Basic principles of Cell injury and

adaptations

By
J.Jayasutha
Lecturer,
Department of Pharmacy Practice
Sri Ramachandra Faculty of Pharmacy
SRIHER
Cell structure
 Cell structure and function
Nucleus
• The nucleus is the “brain” of the cell and controls all activity within the
cell. Using DNA as a blueprint
Ribosomes
• Protein synthesis for the nucleus
Endoplasmic Reticulum
• Rough ER is named for the presence of ribosomes along its membrane and
is the source of proteins.
• Smooth ER lacks ribosomes and is responsible for lipid synthesis and
processes a variety of metabolic processes such as drug detoxification.
cell membranes
• cell membranes surround the cell and have the ability to regulate entrance
and exit of substances, thereby maintaining internal balance. These
membranes also protect the inner cell from outside forces
Cytoskeleton
cyotoskeleton represents the cell's skeleton
• It is important for cell movement and cell division (mitosis).
• Microtubules consists of a strong protein called tubulin and helps in movement
of the cell
• Microfilament provide structural support and maintain characteristic shape of the
cell
• Actin filament are made up of two chains of the protein actin twisted together
Golgi complex
• Consists of a series of flattened sacs (or cisternae)
• Functions include: synthesis (of substances likes phospholipids), packaging of
materials for transport (in vesicles), and production of lysosomes
Lysosomes
• Membrane-enclosed spheres that contain powerful digestive enzymes
• Functions include destruction of damaged cells (called 'suicide bags') & digestion
of phagocytosed materials (such as bacteria)
 Mitochondria -
– Have a double-membrane: outer membrane & highly convoluted inner
membrane
– Inner membrane has folds or shelf-like structures called cristae
– Primary function is production of adenosine triphosphate (ATP)
Centrioles -
• paired cylindrical structures located near the nucleus
• play an important role in cell division
– Flagella & cilia -
• Hair-like projections from some human cells
– Cilia are relatively short & numerous (e.g Those lining trachea)
– A flagellum is relatively long
 Cell injury
• Definition:

• Cell injury is defined as a variety of stresses due to etiologic agents a cell

encounters, resulting in changes in its internal and external environment

• Cellular response to stress may vary and depends upon following two
variables:

• i.) The type of cell and tissue involved.

• ii) Factors pertaining to injurious agent (Extent and type of cell injury)
 Various forms of cellular responses to cell injury

• Cellular adaptations : When there is increased functional demand, the

cell may adapt to the changes which are expressed morphologically, which
then revert back to normal after the stress is removed

• Reversible cell injury: When the stress is mild to moderate, the injured cell
may recover

• Irreversible cell injury: Persistent and severe form of cell injury may
cause cell death
Cell injury:
– Reversible injury (non-lethal)
– Irreversible injury (cell death): Apoptosis and Necrosis
Adaptations:
– Hypertrophy,
– Hyperplasia,
– Atrophy,
– Metaplasia
Cell/Tissue adaptive changes
Metaplasia relevant to human diseases
 Causes of cell injury
The cells may be broadly injured by two major ways:
A. Genetic causes
B. Acquired causes
1. Oxygen deprivation:
• Hypoxia
Causes of hypoxia
• Ischemia (reduced supply of blood to cells due to interruption)
Impaired blood supply from causes other than interruption
• Anaemia
• heart diseases, lung diseases
• Increased demand of tissue
2. Physical agents
– Mechanical trauma (Road accident)
– Extreme temperature
– Electric shock
– Radiations
3. Chemical agents and Drugs
– strong acids and alkalis
– Any gases at high concentration-toxic
– Arsenic, heavy metals etc..- destroys the cells within few seconds
– Environmental pollutants
– Pesticides
– Alcohol
4. Infectious agents (Injuries by microbes include infections)
– Bacteria
– Fungi
– Virus
– Worms
– Parasites
5. Immunologic reactions
– Autoimmune disorders (Rheumatoid arthritis, Diabeted Mellitus Type 1)
– Immunodeficiency diseases (AIDS)
– Hypersensitivity
– Anaphylactic reaction
7. Nutritional Imbalances:
– Protein deficiencies (Kwashiorkor)
– Self induced starvation
– Anorexia (Eating Disorder)
– Nutrition in excess
– Cholesterol excess
– Obesity
8.Aging:
• Cellular ageing 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
9. Iatrogenic:
– Due to physician
10. Idiopathic:
- 90% of hypertension
• Mechanism of cell injury
Principles in pathogenesis of cell injury
•Type of injury, its duration, and its severity.

–Brief duration of ischemia may lead to reversible cell injury

–Longer ischemic intervals may result in irreversible injury and cell death.

• Type, status, adaptability, and genetic makeup of the injured cell.

–The same injury has vastly different outcomes depending on the cell type;

–Striated skeletal muscle in the leg accommodates complete ischemia for 2 to 3 hours

without irreversible injury,

–Cardiac muscle dies after only 20 to 30 minutes.

•Cell injury results from functional and biochemical abnormalities in one or
more of several essential cellular components
• Mitochondrial damage causing ATP depletion.
• Cell membrane damage disturbing the metabolic and trans-membrane
exchanges.
• Release of toxic free radicals.
• Usual morphologic changes
• The morphologic changes of reversible cell injury (e.g. hydropic swelling)
appear earlier while later morphologic alterations of cell death are seen
• Functional implications and disease outcome
• Eventually, Cell injury affects cellular function adversely leads to sign and
symptoms
Adaptation and cell injury
Reversible cell injury
 Pathogenesis of ischaemic and hypoxic injury

• REVERSIBLE CELL INJURY

• 1.Decreased generation of cellular ATP
• All living cells require continuous supply of oxygen to produce ATP which is essentially
required for a variety of cellular functions (e.g. membrane transport, protein synthesis,
lipid synthesis and phospholipid metabolism). ATP in human cell is derived from 2
sources:
• Firstly, by aerobic respiration or oxidative phosphorylation (which . requires oxygen) in
the mitochondria.
• Secondly, cells may subsequently switch over to anaerobic glycolytic oxidation to
maintain constant supply of ATP (in which ATP is generated from glucose/glycogen in
the absence of oxygen).
• 2. Intracellular lactic acidosis: Nuclear clumping

• Due to low oxygen supply to the cell, aerobic respiration by mitochondria fails first. This

is followed by switch to anaerobic glycolytic pathway for the requirement of energy (i.e.

ATP). This results in rapid depletion of glycogen and accumulation of lactic acid lowering

the intracellular pH.

• 3. Damage to plasma membrane pumps: Hydropic swelling and other membrane

changes

• Lack of ATP interferes in generation of phospholipids from the cellular fatty acids which

are required for continuous repair of membranes. This results in damage to membrane

pumps operating for regulation of sodium-potassium and calcium.

• i) Failure of sodium-potassium pump

• ii) Failure of calcium pump

• 4. Reduced protein synthesis: Dispersed ribosomes

• As a result of continued hypoxia, membranes of endoplasmic

reticulum and Golgi apparatus swell up. Ribosomes are detached
from granular (rough) endoplasmic reticulum and dispersing
ribosomes in the cytoplasm and inactivating their function.

• withdrawal of acute stress that resulted in reversible cell injury can

restore the cell to normal state
Irreversible cell injury
 IRREVERSIBLE CELL INJURY
• 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.

• Inability of the cell to reverse mitochondrial dysfunction on reperfusion

• Disturbance in cell membrane function in general, and in plasma membrane

in particular

.
1. Calcium influx: Mitochondrial damage

• As a result of continued hypoxia, a large cytosolic influx of calcium ions

occurs, especially after reperfusion of irreversibly injured cell.

• Excess intracellular calcium collects in the mitochondria disabling its

function.

• Morphological changes are in the form of vacuoles in the mitochondria and

deposits of amorphous calcium salts in the mitochondrial matrix.
• Activated phospholipases: Membrane damage
• Damage to membrane function in general, and plasma membrane in particular,
is the most important event in irreversible cell injury.
• Increased cytosolic influx of calcium in the cell activates endogenous
phospholipases.
• These, in turn degrade membrane phospholipids progressively which are the
main constituent of the lipid bilayer

• Intracellular proteases: Cytoskeletal damage

• The normal cytoskeleton of the cell (microfilaments, micro tubules and
intermediate filaments) which anchors the cell membrane is damaged due to
degradation by activated intracellular proteases or by physical effect of cell
swelling producing irreversi ble cell membrane injury
4. Activated endonucleases: Nuclear damage
• DNA or nucleoproteins are damaged by the activated lysosomal enzymes
such as proteases and endonucleases. Irreversible damage to the nucleus
can be in three forms:
• i) Pyknosis: Condensation and clumping
• ii) Karyorrhexis: Nuclear fragmentation in to small bits dispersed in the
cytoplasm.
• iii) Karyolysis: Dissolution of the nucleus.
• Damaged DNA activates proapoptotic proteins leading the cell to death.
• 5. Lysosomal hydrolytic enzymes: Lysosomal damage, cell death and
phagocytosis
• The lysosomal membranes are damaged and result in escape of lysosomal
hydrolytic enzymes.
• These enzymes are activated due to lack of oxygen in the cell and acidic
pH.
• These hydrolytic enzymes: (e.g. hydrolase, RNAase, DNAase, protease,
glycosidase, phosphatase, lipase, amylase, cathepsin etc) on activation
bring about enzymatic digestion of cellular components and hence cell
death.
• The dead cell is eventually replaced by masses of phospholipids called
myelin figures which are either phagocytosed by macrophages or there may
be formation of calcium soaps.
• Liberated enzymes leak across the abnormally permeable cell membrane
into the serum, the estimation of which may be used as clinical parameters
of cell death.
Reversible and irreversible cell injury
 Mechanisms behind cell injury
• Depletion of ATP
• Damage to mitochondria
• Influx of calcium
• Accumulation of oxygen-derived free radicals
• Defects in membrane permeability
• Damage to DNA and proteins
 Morphology of Reversibility Cell Injury

• Reversible cell injury depict light microscopic changes occurring at

ultrastructural level.

• Hydropic swelling is the earliest form of cell injury from various etiologies
and its main features are cellular swelling due to cytoplasmic vacuoles.

• Hyaline change is intra- and extracellular deposition of pink,

proteinaceous material.

• Mucoid change is deposition of mucinous material in epithelial and

connective tissues in excessive amounts.

• Intracellular accumulations of fats, protein and carbohydrates

 Morphology of reversible cell injury
Cellular swelling
• common cause: bacterial toxins, chemicals , poisons, burns, high fever etc
– Types: hydropic change: Accumulation of water within the cell
– Vacuolar degeneration: small clear vacuoles are seen in the cell represent
distended cisternae of the endoplasmic reticullum

Hyaline change
– The term hyaline usually refers to an alteration within cells or in the
extracellular space that gives a homogeneous, glassy, pink appearance
eosinophilic appearance of proteinaceous material in routine histologic sections
stained with hematoxylin and eosin.
 – Intracellular hyaline:seen in epithelial cells
– Eg: hyaline droplets in the proximal tubular epithelial cells in
case of excessive reabsorption of plasma proteins
– Extracellular hyaline: seen in connective tissue
– Hyaline arteriolosclerosis in renal vessels in hypertension and diabetes
mellitus.
– Hyalinised glomeruli in chronic glomerulonephritis

Mucoid change

Mucus secreted by mucous gland is a combination of proteins complexed

with mucopolysaccharides. Mucin, a glycoprotein and it is chief constituent
produced by epithelial cells of mucous membranes and mucous glands, as
well as by some connective tissue

• Epithelial mucin stained positively with periodic acid-schiff

• Connective tissue mucin stained positively with colloidal iron
 Subcellular alteration in cell injury
• 1. Cytoskeletal Changes

2. . Lysosomal Change

3. Smooth Endoplasmic Reticulum Hypertrophy

4. Mitochondrial Changes
Intracellular accumulation of substances in abnormal amounts

It can occur within the cytoplasm (especially lysosomes) or nucleus of the cell.

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 carbohydrates.

ii) Accumulation of abnormal substances produced as a result of abnormal metabolism due to

lack of some enzymes e.g. storage diseases (glycogen storage diseases or glycogenosis,

there is defective metabolism of glycogen due to genetic disorders.)

iii) Accumulation of pigments e.g. endogenous pigments and exogenous pigments

 A. ENDOGENOUS PIGMENTS

Endogenous pigments are either normal constituents of cells or accumulate under

special circumstances e.g.melanin, haemoprotein, etc.,

• B. EXOGENOUS PIGMENTS

• Exogenous pigments are the pigments introduced into the body from outside

• such as by inhalation, ingestion or inoculation

• 1. Inhaled pigments: The lungs of most individuals, specially of those living in

urban areas due to atmospheric pollutants and of smokers, show a large number of
inhaled pigmented materials

• 2. Ingested pigments: Argyria is chronic ingestion of silver compounds.

• 3. Injected pigments (Tattooing)

FATTY CHANGE (STEATOSIS)
• Fatty change, steatosis is the intracellular accumulation of neutral fat within
parenchymal cells.
• It is especially common in the liver
FATTY LIVER:
• Liver is the commonest site for accumulation of fat because it plays central
role in fat metabolism.
• Depending up on the cause and amount of accumulation, fatty change may
be mild and reversible , or severe producing irreversible cell injury and cell
death.
• PATHOGENESIS:

Lipids are free acids enter the liver cell from either of the following 2
sources:

•From diet as chylomicrons (containing triglycerides and phospholipids)

and as free fatty acids; and

•From adipose tissue as free fatty acids.

IN FATTY LIVER, intracellular accumulation of triglycerides can occur

 Cholesterol Deposits

• Intracellular deposits of cholesterol may occur when there is

hypercholesterolaemia.

• 1. Fibrofatty plaques of atherosclerosis

 INTRACELLULAR ACCUMULATION OF PROTIENS:

Pathological accumulation of protiens in the cytoplasm of cells may occur in the

following conditions
– hyaline droplets in the proximal tubular epithelial cells in case of
excessive reabsorption of plasma proteins
 INTRACELLULAR ACCUMULATION OF GLYCOGEN

1. In diabetes mellitus, there is intracellular accumulation of glycogen in different

tissues because normal cellular uptake of glucose is impaired.

2. In glycogen storage diseases or glycogenosis, there is defective metabolism of

glycogen due to genetic disorders.
– Glycogen storage diseases (GSDs) also known as glycogenoses are a group of inherited genetic
disorders

– GSDs are caused by a genetic enzyme defect.

– Various enzymes are involved in the synthesis or glycogenesis (conversion of glucose into
glycogen) and degradation or glycogenolysis (conversion of glycogen back into glucose) of
glycogen.

– This metabolic process may be affected in the lack of enzymes.

– Glycogen storage diseases, characterized by accumulation of glycogen.

 Morphology of irreversible cell
injury
• Autolysis
• Apoptosis
• Necrosis
• Gangrene
• Pathologic calcification
– Dystrophic-deposits of calcium salt in dead and degenerated tissue
– Metastatic –deposits of calcium salts in normal tissue
• Autolysis

– Disintegration of cell by its own hydrolytic enzyme liberated from lysosome

– Autolysis is rapid in some tissues rich in hydrolytic enzymes such as in the

pancreas, and gastric mucosa; intermediate in tissues like the heart, liver and
kidney; and slow in fibrous tissue.

 Necrosis

• COAGULATIVE NECROSIS

• -Most common pattern of necrosis, is characteristic of hypoxic cell death

– Macroscopic appearance: firm consistency, yellowish colour, dry appearance of

the cut section

– -This pattern of necrosis-most commonly results from sudden severe ischemia

(is encountered mostly in organs, such as kidney, heart, spleen, adrenal gland)

• Example of coagulative necrosis- myocardial infarction

• 2. LIQUEFACTIVE NECROSIS

• Lique - faction or colliquative necrosis also occurs commonly due to ischaemic

injury and bacterial or fungal infections

• -Results from the rapid action of hydrolytic enzymes leads to degradation of tissue

• Characteristic of ischemic necrosis of brain, pancreas

• 3. CASEOUS NECROSIS

• Caseous (caseous= cheese-like) necrosis combines features of both coagulative and

liquefactive necrosis.

• It is encountered in tuberculousis.

• 4. FAT NECROSIS

• Fat necrosis is a special form of cell death occurring at mainly fat-rich anatomic
locations in the body.

This refers to necrosis in adipose tissue -due to action of activated lipases

• Most common-in acute pancreatic necrosis,

• 5. FIBRINOID NECROSIS

• Fibrinoid necrosis is characterised by deposition of fibrin-like material

which has the staining properties of fibrin such as phosphotungistic acid
haematoxylin (PTAH) stain

• Seen in autoimmune disease

 Definition
• Form of cell death, also known as programmed cell death, in which a
‘suicide’ program is activated within the cell

• To eliminate unwanted, aged or harmful cells

49
 Role of Apoptosis

Apoptosis is needed for proper development

Examples:
– The formation of the fingers and toes of the fetus
– The sloughing off of the inner lining of the uterus
– The resorption of the tadpole tail
Apoptosis is needed to destroy cells
Examples:
– Cells infected with viruses
– Cells with DNA damage
– Cancer cells

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 Etiology of Apoptosis
Receipt of negative signals
examples :
– Increased levels of oxidants within the cell
– Damage to DNA by oxidants
– Release:
• Tumor necrosis factor alpha (TNF-)
• Lymphotoxin (TNF-β)
• Fas ligand (FasL)

51
 APOPTOSIS: Morphological events
Cell shrinkage

Organelle reduction

Mitochondrial leakage

Chromatin condensation
Nuclear fragmentation

Membrane blebbing & changes

52
 Necrosis vs. Apoptosis

Necrosis
• Cellular swelling
• Membranes are broken
• ATP is depleted
• Cell lyses, eliciting an
inflammatory reaction
• In vivo, whole areas of the
tissue are affected
Apoptosis
• Cellular condensation
• Membranes remain intact
• Requires ATP
• Cell is phagocytosed, no
tissue reaction
• In vivo, individual cells appear
affected

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 Pathways of Apoptosis
“Extrinsic Pathway”

Death Death Initiator

Ligands Receptors Caspase 8

Effector
“Intrinsic Pathway”
Caspase 3 PCD

DNA Initiator
Mitochondria/
damage Caspase 9
Cytochrome C
& p53

54
• Caspases are a series of proteolytic or protein-splitting enzymes which act
on nuclear proteins and organelles containing protein components.

• Adaptor proteins contain a variety of protein-binding modules that link

protein-binding partners together and facilitate the creation of larger
signaling complexes. By linking specific proteins together, cellular signals
can be propagated

• Initiator caspases (caspase 2, 8, 9, and 10), executioner caspases (caspase

3, 6, and 7
56
 GANGRENOUS NECROSIS

• It is a necrosis secondary modified usually by the attack of bacterial agents. The

term gangrene is commonly used in clinical practise to describe a condition when
extensive tissue necrosis is complicated by bacterial infection.

• There are three major types of gangrene:

– Dry gangrene-distal part of limb due to ischemia

– Wet gangrene-moist tissues and organs. Eg:mouth, bowel,cervix etc

– Gas gangrene

•
 Dry gangrene

– This form of gangrene begins in the distal part of a limb due to ischaemia.

– The typical example is the dry gangrene in the toes and feet of an old patient

Due to severe atherossclerosis.

– -Dry gangrene- necrotic tissue appears black and dry

• Wet gangrene

• Wet gangrene occurs in naturally moist tissues and organs such as the bowel, lung,
mouth, cervix. Two other examples of wet gangrene having clinical significance are
as follows:

• .Diabetic foot which is due to high glucose content in the necrosed tissue which
favours growth of bacteria.

• .Bed sores occurring in a bed-ridden patient due to pressure on sites

• Gas gangrene

• It is a special form of wet gangrene caused by clostridia (gram-positive

anaerobic bacteria) which gain entry into the tissues through open
contaminated wounds, especially in the muscles
• Thank You