Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
CELL ADAPTATIONS, CELL INJURY and CELL DEATH
Cells maintain normal homeostasis; they are constantly adjusting their structure and function
to accommodate changing demands and extracellular stresses.
Adaptations
 are reversible changes in the cells in response to changes in their environment.
 When the stress is eliminated the cell can recover to its original state .
HYPERTROPHY
 Is an increase in the size of cells, resulting in an increase in the size of the organ.
 No new cells, just bigger cells enlarged by an increased amount of structural proteins and
organelles.
 Hypertrophy and hyperplasia(increase in cell number) can also occur together, and
result in an enlarged (hypertrophic) organ. Thus, the massive physiologic enlargement of
the uterus during pregnancy occurs as a consequence of estrogen-stimulated smooth
muscle hypertrophy and smooth muscle hyperplasia.
 In contrast, the striated muscle cells in both the skeletal muscle and the heart can
undergo only hypertrophy in response to increased demand because in the adult they
have limited capacity to divide.
 Can be:
 Physiological :

Muscles hypertrophy of bodybuilders caused by increased workload.

Enlargement of the uterus during pregnancy caused by estrogen.
 Pathological:
Myocardial muscle fibers hypertrophy resulting from hypertension.
HYPERPLASIA
 Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting
in increased mass of the organ or tissue.
 Occurs in cells capable of replication
 Can occur with hypertrophy and often in response to the same stimuli e.g pregnant
uterus
 Hyperplasia can be physiologic or pathologic:
1
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
Physiologic Hyperplasia
 The proliferation of the glandular epithelium of the female breast in puberty and
pregnancy.
 When a liver is partially resected, mitotic activity in the remaining cells begins as early
as 12 hours later, eventually restoring the liver to its normal weight. The stimuli for
hyperplasia are polypeptide growth factors produced by remnant hepatocytes as well
as nonparenchymal cells in the liver.
Pathologic Hyperplasia
 Endometrial hyperplasia due to increases in the amount of estrogen, with consequent
hyperplasia of the endometrial glands. This is a common cause of abnormal menstrual
bleeding.
 Benign prostatic hyperplasia induced by androgens.
The hyperplastic process remains controlled; if hormonal or growth factor stimulation
abates, the hyperplasia disappears while in cancer the growth control mechanisms
become dysregulated .However, pathologic hyperplasia constitutes a risk for cancerous
proliferation. Thus, patients with hyperplasia of the endometrium are at increased risk of
developing endometrial cancer.
ATROPHY
 Shrinkage of the size of the cell by the loss of cell substance.
 When a sufficient number of cells involved , the entire tissue or organ diminishes in
size , becoming atrophic.
 Although atrophic cells may have diminished function, they are not dead.
 Atrophy results from decreased protein synthesis and increased protein
degradation in cells.
 The common causes of atrophy are the following:
 Decreased workload (disuse atrophy): skeletal muscle atrophy due to immobilization
caused by fractured bone.
 Loss of innervation (denervation atrophy). Nerve damage
 Diminished blood supply (ischemia): Brain atrophy in elderly because of reduced
blood supply as a result of atherosclerosis.

Inadequate nutrition: is associated with the use of skeletal muscle as a source of
energy after other reserves such as adipose stores have been depleted.

Loss of endocrine stimulation : e.g: loss of hormone stimulation after menapause leads
to endometrial atrophy.
2
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa

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.
 It may represent substitution of cells that are sensitive to stress by cell types better
able to withstand the adverse environment.
 It is a genetic “reprogramming” of stem cells and not changing of already
differentiated cells
 Metaplastic cells survive but protective mechanism is lost.
 If the influences are persistent, there is an increased chance of malignant
transformation
Types of metaplasia:
1) Epithelial metaplasia :
a)Metaplasia from columnar to squamous ( Squamous metaplasia) .E.g.,In the
habitual cigarette smoker, the normal ciliated columnar epithelial cells of the trachea
and bronchi are often replaced by stratified squamous epithelial cells. Although the
metaplastic squamous epithelium has survival advantages, important protective
mechanisms are lost, such as mucus secretion and ciliary clearance. Lung cancer
(squamous cell carcinoma) may arise later in areas of squamous metaplasia
b)Metaplasia from squamous to columnar type may also occur, as in Barrett
esophagus, in which the esophageal squamous epithelium is replaced by intestinal-like
columnar cells under the influence of refluxed gastric acid. Cancers may arise in these
areas; these are typically glandular (adeno)carcinomas
2) Connective tissue metaplasia : Bone is occasionally formed in soft tissues (fibrous tissue)
in foci of injury.
Cell Injury and Cell Death
 Cell injury occurs when cells are exposed to severe stress or damaging agents that they
are no longer able to adapt .
 Cell injury is reversible up to a certain point, but if the stimulus persists or is severe,
the cell suffers irreversible injury and ultimately cell death.
3
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
Reversible cell injury
In early stages or mild forms of injury, the changes are reversible if the damaging stimulus is
removed. At this stage, although there may be significant structural and functional
abnormalities, the injury has not progressed to severe membrane damage and nuclear
dissolution. The hallmarks of reversible injury is depletion of energy stores (ATP),
and cellular swelling.
Irreversible cell injury (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 and apoptosis -which differ in their
morphology, mechanisms, and roles in disease and physiology.
 When large numbers of cells die the tissue or organ is said to be necrotic.
 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.
 Severe depletion of ATP and loss of membrane integrity are typically associated with
necrosis
 There is membrane damage of necrotic cells ;their contents leak out; this can result in
an inflammation in the surrounding tissue.
4
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
 The enzymes that digest the necrotic cell are derived from the lysosomes of the dying
cells(autolysis)
 Release of enzymes from the breakdown tissue into the blood forms the basis of
clinical tests for diagnosis e.g:

Heart – creatine kinase, troponin

Liver – alkaline phosphatase, transaminases (ALT, AST)
 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.
 It is characterized by nuclear dissolution without complete loss of membrane integrity.
 Apoptosis is an active and regulated process not associated with ATP depletion.
 Whereas necrosis is always a pathologic process, apoptosis serves many normal
functions and is not necessarily associated with pathologic cell injury.
 Cellular function may be lost long before cell death occurs, and the morphologic changes
of cell injury (or death) occur later .For example, myocardial cells become
noncontractile after 1 to 2 minutes of ischemia, although they do not die until 20 to 30
minutes have passed. These myocytes appear dead by electron microscopy after 2 to 3
hours, and by light microscopy after 6 to 12 hours.
Causes of Cell Injury
1. Hypoxia (deficiency of oxygen) due to: (i) Ischaemia (ii) decrease of oxygen carrying
capacity of blood due to anaemia, cardiac or respiratory failure and CO poisoning.
2. Physical Agents: burns, deep cold, radiation, mechanical trauma and electric shock.
3. Chemical Agents and Drugs: e.g. alkalis, acids, insecticides, alcohol and narcotic drugs
& air pollutants et..
4. Infectious Agents:e.g. viruses, bacterial toxins, fungi and parasites.
5. Immunologic Reactions: (Hypersensitivity).
6. Genetic Derangements: as in Down syndrome & sickle cell anemia.
7. Nutritional imbalances such as protein calorie malnutrition, starvation and deficiency
of vitamins, and excesses in nutrition as obesity and diabetes mellitus.
Changes of reversible cell injury
Two features of reversible cell injury can be recognized under the light microscope:
5
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
 1.Cellular swelling is the result of failure of energy-dependent ion pumps in the plasma
membrane.
 2. Fatty change :It is the appearance of lipid vacuoles in the cytoplasm. It is seen in
cells dependent on fat metabolism, such as hepatocytes and myocardial cells.
The ultrastructural changes (Electron microscopic) (EM) of reversible cell injury
include:
1. Blebbing of plasma membrane
2.
3.
Mitochondrial swelling
Detachment of ribosomes from the ER
4. Nuclear chromatin clumping.
6
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
Changes of irreversible cell injury “necrosis”
By light microscopy:
 Cytoplasm of necrotic cells show increased eosinophilia.
 Nuclear changes appear in one of three patterns:
 Pyknosis: nuclear shrinkage and increased basophilia.
 Karyorrhexis: nucleal fragmentation.
 Karyolysis: The basophilia of the chromatin may fade.
With the passage of time (a day or two), the nucleus in the necrotic cell totally disappears
By electron microscopy:
 1.Defect in the cell membrane
 2. lysis of ER
 3.Rupture of lysosomes and autolysis
 4.Nucleus: Pyknosis,karyorhexis, karyolysis
Patterns of Tissue Necrosis
1. Coagulative necrosis: the architecture of dead tissues is preserved. The cells are
eosinophilic, anucleated cells.
 Cause: Ischemia in all organs except the brain.
 A localized area of coagulative necrosis is called an infarct.
7
.
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
2. Liquefactive necrosis: is characterized by digestion of the dead cells, resulting in
transformation of the tissue into a liquid.
Examples:
 Hypoxic cell death of the brain
 Abscess
3. Gangrenous necrosis: It is usually applied to a limb, generally the lower leg, that has lost
its blood supply and has undergone necrosis (coagulative necrosis). When bacterial infection
is superimposed there is more liquefactive necrosis because of the actions of degradative
enzymes of the bacteria and leukocytes (giving rise to wet gangrene).
4. Caseous necrosis: is seen in tuberculous infection .The term “caseous” (cheeselike) is
derived from the friable white appearance of the area of necrosis.
5. Fat necrosis:
 Enzymatic fat necrosis: occurs in acute pancreatitis. Pancreatic enzymes leak out and
liquefy the fat cells in the peritoneum. The derived fatty acids combine with calcium to
produce chalky-white areas (fat saponification).
 Traumatic fat necrosis: e.g .fat necrosis of breast after trauma which induces rupture of
fat cells. The released fat causes chronic inflammation and foreign body reaction,
resulting in a hard mass mistaken as malignant tumor.
6. Fibrinoid necrosis:
 It is seen in immune reactions involving blood vessels (e.g.polyarteritis nodosa) .
Complexes of antigens and antibodies “immune complexes,” are deposited in the walls
of arteries resulting in a bright pink and amorphous appearance “fibrinoid” (fibrin-like)
in H&E.
Mechanisms of Cell Injury
1.DEPLETION OF ATP
The major causes are reduced supply of oxygen ( ischemia) and nutrients, and some toxins
(e.g., cyanide).
Tissues with a greater glycolytic capacity (e.g., the liver) are able to survive better than are
tissues with limited capacity for glycolysis (e.g., the brain).
Depletion of ATP to less than 5% to 10% of normal levels has widespread effects on many critical
cellular systems:
 The activity of the plasma membrane energy-dependent sodium pump is reduced,
resulting in intracellular accumulation of sodium and water and efflux of potassium.
causing cell swelling and dilation of the ER.
8
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
 Increase in anaerobic glycolysis ,intracellular glycogen is depleted, and lactic acid
accumulates, leading to decreased intracellular pH and decreased activity of many
cellular enzymes.
 Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous
cellular components.
 Prolonged or worsening depletion of ATP causes structural disruption of the protein
synthetic apparatus, manifested as detachment of ribosomes from the rough
endoplastic reticulum (RER) with a consequent reduction in protein synthesis.
 Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes,
and the cell undergoes necrosis.
2. MITOCHONDRIAL DAMAGE
Mitochondria can be damaged by increases of cytosolic Ca2+, reactive oxygen species ,hypoxia
and toxins. Mitochondrial damage results in failure of oxidative phosphorylation and
progressive depletion of ATP, culminating in necrosis of the cell.
9
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
3. INFLUX OF CALCIUM: Ischemia and certain toxins cause an increase in cytosolic calcium
concentration. Increased cytosolic Ca2+ activates a number of enzymes, including:
phospholipases (which cause membrane damage), proteases (which break down both
membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and
chromatin fragmentation), and adenosine triphosphatases (ATPases; causing ATP depletion).
4. ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS)
Free radicals are chemical species with a single unpaired electron in an outer orbital. Such
chemical states are extremely unstable and readily react with inorganic and organic chemicals;
when generated in cells they avidly attack nucleic acids as well as a variety of cellular proteins
and lipids. In addition, free radicals initiate autocatalytic reactions; molecules that react with
free radicals are in turn converted into free radicals, thus propagating the chain of damage.
Reactive oxygen species (ROS) are a type of oxygen-derived free radical whose role in cell
injury is well established. They are produced normally in cells during mitochondrial
respiration and energy generation, but they are degraded and removed by cellular defense
systems. When the production of ROS increases or the scavenging systems are ineffective, the
result is an excess of these free radicals, leading to a condition called oxidative stress. Cell
injury in many circumstances involves damage by free radicals; these situations include:
ischemia-reperfusion, chemical and radiation injury, oxygen toxicity, infection, and
inflammation.
Free radicals are unstable and decay spontaneously. Cells have developed many mechanisms
to remove free radicals:
 Superoxide dismutases (SODs)
 Glutathione (GSH) peroxidase
 Catalase
 Endogenous or exogenous antioxidants (e.g., vitamins E, A, and C, and β-carotene)
Three reactions are particularly occur in cell injury mediated by free radicals
 Lipid peroxidation of membranes: The lipid-radical interactions yield peroxides, which
are themselves unstable and reactive, and an autocatalytic chain reaction ensues.
 Cross-linking of proteins: resulting in enhanced degradation of proteins.
 DNA fragmentation.
10
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
 5. DEFECTS IN MEMBRANE PERMEABILITY
The plasma membrane can be damaged by ischemia, various microbial toxins, and a
variety of physical and chemical agents. Leads ultimately to membrane damage
(mitochondrial membrane, the plasma membrane, and membranes of lysosomes).
6. DAMAGE TO DNA AND PROTEINS
If damage is too severe to be corrected (e.g., after radiation injury or oxidative stress), the cell
initiates its suicide program and dies by apoptosis.
Apoptosis
 Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide
program in which cells destined to die activate enzymes capable of degrading the cells'
own nuclear DNA and nuclear and cytoplasmic proteins.
 Fragments of the apoptotic cells then break off, giving the appearance that is
responsible for the name (apoptosis, "falling off").
 The plasma membrane of the apoptotic cell remains intact, but the membrane is
altered in such a way that the cell and its fragments become avid targets for
phagocytes.
 The dead cell is rapidly cleared before its contents have leaked out, and therefore cell
death by this pathway does not elicit an inflammatory reaction in the host.
 Thus, apoptosis differs from necrosis, which is characterized by loss of membrane
integrity, enzymatic digestion of cells, leakage of cellular contents, and frequently a
host reaction.
 However, apoptosis and necrosis sometimes coexist, and apoptosis induced by some
pathologic stimuli may progress to necrosis.
MORPHOLOGIC CHANGES IN APOPTOSIS
 Cell shrinkage.
 The nucleus breaks up into small fragments.
 Formation of apoptotic bodies composed of cytoplasm nuclear fragments and
organelles
 The apoptotic bodies are rapidly ingested by phagocytes.
 Plasma membranes remain intact during apoptosis
11
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
 On histologic examination, in tissues stained with hematoxylin and eosin, the
apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with
dense nuclear chromatin fragments.
Feature
Necrosis
Apoptosis
Cell size
Enlarged (swelling)
Reduced (shrinkage)
Nucleus
Pyknosis ➙
karyorrhexis ➙
karyolysis
Fragmentation into
nucleosome-size fragments
Plasma
membrane
Disrupted
Intact
Cellular contents
Enzymatic digestion; Intact
may leak out of cell
Adjacent
inflammation
Frequent
No
Physiologic or
pathologic role
pathologic
Often physiologic,
may be pathologic after some
forms of cell injury, especially
DNA damage
12
Cell adaptations and cell injury
2014-2015/Dr.Ban Jumaa
CAUSES OF APOPTOSIS
Physiologic

During embryogenesis
 Involution of hormone-dependent tissues upon hormone withdrawal,
such as, the regression of the lactating breast after weaning

Cell loss in proliferating cell populations, such as, epithelial cells in
intestinal crypts, to maintain a constant number.
 Death of cells that served their purpose: Neutrophils in an acute
inflammatory response
 Elimination of potential harmful self-reactive lymphocytes :Prevents
reaction against one’s own tissue.
 Cell death by cytotoxic T lymphocytes , a defense mechanism against viruses
and tumors.
Pathological
 DNA damage: Radiation, cytotoxic anticancer drugs
 Accumulation of misfolded protein:. Because of mutations in the genes or free
radicals.
 Viral infections e.g. viral hepatitis in which apoptotic cells are known as
councilman bodies and HIV infections)
 Pathologic atrophy in paranchymal organs after duct obstruction such
pancreas and parotid gland.
13