Cell injury, Cell Death

Cell Injury. Necrosis.
Apoptosis.
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Theme
 Definition of cell injury. Causes of cell injury: hypoxia, immune reactions,
microorganisms, chemicals, aging, nutritional imbalances, physical agents,
genetic defects.
 Mechanisms of cell injury: ischemic, free-radical mediated, chemical
mediated, age mediated.
 Types of cell injury: reversible, irreversible. Reversible cell injury
(degeneration): definition, patterns (cellular swelling, fatty change),
morphology, outcomes.
 Cell death: definition, morphology. Necrosis (irreversible cell injury):
definition, morphogenesis, gross and microscopic morphology.
 Types of necrosis: Coagulative, Liquefactive, fat, caseous, fibrinoid, gangrene.
Functional significance and outcomes of necrosis.
 Apoptosis – definition, pathogenesis, morphology.
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“Normal homeostasis; Adaptation”
 Normal homeostasis - is maintenance of static or constant structure or
function of cells, permitting changes in structure and function within a
narrow range.
 Adaptation - is a condition when cells encounter physiologic stresses or
pathologic stimuli, they achieve an altered but steady state while
preserving their health in the face of continued stress.
Examples of cellular adaptation:
1) atrophy - decrease in cell size,
2) hypertrophy - increase in cell size,
3) hyperplasia - increase in cell number.
4) metaplasia - change in cell type.
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“Cell Injury”
 Cell injury- is a process, when cell fails to preserve its health (or steady
state of structure and function) in the face of continued physiological
stress and pathological stimuli, its structure and function undergo
abnormal changes.
 Types of cell injury:
 1) reversible - when former steady state of cell’s structure and function
can be re-gained after the removal of physiologic stress or pathologic
stimuli. It results in recovery and reestablishment of cell’s health;
 2) irreversible - when former steady state of cell’s structure and function
cannot be regained after the removal of physiologic stress and
pathologic stimuli. It results in cell death.
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Causes of cell injury.
1. Hypoxia - reduction of oxygen supply to tissues below physiological
level.
2. Immune reactions - cause cell injury in two ways:
a) hypersensitivity reactions: here, cell injury is mediated by antibodies or
T-cells directed against exogenous (non-self) antigens;
b) autoimmune diseases - here, cell injury is mediated by antibodies or T-
cells directed against endogenous (self) antigens.
3. Microorganisms:
a) viruses, b) rickettsias, c) bacteria, d) fungi, e) protozoa, f) helmints.
4. Chemicals and drugs - innocuous (harmless) substances: poisons,
toxins,
5. Aging. mbbshelp.com

Causes of Cell Injury
6. Nutritional imbalances - nutritional deficiencies and nutritional excesses
may also cause cell injury.
7. Physical agents.
a) mechanical traumas,
b) extremes of temperature (low or high temperature),
c) sudden lowering of atmospheric pressure,
d) radiant energy,
e) electrical energy.
8. Genetic defects:
a) mutations, b) abnormalities in chromosome number.
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Mechanisms of cell injury.
1. Ischemic and hypoxic cell injury.
1) Reversible cell injury:
Tissue ischemia (loss of blood supply to tissues) → Tissue hypoxia →
Decreased oxidative phosphorilation in mitochondria → Decreased ATP
(energy) production.
Reversible cell injury may be correct if oxygen supply is restored.
2) Irreversible cell injury.
If ischemia and hypoxia persist beyond reversible injury → irreversible injury
occurs, characterized by the following:
a) injury to lysosomes,
b) injury to plasma membrane - central factor in pathogenesis,
c) injury to mitochondria
3) Cell death. mbbshelp.com

Following irreversible cell injury, cell death
occurs, characterized by:
a) extensive plasma membrane damage,
b) progressive degradation of cell organelles,
c) leakage of intracellular enzymes into extracellular space,
d) entry of extracellular macromolecules into the dead cell,
e) finally, dead cell is replaced by large masses, composed of
phospholipids in the form of “myelin figures”, which are either
phagocytosed by neutrophils and macrophages or degraded
into fatty acids.
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2. Free radical-mediated cell injury.
Free radical refers to a chemical species that has a single unpared electron in
outermost orbital. Free radicals are highly reactive and initiated autocatalytic
reactions whereby molecules (organic or inorganic) with which they react are
themselves converted into free radicals, thereby propagating the chain of
damage.
3. Chemical-mediated cell injury.
Chemicals induce cell injury by two mechanisms: l) by direct action, 2) by
forming toxic metabolites.
4. Age-mediated cell injury (Aging).
Cellular aging represents progressive accumulation over the years of
in structure and function that lead to cell death or diminished capacity of cell
respond to injury and characterized by steady accumulation of pigment
“lipofuscin”.
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Theories of cellular aging:
l) wear and tear group theories:
a)free radical damage theory,
b) posttranslational modification theory;
2) genome-based theories:
a)somatic mutation hypothesis,
b) programmed aging hypothesis,
c) finite cell replication hypothesis.
Morphology of acute cell injury is of three types:
1. Reversible injury (Degeneration).
2. Necrosis.
3. Apoptosis.
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1. Reversible cell injury (Degeneration)
Reversible cell injury refers to morphologic changes resulting from
nonlethal injury to cell.
Two patterns of reversible injury can be recognized under light
microscope:
1) Cellular swelling - is the first manifestation of almost all form of
injury to cell. When It affects all cells in an organ, it shows pallor,
turgidity (swelling) and increase in weight of the organ. On
microscopic examination, small clear vacuoles are seen within
cytoplasm, which represent distended and pinched-off segments of
endoplasmic reticulum. This pattern is also called “hydropic change”
or “vacuolar degeneration”. It occurs due to inability of cell to
maintain ionic and fluid homeostasis.
2) Fatty change - it is encountered basically in cells involved in fat
metabolism, such as hepatocyte and myocardial cell. It occurs in
response to hypoxic and various forms of toxic injury.
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2. Necrosis
Necrosis refers to a spectrum of morphologic changes that follow cell
death in living tissue, largely resulting from the progressive
degradative action of enzymes on the lethally injured cell. The
morphologic appearance of necrosis is the result of two essentially
concurrent processes:
1) enzymic digestion of cell - this is of two types:
a) autolysis - digestion of cell by enzymes derived from their own
lysosomes;
b) heterolysis - digestion of cell by enzymes derived from lysosomes
of immigrant leukocytes.
2) denaturation of proteins caused by intracellular acidosis.
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Morphology of necrosis.
A. Microscopic morphology - consists of three stages:
1) Changes in nucleus:
a) Pyknosis - it refers to condensation and shrinkage of DNA into a solid mass of
increased basophilia (blue staining);
b) Karyorrhexis - it refers to fragmentation of pyknotic (condensed) nuclear mass;
c) Karyolysis - it refers to fading of basophilia of chromatin due to digestion of DNA
by DNAses activated by decrease pH. Nucleus disappears in 1 or 2 days.
2) Changes in cytoplasm:
a) Increased eosinophilia (pink staining) due to loss of RNA and denaturation of
cytoplasmic proteins;
b) Digestion of cytoplasmic organelles leading to vacuolated cytoplasm and appears
moth-eaten.
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B. Gross morphology
(Types of necrosis).
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1) Coagulative necrosis.
In this type of necrosis, the necrotic cells retain its
cellular outline often over several days.
The cell devoid its nucleus, appears as a mass of
coagulated, pink- staining, homogenous cytoplasm.
This type of necrosis typically occurs in solid organs,
such as the kidney, heart, liver, adrenal gland.
Grossly - area of necrosis is yellow-white in color
and hard in consistence.
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2) Colliquative necrosis.
Liquefaction of necrotic cells results. when lysosomal enzymes
released by the necrotic cells cause rapid liquefaction
This type of necrosis is typically seen in the brain and spinal
cord.
Liquefactive necrosis also occurs during pus formation as a
result of the action of proteolytic enzymes released by
neutrophils.
Grossly - area of necrosis is grey and soft.
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3) Fat necrosis.
a) Enzymatic - most characteristically occurs in acute pancreatitis
(inflammation of pancreas) and pancreatic injures when pancreatic
enzymes are liberated from the ducts into surround tissue.
The gross appearance is one of opaque chalky white plaques and
nodules in the adipose tissue surrounding the pancreas;
b) Nonenzymatic (traumatic) - occurs in the breast, subcutaneous fat
and abdomen.
Many patients have a history of trauma.
This type of necrosis evokes an inflammatory response characterized
by numerous foamy macrophages, neutrophils and lymphocytes.
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4) Caseous necrosis.
Caseous (caseation, cheesy degeneration) necrosis
occurs in tuberculosis infection.
Grossly appears coagulative, white-yellow, cheesy
areas.
Microscopically, the necrotic focus appears as
amorphous granular debris composed of fragmented,
coagulated cells enclosed within a distinctive
inflammatory border.
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5) Fibrinoid necrosis.
It is a type of connective tissue necrosis seen particularly in
autoimmune disease (rheumatic fever etc.).
Collagen and smooth muscle in the media of blood vessels are
especially involved.
Fibrinoid necrosis of arterioles also occurs in malignant
hypertension.
This type of necrosis is characterized by loss of normal structure
and replacement by a homogenous, bright pink-staining
necrotic material that resembles fibrin microscopically.
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6) Gangrene.
It is necrosis of tissues which contacting with air and bacteria.
a) Dry - most commonly occurs in the extremities as a result of ischemic
coagulative necrosis of tissues due to arterial obstruction. The necrotic area
appears black, dry, shriveled, and sharply demarcated from adjacent viable
tissue. Treatment consists of surgical removal of dead tissue;
b) Wet - results from severe bacterial infection superimposed on necrosis. It
occurs in the extremities as well as in internal organs such as the intestine
and lungs. The necrotic area becomes swollen and reddish-black with
extensive liquefaction of dead tissue. Wet gangrene is a spreading
necrotizing inflammation that is not clearly demarcated from adjacent
healthy tissue.
c) Gas - is a wound infection caused by Clostridium perfringens and other
clostridial species. It is characterized by extensive necrosis of tissue and
production of gas by the fermentative action of the bacteria. The gross
appearance is similar to that of wet gangrene, with additional presence of
gas in the tissues.
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C. Outcomes (local fate) of necrosis:
1) Organization - formation of scar due to growth of fibrous
tissue.
2) Calcification - deposition of calcium in dead tissue.
3) Ossification - formation of bone tissue, usually associated
with calcification.
4) Encapsulation - formation of fibrous capsule around of
necrotic tissue.
5) Cyst formation - formation of cavity surrounded with thin
capsule and filled with serous fluid.
6) Supportive (suppuration, purulence) inflammation -
formation of pus due to action of bacteria.
7) Ulceration of epithelial surfaces - defect of epithelium due to
shed of dead epithelial cells.
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3. Apoptosis - programmed cell death.
(“Dropping off’).
It is a pattern of cell death in which single or cluster of cells appear on
sections stained with H. & E. as round or oval masses of intensely
eosinophilic cytoplasm and dense nuclear chromatin fragments (apoptotic
bodies) which are taken up and degraded by phagocytotic cells.
Characteristic features:
1) Chromatin condensation and formation of membrane blebs.
2) Fragmentation of DNA into nucleosome - sized particles (apoptotic
bodies) due to activation of endonuclease caused by increase cyotsolic
Ca++.
3) Requires for RNA and protein synthesis.
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Created by: mbbshelp.com

Cell injury, Cell Death

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Cell injury, Cell Death