Cellular Adaptations, Injury and

Death
Lecture outline
 Cellular adaptations to Stress
 Causes of cellular injury
 Tissue necrosis
 Apoptosis
Adaptations
 Adaptations are reversible changes in the number, size,
appearance, metabolic activity, or functions of cells in
response to changes in their environment.
 Physiologic adaptations usually represent responses of
cells to normal stimulation by hormones or endogenous
chemical mediators (e.g., the hormone-induced enlargement
of the breast and uterus during pregnancy).
 Pathologic adaptations are responses to stress that allow
cells to modulate their structure and function and thus escape
injury. Such adaptations can take several distinct forms.
Cellular and Tissue adaptation to stress

Hypertrophy
Hyperplasia
Atrophy
Metaplasia

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 Adaptation To Environmental stress
 Hypertrophy
 Atrophy
 Hyperplasia
 Metaplasia

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Hypertrophy
 An increase in the size of cells resulting in increase in
the size of the organ.
 Caused either by increased functional demand or
by specific hormonal stimulation.
 Physiologic Hypertrophy
 eg massive enlargement of the uterus during
pregnancy and
 the development of a rippled physique of the avid
weight lifter
 Pathologic Hypertrophy
 eg. cardiac enlargement that occurs with
hypertension or aortic valve disease.
Hyperplasia
 Characterized by an increase in cell number
 Hyperplasia is an adaptive response in cells capable of
dividing.
 Physiologic hyperplasia maybe:
 (1) hormonal hyperplasia
 eg the proliferation of the glandular epithelium of the
female breast at puberty and during pregnancy; or

 (2) compensatory hyperplasia which occurs when a

portion of the tissue is removed or diseased.
Hyperplasia
 Most forms of pathologic hyperplasia are caused
by excessive hormonal or growth factor
stimulation i.e
 in certain viral infections eg skin warts caused
by HPVs.

 Pathologic hyperplasia constitutes a fertile soil in

which cancerous proliferation may eventually
arise
Atrophy
 Shrinkage in the size of the cell by the loss of cell
substance.
 When a sufficient number of cells is involved, the
entire tissue or organ diminishes in size,
becoming atrophic.
 It should be emphasized that although atrophic
cells may have diminished function, they are not
dead.
Atrophy is caused by
- decreased workload,
- denervation,
- diminished blood supply,
- inadequate nutrition,
- loss of endocrine stimulation, and
- aging (senile atrophy).
Metaplasia
 Metaplasia is a reversible change in which one
adult cell type (epithelial or mesenchymal) is
replaced by another adult cell type.
 In this type of cellular adaptation, cells sensitive
to a particular stress are replaced by other cell
types better able to withstand the adverse
environment.
 Epithelial metaplasia is exemplified by the
squamous change that occurs in the respiratory
epithelium in habitual cigarette smokers.
 The normal ciliated columnar epithelial cells of
the trachea and bronchi are focally or widely
replaced by stratified squamous epithelial cells.
Cell injury
Cell injury
• If the cells fail to adapt under stress, they
undergo certain changes called cell injury.
 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 lead to loss of cell function long before
damage is morphologically recognizable
 The affected cells may recover from the injury
(reversible) or may die (irreversible).
 When the cell is exposed to an injurious agent or
stress, a sequence of events follows that is loosely
termed cell injury
 Cell injury is reversible up to a certain point
 If the stimulus persists or is severe enough from
the beginning, the cell reaches a point of no
return and suffers irreversible cell injury and
ultimately cell death.
 Cell death, is the ultimate result of cell injury
Reversible vs Irreversible cell
Injury
 Patterns Of Cell Death
• There are two principal patterns of cell death:
1- Necrosis and
2- Apoptosis
 Necrosis
• Necrosis is the type of cell death that occurs after ischemia and
chemical injury

• Necrosis is always pathologic.

 Apoptosis
• Apoptosis occurs when a cell dies through activation of
an internally controlled suicide program; programmed cell
death.
• Apoptosis is designed to eliminate unwanted cells during
embryogenesis and in various physiologic processes and
certain pathologic conditions.
• It is a pathway of cell death that is induced by a tightly
regulated intracellular program in which cells
destined to die activate their own enzymes to degrade
their own nuclear DNA, nuclear proteins and
cytoplasmic proteins
Causes of Cell injury
 Oxygen deprivation(Hypoxia) affect aerobic respiration
and therefore ability to generate adenosine
triphosphate(ATP).
Hypoxia can be due to :
 inadequate oxygenation of the blood due to
Cardiorespiratory failure
 loss of the oxygen-carrying capacity of the blood, as in
anemia or carbon monoxide poisoning.
Depending on the severity of the hypoxic state, cells may
adapt, undergo injury, or die.
 Physical agents including trauma(hummer blow to the
thumb), t heat, cold, radiation and electric shock.
 Chemical agents and drugs including therapeutic drugs,
poisons and environmental pollutants and social
stimuli(alcohol and narcotics)
 Infectious agents including viruses, bacteria, fungi and
parasites.
 Immunologic agents including autoimmune
diseases and cell injury following responses to
injury.
 Genetic derangements such as chromosomal
alterations and specific gene mutations
 Nutritional imbalances including protein-calorie
deficiency or lack of specific vitamins as well as
nutritional excess.
Dietary excess
 can likewise lead to cellular and tissue alterations
that are detrimental e.g. fat is the biggest offender, or
excess ingestion of "health supplements

 Aging:Cellular senescence leads to alterations in

replicative and repair abilities of individual cells and
tissues. All of these changes result in a diminished
ability to respond to damage and, eventually, the
death of cells and of the organism.
Mechanisms of Cell Death/ Injury
 Mechanisms of cell death caused by different agents may vary.
However, certain biochemical events are seen in the process of cell
necrosis:
 ATP depletion
 Loss of calcium homeostasis and free cytosolic calcium
 Free radicals: superoxide anions, Hydroxyl radicals,
hydrogen peroxide
 Defective membrane permeability
 Mitochondrial damage
 Cytoskeletal damage
 Morphology of Cell Injury
Reversible
• Hydropic Change: one of the early signs of cellular
degeneration in response to injury; refers to the
accumulation of water in the cell
• Fatty changes: The lipid accumulates in the hepatocytes
as vacuoles.
-The most common cause of fatty change in developed
nations is alcoholism.
- In developing nations, kwashiorkor in children is another
cause.
- Diabetes mellitus, obesity, and severe gastrointestinal
malabsorption are additional causes.
 Morphology of Cell Injury…
• Irreversible/Necrosis
– The changes are produced by enzymatic digestion of
dead cellular elements, denatunation of proteins and
autolysis (by lysosomal enzymes)
– Cytoplasm - increased eosinophilia
– Nucleus - nonspecific breakdown of DNA leading to
• pyknosis (shrinkage),
• karyolysis (fading) and
• karyorrhexis (fragmentation).
Cell death
 With continuing damage, the injury becomes
irreversible, at which time the cell cannot recover and it
dies.
 There are two types of cell death
 Necrosis
 Apoptosis.
• Differ in their morphology, mechanisms, and roles in
disease and physiology
Necrosis
 Results when damage to membranes is severe, enzymes
leak out of lysosomes, enter the cytoplasm, and digest
the cell.
 Cellular contents also leak out through the damaged
plasma membrane and elicit a host reaction
(inflammation).
 Necrosis is the major pathway of cell death in many
commonly encountered injuries, such as those resulting
from ischemia, exposure to toxins, various infections,
and trauma.
Pattern of necrosis
Coagulative necrosis
• Is a form of tissue necrosis in which the
component cells are dead but the basic tissue
architecture is preserved for at least several days.
• The affected tissues take on a firm texture.
• Most often results from sudden interruption of
blood supply to an organ. Eg Mycardial infarction
Liquefactive necrosis
• Seen in focal bacterial or, occasionally, fungal
infections, because microbes stimulate the
accumulation of inflammatory cells and the enzymes
of leukocytes digest ("liquefy") the tissue.
• the dead cells undergo disintegration and affected
tissue is liquified. Example: cerebral infarction.
• usually associated with cellular destruction and pus
formation (e.g. pneumonia).
• ischemia (restriction of blood supply) in the brain
produces liquefactive rather than coagulative necrosis.
• Characterized by softening and digestion (liquefaction)
of tissue.
Gangrenous necrosis is
• Due to vascular occlusion.
• Most often affects the lower extremities & the bowel
• It is called wet gangrene if it is complicated by
bacterial infection which leads to superimposed
liquefactive necrosis.
• Whereas it is called dry gangrene if there is only
coagulative necrosis without liquefactive necrosis.
 Caseous Necrosis The term "caseous" (cheese-like) is derived
from the friable yellow-white appearance of the area of necrosis.
It is encountered most often in foci of tuberculous infection.
Fat necrosis
• Caused by trauma to tissue with high fat content, such as the
breast
• It can also be caused by acute hemorrhagic pancreatitis in
which pancreatic enzymes diffuse into the inflamed
pancreatic tissue & digest it.
• The fatty acids released from the digestion form calcium salts
(soap formation or dystrophic calcification).
• In addition, the elastase enzyme digests the blood vessels &
cause the hemorrhage inside the pancreas, hence the name
hemorrhagic pancreatitis.
Fibrinoid necrosis
 Usually seen in immune reactions involving blood
vessels.
 Deposition of antigen-antibody complexes in blood
vessels
Apoptosis
 When a cell is deprived of growth factors or the cell's
DNA or proteins are damaged beyond repair, the cell
kills itself by another type of death, called apoptosis.
 Characterized by nuclear dissolution without complete
loss of membrane integrity.
 Apoptosis is an active, energy-dependent, tightly
regulated type of cell death that is seen in some specific
situations.
 Whereas necrosis is always a pathologic process,
apoptosis serves many normal functions and is not
necessarily associated with pathologic cell injury.
Causes of apoptosis
Physiologic causes
 Programmed deletion during embryogenesis
 Cell deletion in proliferating cell population
 Death of cells that have served their useful purpose
Pathologic causes
 DNA damage(Due to hypoxia, radiation or cytotoxic
drugs
 Cell death in certain viral infections(hepatitis)
Necrosis vs. Apoptosis
• Cellular swelling • Cellular condensation
• Membranes are broken • Membranes remain intact
• ATP is depleted • Requires ATP
• Cell lyses, eliciting an • Cell is phagocytosed, no
inflammatory reaction tissue reaction
• DNA fragmentation is • Ladder-like DNA
random, or smeared fragmentation
• In vivo, whole areas of the • In vivo, individual cells
tissue are affected appear affected
• Always pathologic • May be physiologic
Table 1-2;Features of Necrosis and Apoptosis
Feature Necrosis Apoptosis

Cell size Enlarged (swelling) Reduced (shrinkage)

Pyknosis ➙ karyorrhexis ➙ Fragmentation into

Nucelus
karyolysis nucleosome size fragments

Intact; altered structure,

Plasma membrane Disrupted especially orientation of
lipids

Enzymatic digestion; may Intact; may be released in

Cellular contents
leak out of cell apoptotic bodies

Adjacent inflammation Frequent No

Often physiologic, means of

Invariably pathologic eliminating unwanted cells;
Physiologic or pathologic
(culmination of irreversible may be pathologic after
role
cell injury) some forms of cell injury,
especially DNA damage
 Cell Death: Necrosis & Apoptosis

40 February 28, 2018

 Pathologic calcification
 Abnormal tissue deposition of calcium salts—occurs in
two forms:
 Dystrophic calcification arises in nonviable tissues in the
presence of normal calcium serum levels.
 Metastatic calcification happens in viable tissues in the
setting of hypercalcemia.

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 Dystrophic calcification

 Calcification in previously damaged tissue,

 Deposition occurs in dead tissue or degenerative
tissue
 Its encountered in necrosis, damaged heart
valves, tuberculosis lesions and atheromas of
advanced atherosclerosis
 Calcium serum levels are normal
.

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 Metastatic calcification
 Occurs in normal tissue whenever theres
hypercalcemia
 Reflects some derangement in calcium
metabolism (hypercalcemia).
 Serum calcium levels are elevated
 The cause of metastatic calcification is
hypercalcemia.

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  Hypercalcemia most often results from any of the
following causes:
(1) Elevated parathyroid hormone(eg Hyperparathyroidism
due to parathyroid tumors)
(2) Bone desruction in osteolytic tumors with resultant
mobilization of calcium and phosphorus
(3) Hypervitaminosis D
(4) Excess calcium intake, such as in the milk–alkali
syndrome (nephrocalcinosis and renal stones caused by
milk and antacid self-therap

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 Pathologic calcification

Dystrophic calcification of the aortic valve.

View looking down onto the unopened aortic valve in a
heart with calcific aortic stenosis. It is markedly
View looking down onto the unopened aortic valve in a narrowed (stenosis). The semilunar cusps are thickened
heart with calcific aortic stenosis. Behind each cusp are and fibrotic, and behind each cusp are irregular masses of
seen45irregular masses of piled-up dystrophic calcification. piled-up dystrophic calcification.
 Cellular Aging
 Is the result of a progressive decline in the
proliferative capacity and life span of cells and the
effects of continuous exposure to exogenous
factors that cause accumulation of cellular and
molecular damage.

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  Cellular aging is associated with
Increasing DNA damage
Decreased cellular replication
Reduced regenerative capacity of tissue stem
cells
Accumulation of metabolic damage

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