CELL INJURY-2 by DR. ROOPAM JAIN

Cell Injury, Cellular Adaptations &
Cellular Ageing
2
DR. ROOPAM JAIN
PROFESSOR & HEAD, PATHOLOGY

• effect of a variety of stresses due to etiologic agents a cell
encounters resulting in changes in its internal and external
environment
• The cellular response to stress may vary and depends upon
following two variables:
• i) Host factors i.e. the type of cell and tissue involved.
• ii) Factors pertaining to injurious agent i.e. extent and type of
cell injury.

Cellular responses to cell injury

ETIOLOGY OF CELL INJURY
• The cells may be broadly injured by two major ways:
• A. Genetic causes
• B. Acquired causes

Acquired causes
• 1. Hypoxia and ischaemia
• 2. Physical agents
• 3. Chemical agents and drugs
• 4. Microbial agents
• 5. Immunologic agents
• 6. Nutritional derangements
• 7. Ageing
• 8. Psychogenic diseases
• 9. Iatrogenic factors
• 10. Idiopathic diseases.

HYPOXIA AND ISCHAEMIA
• Th e most common mechanism - by reduced supply
of blood to cells due to interruption i.e. ischaemia.
• impaired blood supply from causes other than
interruption e.g. disorders of oxygencarrying RBCs
(e.g. anaemia, carbon monoxide poisoning), heart
diseases, lung diseases and increased demand of
tissues

PHYSICAL AGENTS
• i) mechanical trauma (e.g. road accidents);
• ii) thermal trauma (e.g. by heat and cold);
• iii) electricity;
• iv) radiation (e.g. ultraviolet and ionising); and
• v) rapid changes in atmospheric pressure.

CHEMICALS AND DRUGS
• i) chemical poisons such as cyanide, arsenic, mercury;
• ii) strong acids and alkalis;
• iii) environmental pollutants;
• iv) insecticides and pesticides;
• v) oxygen at high concentrations;
• vi) hypertonic glucose and salt;
• vii) social agents such as alcohol and narcotic drugs; and
• viii) therapeutic administration of drugs.

MICROBIAL AGENTS
• Injuries by microbes include infections caused
by bacteria, rickettsiae, viru ses, fungi,
protozoa, metazoa, and other parasites

IMMUNOLOGIC AGENTS
• i) hypersensitivity reactions;
• ii) anaphylactic reactions; and
• iii) autoimmune diseases

NUTRITIONAL DERANGEMENTS
• Nutritional deficiency diseases may be due to overall
deficiency of nutrients (e.g. starvation), of protein
calorie (e.g. marasmus, kwashiorkor), of minerals (e.g.
anaemia), or of trace elements.
• Nutritional excess is a problem of affluent societies
resulting in obesity, atherosclerosis, heart disease and
hypertension.

AGEING
• Cellular ageing or senescence leads to impaired ability
of the cells to undergo replication and repair, and
ultimately lead to cell death culminating in death of the
individual.

common scheme applies to most forms of cell injury by
various agents:
• 1. Factors pertaining to etiologic agent and host
• 2. Common underlying mechanisms
• 3. Usual morphologic changes
• 4. Functional implications and disease outcome

PATHOGENESIS OF ISCHAEMIC &
HYPOXIC INJURY

REVERSIBLE CELL INJURY
• 1. Decreased generation of cellular ATP: Damage by
ischaemia from interruption versus hypoxia from other
causes
• 2. Intracellular lactic acidosis: Nuclear clumping
• 3. Damage to plasma membrane pumps: Hydropic
swelling and other membrane changes
• 4. Reduced protein synthesis: Dispersed ribosomes

IRREVERSIBLE CELL INJURY
• Two essential phenomena always distinguish irreversible
from rever sible cell injury
• Inability of the cell to reverse mitochondrial
dysfunction on reperfusion or reoxygenation.
• Disturbance in cell membrane function in general, and
in plasma membrane in particular

• 1. Calcium influx: Mitochondrial damage
• 2. Activated phospholipases: Membrane damage
• 3. Intracellular proteases: Cytoskeletal damage
• 4. Activated endonucleases: Nuclear damage
• 5. Lysosomal hydrolytic enzymes: Lysosomal damage,
cell death and phagocytosis

Ultrastructural changes during cell injury
due to hypoxia-ischaemia.

• Persistence of ischaemia or hypoxia results in irreversible damage
to the structure and function of the cell (cell death).
• Two essential phenomena always distinguish irreversible from
reversible cell injury (Fig. 2.2):
• Inability of the cell to reverse mitochondrial dysfunction on
reperfusion or reoxygenation.
• Disturbance in cell membrane function in general, and in plasma
membrane in particular.

• In addition, there is further reduction in ATP, continued
depletion of proteins, reduced intracellular pH, and
leakage of lysosomal enzymes into the plasma. These
biochemical changes have effects on the ultrastructural
components of the cell (Fig. 2.3, B):

• 1. Calcium influx: Mitochondrial damage
• 2. Activated phospholipases: Membrane damage
• 3. Intracellular proteases: Cytoskeletal damage
• 4. Activated endonucleases: Nuclear damage
• 5. Lysosomal hydrolytic enzymes: Lysosomal
damage, cell death and phagocytosis

Ischaemia-Reperfusion
Injury and Free Radical-
Mediated Cell Injury
• Depending upon the duration of ischaemia/hypoxia,
restoration of blood flow may result in the following 3
different consequences:
• 1. From ischaemia to reversible injury
• 2. From ischaemia to irreversible injury
• 3. From ischaemia to reperfusion injury

• Ischaemia-reperfusion injury occurs due to excessive
accumulation of free radicals or reactive oxygen species.
The mechanism of reperfusion injury by free radicals is
complex but following three aspects are involved:
• 1. Calcium overload.
• 2. Excessive generation of free radicals (superoxide,
H2O2, hydroxyl radical, pernitrite).
• 3. Subsequent inflammatory reaction.

Oxygen free radical generation
• i) Superoxide oxygen (O’2): one electron
• ii) Hydrogen peroxide (H2O2): two electrons
• iii) Hydroxyl radical (OH– ): three electrons

Other free radicals
• i) Nitric oxide (NO) and peroxynitrite (ONOO)
• ii) Halide reagent (chlorine or chloride)
• iii) Exogenous sources

Cytotoxicity of free radicals
• Free radicals may produce membrane damage
by the following mechanisms
• i) Lipid peroxidation
• ii) Oxidation of proteins
• iii) DNA damage
• iv) Cytoskeletal damage

Conditions with free radical injury Currently,
oxygenderived free radicals have been known to play
an important role in many forms of cell injury:
• i) Ischaemic reperfusion injury
• ii) Ionising radiation by causing radiolysis of water
• iii) Chemical toxicity
• iv) Chemical carcinogenesis
• v) Hyperoxia (toxicity due to oxygen therapy)
• vi) Cellular ageing
• vii) Killing of microbial agents
• viii) Inflammatory damage
• ix) Destruction of tumour cells
• x) Atherosclerosis

Stress Proteins in Cell Injury
• When cells are exposed to stress of any type, a
protective response by the cell is by release of
proteins that move molecules within the cell
cytoplasm; these are called stress protein.
• Th ere are 2 types of stress-related proteins:
• heat shock proteins (HSP) and
• ubiquitin (so named due to its universal
presence in the cells of the body)

PATHOGENESIS OF CHEMICAL INJURY
• Chemicals induce cell injury by one of the two
mechanisms:
• by direct cytotoxicity, or
• by conversion of chemical into reactive metabolites.

PATHOGENESIS OF PHYSICAL INJURY
• Killing of cells by ionising radiation is the result of
direct formation of hydroxyl radicals
• These hydroxyl radicals damage the cell membrane
as well as may interact with DNA of the target cell.

Mechanisms of cell injury by ionising radiation.

MORPHOLOGY OF REVERSIBLE CELL INJURY
• Morphologic terms used in cell injury of varying intensity and
from different mechanisms are given in Table

MORPHOLOGY OF REVERSIBLE
CELL INJURY
• Common examples of morphologic forms of
reversible cell injury are as under:
• 1. Hydropic change
• 2. Hyaline change
• 3. Mucoid change
• 4. Fatty change

HYDROPIC CHANGE
• Hydropic change means accumulation of water within
the cytoplasm of the cell.
• cloudy swelling (for gross appearance of the aff ected
organ) and
• vacuolar degeneration (due to cytoplasmic vacuolation).
• Hydropic swelling is an entirely reversible change upon
removal of the injurious agent
• This is the commonest and earliest form of cell injury
from almost all causes

Hydropic change kidney
The tubular epithelial cells are distended with
cytoplasmic vacuoles while the interstitial vasculature is
compressed. The nuclei of affected tubules are pale.

MORPHOLOGIC FEATURES
• Grossly, the affected organ such as kidney, liver,
pancreas, or heart muscle is enlarged due to swelling
• Microscopically, the features of hydropic swelling of
kidney are as under (Fig. 2.7):
• i) The tubular epithelial cells are swollen and their
cytoplasm contains small clear vacuoles and hence the
term vacuolar degeneration.
• ii) Small cytoplasmic blebs may be seen.
• iii) The nucleus may appear pale.
• iv) The microvasculature of the interstitium is
compressed due to swollen tubular cells.

HYALINE CHANGE
• The word ‘hyaline’ or ‘hyalin’ means glassy (hyalos =
glass).
• Hyalinisation is a common descriptive histologic term
for glassy, homo geneous, eosinophilic appearance of
proteinaceous material in haematoxylin and eosin-
stained sections

INTRACELLULAR HYALINE
• Intracellular hyaline is mainly seen in epithelial cells. A few
examples are as follows:
• 1. Hyaline droplets
• 2. Hyaline degeneration
• 3. Mallory’s hyaline
• 4. Nuclear or cytoplasmic hyaline inclusions seen in some
viral infections.
• 5. Russell’s bodies

EXTRACELLULAR HYALINE
• Extracellular hyaline commonly termed hyalinisation is seen
in connective tissues. A few examples of extracellular
hyaline change are as under:
• 1. Hyaline degeneration in leiomyomas of the uterus (Fig.
2.9).
• 2. Hyalinised old scar of fi brocollagenous tissues.
• 3. Hyaline arteriolosclerosis in renal vessels in hypertension
and diabetes mellitus.
• 4. Hyalinised glomeruli in chronic glomerulonephritis.
• 5. Corpora amylacea

MUCOID CHANGE
• Mucoid means mucus-like.
• Mucus is the secretory product of mucous glands
and is a combination of proteins complexed with
mucopolysaccharides.
• Mucin, a glycoprotein, is its chief constituent.

EPITHELIAL MUCIN
• examples of functional excess of epithelial mucin:
• 1. Catarrhal infl ammation of mucous membrane
(e.g. of respiratory tract, alimentary tract, uterus).
• 2. Obstruction of duct leading to mucocele in the oral
cavity and gallbladder.
• 3. Cystic fibrosis of the pancreas.
• 4. Mucin-secreting tumours (e.g. of ovary, stomach,
large bowel etc) (Fig.)

CONNECTIVE TISSUE MUCIN
• examples of disturbances of connective tissue mucin or myxoid
change are as under:
• 1. Mucoid or myxoid change in some tumours e.g. myxomas,
neurofibromas, fibroadenoma, soft tissue sarcomas etc (Fig.
2.11).
• 2. Dissecting aneurysm of the aorta due to Erdheim’s medial
degeneration and Marfan’s syndrome.
• 3. Myxomatous change in the dermis in myxoedema.
• 4. Myxoid change in the synovium in ganglion on the wrist.

INTRACELLULAR ACCUMULATIONS
• Abnormal intracellular accumulations can be divided
into 3 groups:
• i) Accumulation of constituents of normal cell
metabolism produced in excess e.g. accumulations of
lipids (fatty change, cholesterol deposits), proteins and
carbo hydrates.
• ii) Accumulation of abnormal substances
• iii) Accumulation of pigments

FATTY CHANGE (STEATOSIS)
• intracellular accumulation of neutral fat within
parenchymal cells.
• fatty degeneration and fatty infiltration, Fatty
change, steatosis or fatty metamorphosis

Fatty liver.
Sectioned slice of
the liver shows
pale yellow
parenchyma with
rounded borders.

Fatty Liver
• 1. Conditions with excess fat
• e.g. i) Obesity
• ii) Diabetes mellitus
• iii) Congenital hyperlipidaemia
• 2. Liver cell damage These are conditions in which fat
cannot be metabolised due to liver cell injury e.g.
• i) Alcoholic liver disease (most common)
• ii) Starvation
• iii) Protein calorie malnutrition
• iv) Chronic illnesses (e.g. tuberculosis)
• v) Acute fatty liver in late pregnancy

• vi) Hypoxia (e.g. anaemia, cardiac failure)
• vii) Hepatotoxins (e.g. carbon tetrachloride, chloroform,
ether, aflatoxins and other poisons)
• viii) Drug-induced liver cell injury (e.g. administration of
methotrexate, steroids, CCl4, halothane anaesthetic,
tetracycline etc)
• ix) Reye’s syndrome

• In fatty liver, intracellular accumulation of
triglycerides occurs due to defect at one or more of
the 6 steps in the normal fat metabolism shown in
Fig.
• 1. Increased entry of free fatty acids into the liver.
• 2. Increased synthesis of fatty acids by the liver.
• 3. Decreased conversion of fatty acids into ketone
bodies
• 4. Increased -glycerophosphate
• 5. Decreased synthesis of ‘lipid acceptor protein’
• 6. Block in the excretion of lipoprotein from the liver
into plasma

Fatty liver. Many of the hepatocytes are distended with large fat
vacuoles pushing the nuclei to the periphery (macrovesicles),
while others show multiple small vacuoles in the cytoplasm
(microvesicles). Inbox shows red colour in the cytoplasmic fat in
the hepatocytes in Oil Red O stain in frozen section.

Cholesterol Deposits
• Intracellular deposits of cholesterol -
hypercholesterolaemia.
• This turns macrophages into foam cells.
• Th e examples are as follows:
• 1. Fibrofatty plaques of atherosclerosis.
• 2. Clusters of foam cells in tumour-like masses called
xanthomas and xanthelasma

INTRACELLULAR
ACCUMULATION OF PROTEINS
• pink hyaline droplets in their cytoplasm.
• Russell’s bodies
• eosinophilic globular deposits of a mutant
protein.
• Mallory’s body or alcoholic hyaline

INTRACELLULAR
ACCUMULATION OF GLYCOGEN
• Conditions associated with excessive
accumulation of intracellular glycogen are
• 1. In diabetes mellitus
• 2. In glycogen storage diseases or glycogenosis

PIGMENTS
• Pigments are coloured substances present in
most living beings including humans.
• Th ere are 2 broad categories of pigments:
• endogenous and
• exogenous

Compound naevus showing clusters of benign
naevus cells in the dermis as well as in lower
epidermis. These cells contain coarse, granular,
brown-black melanin pigment.

Haemosiderin pigment in the cytoplasm.
H & E stain shows golden brown granules in the
cytoplasm of macrophages (A)
which stain positive in Perl’s stain as Prussian blue
granules (B)

CELL INJURY-2 by DR. ROOPAM JAIN

CELL INJURY-2 by DR. ROOPAM JAIN

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CELL INJURY-2 by DR. ROOPAM JAIN