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CELL INJURY

 Introduction to pathology
 It is the study (logos) of disease (pathos, suffering). It involves the investigation
of the causes of disease and the associated changes at the levels of cells, tissues,
and organs, which in turn give rise to the presenting signs and symptoms of the
patient. There are two important terms to be known:
• Etiology is the origin of a disease, including the underlying causes and modifying
factors. For example, most common diseases like hypertension, diabetes, and
cancer are caused by a combination of inherited genetical factors and various
environmental triggers.
• Pathogenesis refers to the steps in the development of disease. It describes how
etiologic factors trigger cellular and molecular changes that give rise to the
functional and structural abnormalities that characterize the disease.
Therefore, etiology refers to “why” a disease arises, pathogenesis describes “how”
a disease develops.
Morphology of a Living Cell
 Cell injury is defined as a variety of

stresses a cell encounters as a result


of changes in its internal and
external environment. The
pathogenesis of cell injury depends
on: a) type, duration & severity of
injurious agent, b) type, status and
adaptability of target cells e.g:
skeletal muscle can withstand
hypoxic injury for a longer period
when compared to cardiac muscle
and c) underlying intracellular
phenomena i.e. the injury can be
reversible or irrevrsible.
Pathogenesis of Cell injury
Cellular Adaptation
 Cells are constantly exposed to various changes within the body as well as the
external environment in order to meet the increased functional demands, so
that the cell may adapt to the changes which are expressed morphologically
and then reverts back to the normal once the requirements/stress is removed.
Cellular adaptation can be either physiologic (e.g. during fasting, fatty acids
are utilized as main source of energy instead of carbohydrates) or pathologic
(e.g. prolonged exposure to UV rays can cause severe blistering, loss of
epidermis & ulceration).
 Types of cellular adaptation seen in the body are as followed:

o Metaplasia (meta=transformation, plasia=growth):- when cells are faced with


physiological or pathological stresses they respond by adapting in a way called
metaplasia, usually results from reprogramming of stem cells in normal
epithelium or undifferentiated mesenchymal cells in C.T. It is usually a
reversible phenomenon.
Examples:

 Columnar to squamous change in respiratory tract in response to chronic irritation and


vitamin A deficiency.

 Squamous metaplasia of the columnar epithelial cells of salivary gland ducts due to stones

 Connective tissue metaplasia (formation of cartilage , bone or adipose tissue in tissue that
normally do not contain these elements) e.g., bone formation in muscle which occur after
fracture (mysositis ossificans)

Note: the influences that predispose to metaplasia if persistant may induce cancer in metaplastic
epithelium.
o Hyperplasia:- takes place if the tissue contains cell populations capable of
replication; it may occur along with hypertrophy (occur in non-dividing cells)
and often in response to the same stimuli. Hyperplasia occur due to the
production of transcription factors that turn on cellular genes leading to
increased local production of growth factors and its receptors and activation
of intracellular signaling pathways.
1) Physiologic hyperplasia: (a) Hormonal: Its stimulation increases functional
capacity of tissue when needed e.g., breast and uterus in puberty,
pregnancy and lactation. (b) Compensatory: Increases tissue mass
(development of new cells from stem cells) after damage or partial resection
e.g., regeneration of liver.
2) Pathologic hyperplasia: occurs due to excessive hormonal stimulation or
excessive effects of growth factors on target cells e.g., endometrial
hyperplasia (balance between progesterone and estrogen is disturbed)
o Hypertrophy:- An increase in the size of cells due to increased synthesis of
structural components. In other words, in hypertrophy there are no new cells, just
bigger cells.

1) Physiologic hypertrophy: (a) Enlarged size of uterus in pregnancy.

(b) Hypertrophy of breasts during lactation.


2) Pathologic hypertrophy: (a) Hypertrophy of cardiac muscle in cardiovascular
disease e.g., systemic hypertension and aortic valve stenosis.

(b) Compensatory hypertrophy may occur in an organ when contralateral organ is


removed.
o Dysplasia:- indicates disordered cellular development and is recognized by:

1) Loss of orientation

2) Lack of uniformity of individual cells (pleomorophism)

3) Increased mitosis

4) Increased nuclear cytoplasmic ratio

5) Loss of basal cell polarity

6) Nuclear hyperchromatism
o Atrophy:- Shrinkage in the size of the cell is known as atrophy. When a

sufficient number of cells are involved, the entire tissue or organ becomes
smaller in size, becoming atrophic. Although atrophic cells may have
diminished function, they are not dead. Atrophy is caused by increased protein
degradation due to (a) Lysosome containing acid hydrolases and (b) Ubiquitin
proteosome pathway, which causes degradation of many cytosolic and nuclear
protein.

Example:

o Physiologic atrophy e.g. senile atrophy, seen in aging process.

o Pathologic atrophy e.g. Starvation atrophy: nutritional deficiency, Ischemic

atrophy: less O2 & blood supply, Pressure atrophy: body exposed to continuous
pressure will cause atrophy.
o Heat shock proteins (Chaperones):

Normally found in the cells and are expressed during stressful / injurious stimuli.

HSP’s play an important role in normal intracellular protein that includes the
process of protein folding, disaggregation of protein-protein complexes, and
transport of protein to various intracellular organelles (protein kinesis).
Therefore, HSP’ s released from the cell during injurious stimuli plays an
important role in refolding of denatured protein polypeptide to restore their
function before they can cause serious cell dysfunction or death.

If refolding is not successful, then the denatured proteins are tagged by ubiquitin
molecules which is a regulatory protein found in almost all cells and causes the
subjecting of protein to the proteaosome for degradation.
 MORPHOLOGY OF CELL AND TISSUE INJURY:

All stresses and noxious influences exert their effects at the molecular or
biochemical level. Cellular function may be lost long before cell death occurs. For
example, myocardial cells (myocytes) become non-contractile after 1 to 2 minutes
of ischemia, although they do not die until 20 to 30 minutes of ischemia have
elapsed. The cellular derangements of reversible injury can be corrected, and if the
injurious stimulus abates, the cell can return to normalcy. Persistent or excessive
injury, however, causes cells to pass the nebulous “point of no return” into
irreversible injury and cell death. The events that determine when reversible injury
becomes irreversible and progresses to cell death remain poorly understood.
 REVERSIBLE INJURY & its mechanism:

Decreased generation of ATP, required for a variety of cellular functions and


survival. It is obtained either by aerobic respiration within the mitochondria
or by anaerobic glycolytic pathway (glycogen). Both ischemia and hypoxia
limit the supply of oxygen to the cells causing decreased ATP generation.

Reduced intracellular pH:- anaerobic glycolytic pathway gets into the act to
generate ATP, resulting in excess breakdown of glycogen and accumulation of
lactic acid in the body.

Damage to the plasma membrane:- Energy dependent sodium pump allows active
transport of sodium out of the cell and diffusion of potassium into the cell,
which gets disturbed as there is increased ATPase activity and decreased ATP
formation. Results in excess accumulation of sodium within the cell along
with excess accumulation of water within the cell .
Reduced protein synthesis:-Continued hypoxia causes ribosomal detachment.

Ultrastructural changes:- Swelling of mitochondria & Loss of microvilli.


 Hypoxia: means less amount of oxygen in tissue. Mainly caused due to

 a) Ischemia: less blood flow in blood vessels e.g. injury to the vessels,

coronary artery blockage due to atherosclerosis etc.

 b) Hypoxemia: less oxygen in blood i.e., during breathing exchange of gases

takes place within the lungs and distributed to the body through blood. The
following factors are responsible for hypoxemia- i) Reduced PiO2 (reduced
pressure inspired oxygen) ii) Reduced PAO2 (reduced pressure alveoli
oxygen) iii) Reduced PaO2 (reduced oxygen in blood) due to -decreased
inspired air seen in high altitudes, -hypoventilation of less oxygen and high
Carbon dioxide and - poor ventilation where there is poor gas exchange
called Respiratory Distress Syndrome and perfusion defect.

 c) Decreased oxygen carrying capacity in blood due to haemolytic conditions


 IRREVERSIBLE INJURY & its mechanism:

Mitochondrial dysfunction:- Mitochondria is a double layered organelle & it is the


power house of the cell producing ATP.

1) Continuous hypoxia causes mitochondrial dysfunction causing poor ATP


production during which there is formation of high conductance channel called
mitochondrial permeability transition pore, which causes an abnormal increase in
mitochondrial membrane permeability.

2) Mitochondrial damage is caused through Apoptosis, which is activated by an


enzyme called Caspases found in cytosol produced by the proteins called
Cytochrome C, found in between outer & inner membrane of mitochondria.

3) Further, increased concentration calcium is seen within the endoplasmic


reticulum & mitochondria due to initial ischemic injury followed by increased
entry of calcium into the mitochondria from the cytoplasm of the cell (cytosolic
influx of Ca++ ions).
Ca++ Induced reperfusion damage
Increased calcium entry into the mitochondria will cause activation of certain
enzymes causing mitochondrial damage. They are as followed:

o Endogenous phospholipases, damages the membrane phospholipids, main


constituent of the lipid bilayer membrane.

o Intermediate filaments of cytoskeleton damaged by intracellular proteases.

o Endogenous endonuclease causes nuclear chromatin damage.

o Increased ATPase activity causes decreased ATP generation.

4) Reactive oxygen species, produced normally in small amounts in all cells

during reduction-oxidation (redox) reactions that occur during mitochondrial


respiration and energy generation. In this process, oxygen is sequentially
reduced in mitochondria by the addition of four electrons to form water.
However, this reaction is imperfect coz small amounts of highly reactive, short-
lived toxic intermediates are generated when oxygen is only partially reduced.
a) Normal reduction and oxidation reaction during normal metabolism: e.g.,
during respiration process the oxygen gets reduced and transfer 4 electrons to

hydrogen to form water. If oxygen gets reduced partially and transfer only one
electron it forms superoxide (O2 -), transfers two electron it forms hydrogen
peroxide (H2O2) and transfers three electrons it forms hydroxyl radical (OH).
Reactive oxygen species/Free radicals cause cell injury by:
• Lipid peroxidation of membranes: Double bonds in membrane
polyunsaturated lipids are vulnerable to attack by oxygen-derived free
radicals.

• Cross-linking and other changes in proteins: Free radicals promote


sulfhydryl-mediated protein cross-linking, resulting in enhanced degradation
or loss of enzymatic activity.

• DNA damage. Free radical reactions with thymine in nuclear and


mitochondrial DNA produce single-strand breaks.

Therefore the reactive oxygen species/free radicals causes damage to the cells
by oxidation of lipid, protein and DNA damage.
Antioxidants:- Cells develop many mechanisms to remove free radicals and
thereby minimize injury. Free radicals are inherently unstable and decay
spontaneously.

• The rate of decay of superoxide is significantly increased by the action of

superoxide dismutases (SODs) found in many cell types.

• Glutathione (GSH) peroxidases are a family of enzymes whose function is to

protect cells from oxidative damage. Glutathione peroxidase 1, is found in


the cytoplasm of all cells. It catalyzes the breakdown of H2O2 by the
reaction: 2 GSH (glutathione) + H2O2 → GS-SG + 2 H2O.

• Catalase, present in peroxisomes, catalyzes the decomposition of hydrogen

peroxide (2H2O2 → O2 + 2H2O).

• Non-enzymatic antioxidants (e.g., vitamins E, A, and C and β-carotene) may

either block the formation of free radicals or scavenge them once formed.
Morphology Of Reversible Cell Injury
 The term degeneration has been used to

denote the morphological changes of


reversible cell injury and is characterised as
cellular swelling and fatty change.

 Cellular swelling: commonest and earliest

form of cell injury caused by bacterial toxins,


chemicals, poisons, burns, high fever etc.
resulting from impaired sodium regulation.

Grossly, the affected kidney is enlarged and


microscopically, the cell is swollen due to
excess entry of sodium and escape of
potassium followed by the presence of small
vacuoles and degeneration of ER.
Morphology Of Irreversible Cell Injury
 Necrosis (irreversible cell injury):- Defined as a focal/premature death of
tissues by hydrolytic enzymes liberated by the damaged cells itself (autolysis)
and is accompanied by inflammatory reactions (heterolysis). Necrosis is mainly
accompanied by nuclear changes in: Pyknosis (nuclear shrinkage),
Karyorrhexis (fragmentation of nucleus) & Karyolysis (disappearance of
nucleus).
Types of necrosis:-

 Coagulative necrosis: Most common type of necrosis, irreversible focal


injury, mostly due to ischeamia of heart, kidney and spleen.
Microscopically, there is conversion of normal cells into their ‘tomb-stones’
i.e. the outline of the cells are retained but the nuclear and the cytoplasmic
details are lost and appears more eosinophilic than the normal, the reason
for this is that denaturation of protein takes place within the cell
 Liquefaction necrosis: is due to ischaemic
injury of brain form a liquid filled cavity
seen as abscess formation. Microscopically,
there is formation of cystic spaces containing
necrotic cells & macrophages. The reason for
this due to enzymatic degradation

 Caseous (cheese-like) necrosis: Combined

features of both coagulative & liquefactive


necrosis, seen in tuberculosis.
Microscopically, seen as necrosed foci that
are structureless, eosinophilic, surrounded
by epitheliod cells, chronic inflammatory
cells & giant cells called giant cells of
Langhan’s.
 Fat necrosis: A special form of cell death occuring in pancrease causing

acute pancreatic necrosis due to the retaining of lipases. Microscopically,

formation of chalky white/fat saponification (calcification of fat) along with

inflammatory cells are identified in the tissue.

 Fibrinoid necrosis: Characterised by fibrin-like material, seen in certain

immunological disease where the blood vessels gets affected by the

deposition of Antigen-Antibody complex causing injury to the blood vessels

causing fibrin-like material leaking out from the blood vessels.

 Gangrene, a form of necrosis with superadded bacterial infection. Type of

gangrenous necrosis are given as followed:


 Dry gangrene- seen in the toes farthest from the

supply or containing so little blood even the


bacteria find hard to grow in necrosed area.

 Wet gangrene- occurs in moists areas like mouth,

lung, bowel etc. Diabetic foot ulcer occuring due to


high sugar content in necrosed tissue favouring
bacterias to grow.

 Gas gangrene- special form of wet gangrene caused

by gas-forming anaerobic clostridia which gains


entry into the tissue through open wounds or
during colon surgery.
 Apoptosis, a pathway of cell death in which cells activate enzymes that

degrade 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 and its fragments are rapidly cleared before cellular contents have leaked

out, so apoptotic cell death does not elicit an inflammatory reaction in the host.

Apoptosis differs in this respect from necrosis, which is characterized by loss

of membrane integrity, enzymatic digestion of cells, leakage of cellular

contents, and frequently a host reaction.


 Apoptosis in Physiologic Situations: Death by apoptosis is a normal
phenomenon that serves to eliminate cells that are no longer needed and to
maintain a constant cell population. For example: Elimination of cells that
have served their useful purpose, such as neutrophils in an acute inflammatory
response and lymphocytes at the end of an immune response.
• Apoptosis in Pathologic Conditions: Eliminates cells that are genetically
altered or injured beyond repair and does so without eliciting a severe host
reaction, thereby keeping the extent of tissue damage to a minimum. Death by
apoptosis is responsible for loss of cells in a variety of pathologic states. For
example: DNA damage caused by radiation, cytotoxic anticancer drugs, and
even hypoxia etc., either directly or through production of free radicals. If
repair mechanisms cannot cope with the injury, the cell triggers intrinsic
mechanisms to induce apoptosis. In these situations, elimination of the cell may
be a better alternative than risking mutations in the damaged DNA, which
may progress to malignant transformation.
 Morphology of apoptosis:- It is a rapid process and mentioned below in:
 Mechanism of Apoptosis:- The mechanism takes place in two pathways:

i) Extrinsic pathway: Many cells express surface molecules, called death receptors,
that trigger apoptosis. Most of these are members of the tumor necrosis factor (TNF)
receptor family, e.g. Type I TNF, Fas etc. which contain in their cytoplasmic regions a
conserved “death domain,” so named because it mediates interaction with other
proteins involved in cell death. Fas ligand (FasL) is a membrane protein expressed
mainly by T lymphocytes. When these T cells recognize Fas-expressing targets, Fas
molecules are cross-linked by FasL and in turn activates caspase-8. In many cell types
caspase-8 may cleave Bcl-2 family and activate a pro-apoptotic member.
ii) Intrinsic pathway:
A) Mitochondrial pathway: Normally, the growth factor bounds to the growth
receptor found on mitochondrial membrane to form an anti-apoptotic protein called
Bcl2 & Bclx, prevents the leakage of pro-apoptotic molecules. But if there is an
injury/stress it causes activation of Bak & Bax which increases the permeability of the
membrane causing leakage of pro-apoptotic protein into the cytosol where it initiates
cytochrome C protein and binds with Apaf1 and activates caspase 9 to perform
apoptosis.
B) Execution pathway: it is mediated by caspase 3 & caspase 6 which is
responsible for the breakdown of cytoskeleton protein and nuclear matrix protein.
 Autophagy:- “self-eating”. refers to lysosomal digestion of the cell’s own
components. It is a survival mechanism in times of nutrient deprivation, such
that the starved cell subsists by eating its own contents and recycling these
contents to provide nutrients and energy.
 Pathologic calcification, abnormal tissue deposition of calcium salts in
tissues other than osteoid or enamel. The two types of pathological calcification
are: i) Dystrophic calcification- deposition of calcium salts in dead or
degenerated tissues with normal calcium metabolism and normal calcium
serum level. ii) Metastatic calcification- deposition of calcium salts in normal
tissues with deranged calcium metabolism and hypercalcaemia.

i) DYSTROPHIC CALCIFICATION. may occur due to 2 types of causes:

A) Calcification in dead tissue

1. Caseous necrosis in tuberculosis is common site for dystrophic calcification.

2. Liquefaction necrosis in chronic abscesses may get calcified.

3. Infarcts may sometimes undergo dystrophic calcification.


B. Calcification in degenerated tissues

1. Dense old scars may show calcification.

2. Atheromas (collection of degenerated materials in tunica intima of blood


vessels) in the aorta and coronaries frequently undergo calcification.

3. Mönckeberg’s sclerosis , calcification in tunica media of muscular arteries.

4. Cysts present for long time may show calcification.

5. Senile degenerative changes may show dystrophic calcification such as in


costal cartilages, tracheal or bronchial cartilages, and pineal gland in brain etc.
ii) METASTATIC CALCIFICATION. may occur due to 2 types of causes:
A) Excessive immobilisation of calcium from the bone

1. Prolonged immobilisation of a patient results in disuse atrophy of the bones


and hypercalcaemia.

B) Excessive absorption of calcium from the gut. Less often, excess calcium may be
absorbed from the gut causing hypercalcaemia and metastatic calcification. These
causes are:

1. Hypervitaminosis D results in increased calcium absorption.

2. Milk-alkali syndrome caused by excessive oral intake of calcium in the form


of milk and administration of calcium carbonate in the treatment of peptic
ulcer.
Note:- psammoma bodies, a feature that is used to distinguish dystrophic
calcification from metastatic calcification. It is seen as single necrotic cell
surrounded by calcium & phosphate giving an appearance of psamos called sand.

It is seen in conditions like meningioma, papillary carcinoma of thyroid.

psammoma bodies
Intracellular Accumulations
 Amyloidosis- a condition associated with abnormal and excess extracellular
deposition of misfolded proteins (which are soluble in their normal folded
configuration) which are responsible for tissue damage and functional compromise.
The protein deposits bind with a variety of proteoglycans, glycosaminoglycans etc.,
The presence of abundant sugar groups in these adsorbed proteins gives the
deposits staining characteristics that were thought to resemble starch (amylose).
Therefore, the deposits were called “amyloid”.
Two types of amyloidosis:

• AL (amyloid light chain) protein is produced by plasma cells and is made up of


complete immunoglobulin light chains.
• The AA (amyloid-associated) fibril is a unique non-immunoglobulin protein called
SAA (serum amyloid-associated) protein that is synthesized in the liver. SAA is
synthesized by liver cells under the influence of cytokines such as IL-6 and IL-1
that are produced during inflammation; thus, long-standing inflammation leads to
elevated SAA levels, and ultimately the AA form of amyloid deposits
Amyloid staining: a) H&E staining under light microscope- appears as
homogenous, structureless and eosinophilic, b) Congo red staining under
polarising microscope appears as apple-green birefringence.
 Metabolic disturbances

Normally, fatty acid enter the liver either from


diet or from adipose tissue and gets esterified into
triglycerides ,inturn to form lipoprotein and is
released and deposited as lipid within the body.
Small amount of fatty acid undergo oxidation to
release cholesterol.

o Lipid storage disease, intracellular

accumulation of neutral fat within the cells of


liver, kidney caused by starvation, obesity &
alcoholism. Fatty liver, increased free fatty acid
synthesis, decreased triglyceride utilisation &
oxidation of fatty acid, and block in lipoprotein
excretion.
 Mucoid degeneration- excessive accumulation of mucin seen in either

epithelial cells of inflammed mucous membrane of repiratory tract,


alimentary tract or tumor of GIT. Cells are swollen and the cytoplasm is
foamy and vacuolated pushing the nucleus to one side giving a “signet ring
appearance”.
 Pigments- coloured substances present in most living beings:
Endogenous pigments:--
 Melanin- brown-black, non-haemoglobin pigment present in hair, skin,
meninges etc found in basal cells of epidermis. Excess of melanin in
pregnancy (cholasma) & deficient melanin in albinism.

 Hemasiderosis- excessive accumulation of hemosidrin pigments in the tissues


giving a black skin e.g. areas of old hemorrhage & hemolytic anemia.
 Hemochromatosis-iron storage disease caused due to excessive iron intestinal
absorption e.g. liver cirrhosis, heart & kidney.
Jaundice- yellowish discolouration of skin and mucous membranes e.g. excessive
hemolysis, infective hepatitis & liver cirrhosis

Exogenous pigments-

o Tattoing- pigments like India ink, cinnabar and carbonate introduced into the
dermis where the pigments are taken up by the macrophages and lies permanently
in the connective tissue.

o Plumbism- blue line appearing on gums due to chronic lead poisoning & anemia.

o Argyria- chronic ingestion of silver compounds resulting in brownish pigmentation


of skin, bowel and kidney.

o Carotenaemia- yellowish-red colouration of the skin caused by excessive ingestion


of carrots containing carotene.

o Anthracosis- blackish discolouration of the pulmonary interstitial tissues due to


inhalation of carbon particles from industrial factories.
Thank you