections cause cell injury primarily by invading tissue and

releasing exotoxins and endotoxins

that can cause cell lysis and degradation of extracellular matrix and aid in
the spread of the infection.

Injury can also result from the inflammatory/immunologic reactions

induced by bacteria in the host. For

example, exotoxins may be released by clostridial organisms that cause gas

gangrene, tetanus, and

botulism.
Viruses kill cells by one of two mechanisms and are the consequence of
complete redirection of the

cell’s biosynthesis toward viral replication. The first is a direct cytopathic

effect usually found with

ribonucleic (RNA) viruses.

Immune Reactions

Although the immune system normally functions in defense against foreign

antigens, sometimes the

system becomes overzealous in its activity, leading to hypersensitivities

ranging from a mild allergy to

life-threatening anaphylactic reactions or autoimmune (attacking oneself)

disorders. The mechanisms by

which the immune system can lead to cell injury or death include antibody
attachment, complement

activation, and activation of the inflammatory cells (e.g., neutrophils,

macrophages, T and B

lymphocytes, mast cells, and basophils).

Cell injury and disease can be caused by the immune system in numerous
ways. For example, allergies

are caused by the presence of high numbers of a specific antibody-E (IgE)

on the surface of specialized

HS-CI-IV-PATH. Injury, Inflamm, Healing, and Repair

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cells (mast cells and basophils, which release histamine), resulting in mild,
moderate, or severe allergic

reactions.

Chemical Factors

Toxic substances cause chemical injury. These substances can be divided

into two categories: those that

can injure cells directly and those that require metabolic transformation
into the toxic agent. Examples

of chemicals that injure cells directly are heavy metals, such as mercury,
that bind to and disrupt critical

membrane proteins and a number of toxins and drugs, such as alkylating

agents, used in chemotherapy.

Carbon tetrachloride and acetaminophen are examples of inert substances

that must be metabolized to

reactive intermediates to cause cell injury. Taken in large amounts, most

medications can be toxic, and

many are even lethal. Suicide by drug overdose is a common example of

drug-induced chemical toxicity.

Genetic Factors

Genetic alterations lead to cellular injury or death by three primary means:

(1) alterations in the
structure or number of chromosomes that induce multiple abnormalities,
(2) single mutations of genes

that cause changes in the amount or functions of proteins, and (3) multiple
gene mutations that interact

with environmental factors to cause multifactorial disorders.

Mechanical Factors

The physical stress theory may help explain mechanical factors influencing
tissue adaptation and injury.

The physical stress theory proposes that changes in the relative level of
physical stress cause a

predictable adaptive response in all biologic tissue. Typical tissue response

to physical stress includes

decreased stress tolerance (e.g., atrophy), maintenance, increased stress

tolerance (e.g., hypertrophy),

injury, and death. Conversely, a decrease in mechanical stress may also be

detrimental, particularly as it

relates to bone health.

Irradiation for the treatment of cancer can cause injury of susceptible

normal cells. Ionizing radiation

causes radiolysis of water and the production of hydroxyl radicals (‾OH).

Nutritional Factors

Imbalances in essential nutrients can lead to cell injury or cell death. For
example, deficiencies of
essential aminoacids interfere with protein synthesis. Synthesis of proteins
is required to replace cell

proteins lost through normal catabolism, through growth, and in

preparation for cell replication. Cell

replication is essential for the healing processes after cell injury and the
replacement of cells lost

through normal turnover.

Common cellular adaptations include atrophy, hypertrophy, hyperplasia,

metaplasia, and

dysplasia.

Atrophy is a reduction in cell and organ size. Atrophy can occur with
vascular insufficiency, reduction in

hormone levels, malnutrition, immobilization, and pain that limits

movement and function, and chronic

inflammation. Bone loss, muscle wasting, and brain cell loss are examples
of either tissue or organ

atrophy associated with aging. Pathologic atrophy occurs as a consequence

of cell injury due to

ischemia, inadequate nutrition, or physical factors previously mentioned.

Hypertrophy is an increase in the size of the cell and organ. Hypertrophy
can occur when increased

functional demands are placed on the cells, tissue, or organs and with
increased hormonal input

Lethal Injury (Necrosis)

Lethal injuries to the tissues of a living individual cause cell death
(necrosis). Necrosis is accompanied by biochemical and structural changes
(see below) and is irreversible. The necrotic cells cease to function; if
necrosis is sufficiently extensive, clinical disease results.

Cell necrosis should be distinguished from the death of the individual,

which is difficult to define. From a legal standpoint in many countries, an
individual is considered dead when there is complete and irreversible
cessation of brain function. Many individual cells and tissues in a legally
dead individual remain viable for some time after death, however, and
constitute a major source of organs for transplantation.

Nonlethal Injury (Degeneration)

Nonlethal injury to a cell may produce cell degeneration, which is

manifested as some abnormality of biochemical function, a recognizable
structural change, or a combined biochemical and structural abnormality.
Degeneration is reversible but may progress to necrosis if injury persists.
When it is associated with abnormal cell function, cell degeneration may
also cause clinical disease.

Programmed Cell Death (Apoptosis)

It is worth remembering that cell degeneration and cell death are ongoing
phenomena in multicellular organisms and that in the healthy state, they
are balanced by cell renewal. This process, through which effete cells are
removed from normal tissue, is termed apoptosis. It differs from necrosis in
that apoptotic cells are rapidly removed by phagocytes and there is no
overt inflammation associated with their removal. In addition, apoptosis
typically is initiated within the cell by nuclear fragmentation (pyknosis) and
cytoplasmic condensation. Cell membranes remain intact in the early
stages, leading to small shrunken cells containing cytoplasmic or nuclear
debris (apoptotic bodies). Certain growth control genes may initiate
apoptosis
DEGENERATION

Degeneration is deterioration in the medical sense. Generally, it is the

change from a higher to a lower form. More specifically, it is the change of
tissue to a lower or less functionally active form.

. There are following types of degeneration:

Cellular degeneration Causes – Bacterial toxins, burns, chemicals, high

fever etc. it results from impaired cellular volume- operative at 3 levels
1)Plasma membrane 2)Sodium pump on plasma membrane 3)Supply of
ATP. Grossly – organ such as kidney, liver & heart, muscle enlarge due to
swelling, cut surface bulges outward & slightly opaque. Microscopically – 1.
Cells are swollen & microvasculature compressed. 2. Small clear vacuoles
are seen those represent distended cisternae of ER. 3. Ultra structural
changesa) Dialatation of ER b) Detachment of polysoms from the surface
of RER c) Mitochondrial swelling.
Hyline Degeneration A. B. Descriptive histologic term for glassy
homogenous eosinofilic appearance of material under hematoxyline & eosin
stained section & does not refer to any specific substance. Intracellular
hyline- mainly seen in epithelial cells e. g. Hyline drpoplets in proximal
epithelium cells in case of exessive reabsorption of plasma protein. Nuclear
or cytoplasmic hyaline inclusions seen in viral infection. Extra cellular
hyline- seen in connective tissue e. g. Hyaline degeneration seen in
leiomyomas of uterus. Hylinised old scar of fibrocollagenous tissue.

Mucoid Degeneration Mucine is normally produced by epithelial cells of

mucus membrane & mucous glands as well as by some connective tissues
like umbilical cord. 1) Disturbances in epithelial mucin e. g. catarrhal
inflammation of mucous membrane. Cystic fibrosis of pancreas. 2)
Connective tissue mucin disturbances e. g. Myxomatous change in dermis
in myoedema. Myxoid change in synovium of ganglion on the wrist.

Fatty Degeneration Intracellular accumulation of neutral fat within

parechymal cells. It occurs especially in liver but may occur in nonfatty
tissue like heart, skeletal muscles, kidneys & other. n Fatty liver –
Accumulation of fat in liver. Etilogy – 1)Alcohol consumption 2)Starvatoin
3)Malnutrition etc. Pathologic changes. Enlarge with tense glistering
capsule & rounded margines cut surface is pale yellow to yellow &greesy to
touch. Microscopically – Vacuoles are initially small & present around
nucleus. But with progression becomes layer pushing the nucleus to
periphery.
NECROSIS

It is focal death of cell along with degeneration of tissue by hydrolytic

enzyme liberated by cells. There are 5 types of Necrosis 1)Coagulative
necrosis 2)liquification (colliquative) necrosis. 3)Caseous necrosis. 4)Fat
necrosis 5)Fibrinoid necrosis.

Coagulative Necrosis It is most common type. n Causes- mostly due to

sudden cessation of blood flow & less often from bacterial & chemical
agents. Organs affected are heart, kidney & spleen n Appearance of
affected organ. Grossly-: In early stage pale firm & slightly swollen with
progression becomes yellowish softer & shrunken. Microscopically. Cells
swollen more eosinofillic conversion of normal cell to tombstone i. e.
outline retained but the nuclear details are lost. Those results from 1)
Denaturation of proteins & 2) 2)Enzymatic digestion of cell

Liquefaction (colliquative) Necrosis Causes- It occurs due to ischemic &

hypoxic injury & bacterial agents as well as degradation tissue by action of
hydrolytic enzymes. n Organs affected- infarcts of brain. Abscess cavity. n
Appearance. Grossly. Affected organ is soft with liquefied center containing
necrotic debris. Microscopically. Macrophages filled with phagocytosed
material cell wall formed by proliferating capillaries inflammatory cells &
gliosis in case of brain & proliferating fibroblast in case of abscess cavity. N

Caseous Necrosis Found in the center of foci of tubercular infection it has

combine features of both above necrosis. n Appearance. Grossly. Dry
cheese & soft granular & yellowish appearance partly attributed to
histotoxic effect of lipopolyscchariedes present in capsule of tubercle bacilli.
Microscopically. Foci are eosinophilic structure less & contain granular
debris. Surrounding tissue shows inflammatory reaction consisting of
epitheloid cells with interspersed giant cells of langerhans & foreign body &
peripheral mantle of lymphocytes. N

Fat Necrosis Occurs in two types

1)Accute pancreatic necrosisthere is liberation of pancreatic lipase from

injured or inflamed tissue results in necrosis.

2)Tramatic fat necrosis. Damage adipose cells assume cloudy appearance

when only free fatty acids complex with Ca+ to form calcium soaps. n
Appearance – Grossly- Yellowish white & firm deposits. Chalky white
appearance. Microscopically- Cloudy appearance & surrounded by
inflammatory tissue. Formation of calcium soap as amorphous granular &
basophilic material. N
Fibrinoid Necrosis Characterised by deposition of fibrinlike material which
has staining properties of fibrin. It occurs in immunologic tissue injury. E.
g. Immune complex vasculitis. Autoimmune diseases. Appearance –
Microscopically – Identified by brightly eosinophilic hyaline like deposition
in vessel wall or on luminal surface of peptic ulcer. Local hemorrhage occur
due to rupture of these blood vessels. N

GANGRENE It is form of necrosis of tissue with superadded putra function.

There are 3 types of gangrene: n 1)Dry gangrene n 2)Wet gangrene n
3)Gas gangrene 1)Dry gangrene-Begins in distal part of limb due to
ischemia occurs in toes & feet of old patient. Causes -Atherosclerosis,
thromboangitis obliterance, rayaund’s disease, trauma, ergot poisoning.
Line of separation present between gangrenous & viable part. Pathologic
changes-Dry, shrunken & dark black due to liberation of Hb from
hemolysed RBCs acted by H 2 S produced by bacteria result in iron
sulphied. Histologically- Line of separation consist of inflammatory tissue.
Calcification
Calcification is the accumulation of calcium salts in a body tissue. It
normally occurs in the formation of bone, but calcium can be deposited
abnormally in soft tissue, causing it to harden. Calcifications may be
classified on whether there is mineral balance or not, and the location of
the calcification

• Pathologic Calcification

• •Dystrophic calcificationis the abnormal deposition of calcium

phosphate in dead or dying tissue

• •Dystrophic calcification is an important component of the

pathogenesis of atherosclerotic disease and valvularheart disease

• •Metastaticcalcificationis calcium deposition in normal tissues as a

consequence of hypercalcemia:

• –Increased PTH with subsequent bone resorption

• –Bone destruction

• –Vitamin D disorders (intoxication, Sarcoidosis, Williams syndrome)

• –Renal failure with 2º↑PTH

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