CELL INJURY, CELL DEATH &

ADAPTATIONS
By: HIRA IRFAN
 Introduction To Pathology
In Latin;
Pathos --- suffering / disease
Logos --- study

Pathology --- study of disease by scientific method

It explains the “WHY” & “HOW”

Disease --- abnormal variation in structure / function of any

body part at cellular, tissue or organ level
 Types

Pathology Bridge
Basic science Clinical practice
Normal Cell & Its Functions
Cell wall Don’t have cell wall
Cell membrane Support, protection, controls movement of its components,
barrier, maintain homeostasis
Nucleus Controls cell activity, contains hereditary material
Nuclear membrane Controls movement of materials
Cytoplasm Supports & protects cell organelles
Endoplasmic reticulum Aids in protein synthesis, carries materials through cell
Ribosome Synthesizes proteins
Mitochondria Breaks down sugar to release energy, site of aerobic cellular
respiration
Vacuole Store food, water, metabolic & toxic wastes
Lysosome Breaks down larger particles, digests
Nucleolus Makes ribosomes
Golgi apparatus Modify, package & export proteins
Cilia Movement
Centrioles Separate chromosome pairs during mitosis
Cytoskeleton Strengthens cell, maintains shape, moves organelles within
cell
Normal Cell
 4 Aspects Of Disease
Etiology --- Cause
2 Factors --- 1. Intrinsic / genetic
2. Acquired (infections, nutritional, chemical, physical)

Pathogenesis --- sequence of events in response to cells or tissues to etiologic agent from initial
stimulus to ultimate expression of disease

Morphological Changes --- structural alteration in cells or tissues that are either characteristic of the
disease or diagnostic of etiologic process

Functional Derangements / Clinical Manifestations --- morphological changes normal cell

functions influenced clinical features determined course is recognized prognosis
Cellular Response To Stress
& Noxious Stimuli
 Adaptive Responses
Hypertrophy
Hyperplasia
Atrophy
Metaplasia

Causes Of Cell Death

▪ Ischemia
▪ Infection
▪ Toxins
▪ Immune Reactions

2 Patterns --- a) Necrosis

b) Apoptosis
 Hypertrophy
• Increase in cell size resulting in increase in organ size
• No new cells formed just existing cells become larger
• Increase in size is due to increase in cellular component & NOT due
to swelling
 Causes
1. Increased functional demand
2. Hormonal stimulation
3. Growth factors

Physiological
• Uterus in pregnancy (hormonal stimulation)
• Body builders --- (increased workload)

Pathological
Cardiac overload (increase workload e.g. HTN, aortic stenosis)
2 signals --- a) Mechanical Triggers --- stretch
b) Trophic Triggers --- Growth factors
Adrenergic hormones
(soluble mediators)
Possible Causes Of Degenerative Changes

• Finite vascular supply

• Finite capacity of mitochondria to supply ATP
• Finite capacity of biosynthetic machinery to
provide contractile protein & other cytoskeletal
elements
 Hyperplasia

1. Increase in number of cells in an organ / tissue

resulting in an increase in volume of that organ.
2. Takes place in cells that can replicate i.e. can make
DNA (mitotic division)
3. Usually concurrently occurs with hypertrophy & has
the same stimulus
Physiological
• Hormonal --- increased functional capacity of tissue when needed
• Compensatory --- residual tissue grows after removal / partial loss of an organ

Mechanism --- increased local production of growth factors

OR increase levels of growth factor receptors on cells
OR activation of intracellular signaling pathway
All these lead to cell proliferation

Pathological
• Increased growth stimulation
• Increased hormonal stimulation

Sebaceous hyperplasia
 Atrophy
1. Decrease in cell size by loss of cell substance
2. When sufficient cells involved the organ decreases in
size
3. Atrophic cells have decreased function but they are NOT
dead
4. Progressive atrophy can lead to death
5. Cells retreat to smaller size to survive
Physiological
Common in early development

Pathological
• Local
• Generalised
It depends on the cause
Cellular changes are the same in physiological & pathological
atrophy
 Causes
1. Decrease workload (Disuse Atrophy)
2. Loss of innervation (Denervation Atrophy)
3. Decreased blood supply (Ischemia)
4. Inadequate nutrition
5. Loss of endocrine stimulation
6. Aging (Senile Atrophy)
7. Pressure
Mechanism
Not understood but;
• Decrease protein synthesis
• Degradation of cellular protein
• In some cases, accompanied by increased autophagy
 Metaplasia
1. Reversible change in which one adult cell type is replaced by
another adult cell type
2. Reprogramming of stem cells to differentiate along new pathway
3. Sensitive cells replaced by rugged cells who can withstand the
adverse stimuli/environment
Disadvantages
o Decrease in function
o Increased propensity for malignancy
 Causes Of Cell Injury
Overview
Reversible Cell Injury: Reversible if damaging stimulus is removed
Hallmark: Decreased oxidative phosphorylation
ATP depletion
Cellular swelling

Irreversible Cell Injury: Continuous damage = irreversible damage

Probable causes --- Amorphous densities in mitochondria signifying severe damage
Functional changes eg, change in cell membrane permeability

Causes of Cell Injury can range from external gross physical violence to internal
endogenous causes
 Causes Of Cell Injury
Oxygen Deprivation
Hypoxia deficiency of O2 cell injury cell death
Injury due to reduced aerobic oxidative respiration
Ischemia not only causes hypoxia but other substrates carried by it are . Therefore
ischemic cells are injured more rapidly & severely
Causes: 1. Cardiorespiratory failure 2. Loss of O2 carrying capacity
Physical Agents
1. Mechanical trauma
2. Extreme temperature
3. Radiation
4. Electric shock
5. Sudden change in atmospheric pressure
Chemical Agents & Drugs
List is endless but some e.g. are:
Hypertonic homeostatic imbalance
Increased O2 concentration
Poisons eg, Hg, arsenic, cyanide --- destroy cells
Environmental & air pollutants
Insecticides & herbicides
Industrial & occupational hazard eg, CO, asbestos
Social stimuli eg alcohol, drugs
Therapeutic drugs
Infectious Diseases
Virus, rickettsiae, bacteria, higher parasite forms, tapeworm
Immunological Reactions
Autoimmune reactions
Anaphylactic reactions
 Genetic Derangement
1. Down’s syndrome --- chromosomal defect
2. Sickle cell anemia --- decreased RBC

Nutritional Imbalance
• Anorexia nervosa
• Marasmus
• Vitamin deficiency
• Atherosclerosis (excess fats)
 Genetic Derangement
1. Down’s syndrome --- chromosomal defect
2. Sickle cell anemia --- decreased RBC

Nutritional Imbalance
• Anorexia nervosa
• Marasmus
• Vitamin deficiency
• Atherosclerosis (excess fats)
 Necrosis

Spectrum of morphologic changes that follow cell

death in living tissue, resulting from progressive
degradative action of enzymes on lethally injured
cells
 Morphologic Appearance
• Denaturation of intracellular proteins & enzymatic digestion of cells
• Enzymes come from lysosomes of dead cells itself (autolysis) OR from
immigrant leukocytes during inflammatory reactions
Nuclear change shows 3 patterns
• Pyknosis: chromatin clumping & shrinking with increased basophilia
• Karyorrhexis: fragmentation of chromatin
• Karyolysis: fading of chromatin material

Necrotic debris removed by phagocytosis. If debris is not removed it attracts

Ca salts & other minerals & become calcified --- Dystrophic calcification
 Mechanisms O f Necrosis

Hypoxia
Caused by
1. Ischemia
2. Anemia
3. CO poisoning
4. Poor oxygenation of blood due to pulmonary disease
Hypoxic cell injury can be:
• Early (Reversible ) stage
• Late (Irreversible ) stage
 Mechanisms O f Necrosis
Early (Reversible ) stage: Decreased ATP which causes
1. Failure of cell membrane Na-K pump.
Increased intracellular Na & water which cause cellular & organelles swelling
Hydropic Change seen in cellular swelling as large vacuoles in cytoplasm
2. Disaggregation of ribosomes & failure of protein synthesis
Late (Irreversible ) stage: Severe or prolonged cause
Massive Ca influx & very low ph enzymes activated
Damage cell & organelle membranes irreversible damage to mitochondria,
cell membrane & nucleus
cell death
 Mechanisms O f Necrosis
Free Radical Induced Injury
Any molecule with single unpaired electron in outer orbital eg superoxide
Formed by
Normal metabolism
O2 toxicity
Ionizing radiation
Drugs
Chemicals
Reperfusion injury
Degraded by
Spontaneous decay
Intracellular enzymes eg catalase
Endogenous substances eg transferrin
 Mechanisms O f Necrosis

Cell Membrane Damage

Direct --- extreme temperature
toxins
virus
Indirect --- hypoxia
Increased Intracellular Ca Level
Cell membrane damage
Increased intracellular level
Activate enzymes in low ph
Degrade cell organelles
 Types Of Necrosis

Coagulative Necrosis
Sudden interruption of blood supply especially to heart
General preservation of tissue architecture
Mechanism
Injury or increased intracellular acidosis denatures proteins & enzymes
Proteolysis is blocked
Ultimately necrotic cells removed by fragmentation & phagocytosis of
debris by scavenger WBC & their lysosomal enzymes
 Types Of Necrosis
Liquefactive Necrosis
• Digestion of tissue is seen
• Focal bacterial & fungal infections cause inflammation
• Seen in CNS
• Cells are digested completely leaving behind liquidly
viscous mass
• If acute inflammation initiated the necrosis, the liquid is
creamy yellow because of pus
 Types Of Necrosis
Fat Necrosis
Caused by trauma to tissue with high fat content OR
Pancreatic enzymes in acute haemorrhagic pancreatitis
Enzymes diffuse into inflamed pancreatic tissue &
digest it
Fatty acid released
Form Ca salts (Soap formation or Dystrophic
calcification)
Elastase enzymes digests blood vessels & causes
haemorrhage in pancreatitis.
 Types Of Necrosis

Caseous Necrosis
Typical of tuberculosis
Cheesy white gross appearance
Tissue architecture completely obliterated
Microscopically – amorphous granular
eosinophilic debris enclosed within
inflammatory border – Granulomatous Reaction
 Types Of Necrosis

Gangrenous Necrosis
Vascular occlusion (often to lower limbs & bowel) + coagulative
necrosis = Dry Gangrene

Coagulative necrosis + superimposed bacterial infection + attached

leukocytes = Wet Gangrene
In other words
Coagulative necrosis + liquefactive necrosis = Wet Gangrene
Wet Gangrene
Dry Gangrene
 Apoptosis
It’s a pathway of cell death that is induced by tightly regulated intracellular program in which
cells destined to die activate enzymes that degrade the cell’s own nuclear DNA & nuclear &
cytoplasmic proteins.
Cell membrane remains intact.
Structures that are altered become apoptotic cell & become target to phagocytosis.
Dead cells are cleaned up before its contents can leak out.
So no inflammatory reaction is elicited.

Causes
Physiological
Adaptive
Pathological
 Physiological Situations
It eliminates cells that are no longer needed
It is “Programmed Cell Death”
1. During Embryogenesis. eg organogenesis
2. Hormone dependent involution in adults. eg ovarian follicle atresia in
menopause
3. Cell deletion in proliferating cell population. eg intestinal crypt epithelium to
keep constant number
4. Death of host cells who have served their purpose. eg neutrophils in acute
inflammation
5. Elimination of potentially harmful self reactive lymphocytes
6. Cell death induced by cytotoxic T cells
Physiological Situations
 Pathological Conditions

1. Cell death by injurious stimuli. eg

radiation
2. Cell injury in viral diseases. eg
hepatitis
3. Pathologic atrophy in parenchymal
organs after duct obstruction. eg
pancreas, kidney, parotid gland
4. Cell death in tumors
5. Sometimes in various necrosis
 Morphology
1. Cell shrinkage --- Cytoplasm dense --- organelle tightly packed but
are normal
2. Chromatin condensation --- aggregate peripherally under nuclear
membrane. Nucleus may break into 2 or more fragments
3. Cytoplasmic blebs & apoptotic bodies --- blebbing --- fragmentation
--- membrane bound apoptotic bodies formed containing
cytoplasm, organelles with or without nucleus
4. Phagocytosis of apoptotic bodies usually by macrophages ---
Degraded by lysosomal enzymes --- Adjacent healthy tissue migrate
or proliferate to replace the space occupied by now deleted
apoptotic cells
 Mechanism of Apoptosis
1. Initiation Phase --- caspases become catalytically active
2. Execution Phase --- these enzymes act to cause death

Initiation Of Apoptosis
Extrinsic or Receptor initiated pathway
activate
Intrinsic or Mitochondrial pathway caspases
Necrosis vs Apoptosis
 Sub Cellular Responses to Injury

A - Lysosomal Catabolism
Primary Lysosome --- Membrane bound organelle containing
enzymes.
Secondary Lysosome or Phagolysosome --- When primary lysosome
fuses with the vacuole membrane which contains the material to be
digested.

Primary lysosome
 Heterophagy

Heterophagy

1. Digestion of material ingested from extracellular environment

2. Material taken up through Endocytosis (Phagocytosis or Pinocytosis
3. Material endocystosed into vacuoles (endosome or phagosome
4. Fuse with lysosome
5. Phagolysosome

eg uptake/digestion of bacteria by neutrophils

 Autophagy

Autophagy

1. Own intracellular material digested

2. Autophagic vacuoles formed – Sequestered material
3. Fuse with lysosomes
4. Autophagolysosome

eg Removal of damaged organelle after cell injury

Heterophagy/Autophagy
 Heterophagy/Autophagy

Lysosomes degrade most of the CHO & proteins. Some fat remains
undigested --- form Residual Bodies within cells
eg Inhaled carbon
Tattoo pigment
Lipofuscin pigment granules
 Induction Of SER

B - Induction of Smooth Endoplasmic Reticulum

• SER is involved with metabolism of various chemicals.

• If cells are exposed to these chemicals, they show hypertrophy of ER as an
adaptive response
• eg Prolonged use of barbiturates --- tolerance develops --- need to increase the
dose --- shows patient has “adapted” to the medicine.
• This adaptation is due to increase volume (hypertrophy) of SER of hepatocytes
which metabolise the drug
 Mitochondrial Alterations
C – Mitochondrial Alterations

• Important role in cell injury & apoptosis played by

Dysfunctional Mitochondria
• Various alteration in size, number & shape occur in some
pathological diseases
• eg Hypertrophy -- Increase in number of mitochondria in
cell
• eg Atrophy – Decrease in number of mitochondria in cell
• eg Alcoholic Liver – Large & abnormal shape
 Cytoskeletal Abnormalities
D – Cytoskeletal Abnormalities
It consists of:-
• Microtubules
• Thin actin filaments
• Thick myosin filaments
• Intermediate filaments
o Keratin filaments – epithelial cells
o Neuro filaments – neurons
o Desmin filaments – muscles
o Vimentin filaments – CT cells
o Glial filaments - CNS
• Contractile proteins
 Cytoskeletal Abnormalities

Examples

1. Defect in microtubules – sperm

motility inhibited leading to
sterility
2. Neuro filament – Alzheimer’s
disease
3. Keratin filament – Alcoholic liver
disease in which Mallory body
(intracytoplasmic inclusion) is seen
 Intracellular Accumulation
Deranged metabolism leads to accumulation of abnormal amount of various
intracellular substances.

3 pathways of intracellular accumulation

• Normal endogenous cellular component accumulates in excess eg water, lipid,
CHO, protein. They are produced at a normal or increased rate but rate of
metabolism is inadequate to remove it.
eg Fatty change in liver (TG accumulate)
• Normal or abnormal substances due to genetic or acquired defects in
metabolism, packaging, transport or secretion of these substances
• Exogenous eg products of infectious agents
• Endogenous eg product of abnormal synthesis/metabolism
 Intracellular Accumulation

• Abnormal exogenous substance is deposited & it accumulates

because cell has neither enzymatic machinery to degrade it nor to
transport it to other sites. They can accumulate
1. Transiently
2. Permanently
eg Accumulation of carbon & silica particles

Carbon pigment
Intracellular Accumulation
 Lipids - Steatosis

• Any abnormal accumulation of TG within parenchymal cells

• Seen in liver but may also occur in heart, skeletal muscle,
kidney & other organs
• Caused by toxins, protein malnutrition, DM, obesity, anoxia
• Most common causes – Alcohol abuse. DM with obesity
• Fatty change mild – may have no effect on cellular function
• Severe change – impair cellular function, even cause cell death
 Lipids – Cholesterol (Esters)
Result of defective catabolism & excessive intake
It s accumulation is seen intracellularly within macrophages

Atherosclerosis in smooth muscles & macrophages as lipid vacuoles (foam cells)

Xanthomas. Cholesterol accumulates within macrophages in acquired or hereditary

hyperlipidemia states

Inflammation & necrosis. Foamy macrophages found at all sites of cell injury &
inflammation

Cholesterolosis. Focal accumulation of foamy macrophages in gall bladder wall

Lipids – Cholesterol (Esters)

Foamy macrophage Cholesterolosis

Xanthoma
 Proteins

• Intracellular protein accumulation appears as rounded eosinophilic droplets, vacuoles or

aggregates in cytoplasm
• Less common than lipid accumulation
• Occurs because present in excess or synthesized in excess
eg Nephrotic syndrome
Mallory bodies in alcoholic liver
Neurofibrillary tangle in brain in Alzheimer’s

Russell Body
 Glycogen
Associated with metabolic abnormalities of either glucose
or glycogen
eg Poorly controlled DM
Glycogen storage diseases or Glycogenesis
 Pigments
Colored substances
1. Endogenous
2. Exogenous

Exogenous
1. Come from outside the body
2. Most common pigment is Carbon
Inhaled – picked up by macrophages – transported to regional
LN via lymphatics where pigment blackens regional LN & pulmonary parenchyma –
Anthracosis
Heavy accumulation leads to emphysema/fibroblastic reaction – Coal workers
pneumoconiosis
3. Tattooing – local exogenous pigment in skin
 Pigments
Endogenous
Synthesized within the body

Lipofuscin (Lipochrome /wear & tear / aging pigment)

Insoluble pigment with brownish yellow intracellular material that
accumulates in heart, liver & brain as a function of age or atrophy. If
present in large amount – Brown Atrophy
It is not injurious to cell but is important as marker of past free radical
injury
 Pigments
Melanin
• Brown black pigment
• Synthesized exclusively by melanocytes
when tyrosinase catalyzes tyrosine to DOPA
located in epidermis
• Acts as screen against harmful UV radiation
• eg freckles, melanin accumulated in basal
keratinocytes
 Pigments

Hemosiderin
• Hb derived granular pigment
• Golden yellow to brown
• Accumulates in tissues when there is local or systemic excess of Fe
• Local excess of Fe & consequently hemosiderin rsult from
haemorrhage eg bruise
 Pigments
Hemosiderosis
• Systemic overload of Fe
• Hemosiderin deposited in many organs
Causes
• Increased absorption of dietary Fe
• Impaired utilization of Fe
• Hemolytic anemia
• Transfusions

Hereditary Hemochromatosis
Extensive accumulation of Fe with tissue injury
eg liver fibrosis, heart failure, DM
 Pathologic Calcification

• Abnormal deposition of Ca salts & small amounts of

Fe, Mg & other minerals

Dystrophic Calcification
Deposition of Ca in dead or dying tissue, Occurs in
absence of Ca metabolic derangement (normal serum Ca
levels)

Metastatic Calcification
Deposition of Ca salts in normal tissue. Ca metabolism
derangement present (hypercalcemia)
Pathologic Calcification

Dystrophic Metastatic