Cell Adaptation, Injury and

Death
Dr Mbayah J. Etabale
Lecturer and Anatomical Pathologist
Maseno University
Outline
• Introduction
• Cellular Adaptation
• Cell Injury
• Cell Death

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 Introduction
• Cells maintain their intracellular milieu (structure and function) within
narrow range of physiologic parameters while meeting physiologic
demands – homeostasis
• Adaptation is a reversible structural and functional change in
response to an external stimulus/stressor that allows for continued
survival of the cell
• Beyond a certain limit of adaptation, cell injury occurs
• Cell injury may be reversible up to a certain limit beyond which cell
death occurs
Cell Adaptation Cell Injury Cell Death
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 Introduction

Source: Robbins Pathologic Basis of Disease, 8e 4

A. Cellular Adaptation
Hypertrophy
Hyperplasia
Atrophy
Metaplasia

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 Cellular Adaptation
• Reversible changes in the number, size, phenotype, metabolic activity, or
functions of cells in response to changes in their environment
• Physiological adaptation
• Responses of cells to normal stimulation by hormones, chemical mediators or mechanical
stress
• Pathological adaptation
• Responses of cells that allow them to escape injury by adjusting their structure or function
• Leads to compromise of normal function
• Four adaptive responses
• Hypertrophy
• Hyperplasia
• Atrophy
• Metaplasia

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 1. Hypertrophy
• An increase in the size of cells that results in an increase in the size of
the affected organ
• Often caused by increased workload
• The increase in size is due to increased synthesis of intracellular
structural components
• Pure hypertrophy occurs in tissue incapable of cell division
• Stimuli
• Mechanical forces
• Trophic factors

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Mechanisms of Myocardial Hypertrophy

Source: Robbins Pathologic Basis of Disease, 8e 8

 Morphology of Myocardial Hypertrophy

Source: http://hit-micrscopewb.hc.msu.edu/Pathology-Static/Injury/Lab1- Source: https://medicine.nus.edu.sg/pathweb/wp-

Image02.html content/uploads/2017/02/left-ventricular-hypertrophy.png

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 2. Hyperplasia
• An increase in organ size due to an increase in number of cells
• A property of cells capable of cell division or that contain abundant tissue stem
cells
• Physiological vs pathological hyperplasia
• Physiological
• Hormonal – female breast during puberty, in pregnancy
• Compensatory – liver, kidney, bone marrow
• Pathological
• Excess of trophic factors
• Endometrial hyperplasia
• Prostatic hyperplasia
• Thyroid hyperplasia
• Deregulation of cell proliferation
• HPV-induced warts
• Pathological hyperplasia is a fertile soil for malignant neoplasms

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2. Hyperplasia

Source: Robbins Pathologic Basis of Disease, 8e

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 3. Atrophy
• Decrease in size of an organ due to decrease in size (and number) of cells
• Physiological vs Pathological
• Physiological
• Embryogenesis
• Notochord
• Thyroglossal duct
• Post-partum uterus
• Post-menopausal breast, uterine tissue
• Senile brain atrophy
• Pathological
• Localised
• Generalised

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 3. Atrophy
Causes
• Decreased workload – disuse atrophy
• Skeletal muscle atrophy
• Osteoporosis of disuse
• Loss of innervation – denervation
atrophy
• Diminished blood supply – ischaemia
• Inadequate nutrition
• Reduction in trophic factors
• Local pressure
• Ageing
Mechanisms of Atrophy
• Shrinkage in cell size is due to loss
of cell substance
• Reduced protein synthesis
• Increased breakdown of cellular
organelles
• Ubiquitin-proteasome pathway
degrades cytosolic and nuclear
proteins
• Autophagic vacuoles
• Reduces the metabolic needs of
cells sufficiently to permit survival
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3. Atrophy

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 4. Metaplasia
• Reversible substitution of one differentiated cell type for another
• Replacement of cells under some form of stress by cells that are more
resistant to that stress
• Replacement of specialised columnar epithelium with squamous epithelium
• Bronchial epithelium in smokers
• Corneal and bronchial epithelium in vitamin A deficiency
• Excretory duct epithelium (salivary gland ducts, pancreatic ducts, biliary ducts in response to
calculi
• Replacement of squamous epithelium with columnar epithelium
• Barrett oesophagus in reflux oesophagitis
• Induced by altered differentiation pathway of the tissue stem cells
• May result in reduced functions and / or propensity for malignant
transformation
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4. Metaplasia

Source: Robbins Pathologic Basis of Disease, 10e

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But things can get worse
• Cell injury will occur if:
• the limits of adaptive response are exceeded
• the external stress is inherently harmful
• an intrinsic damage to the cell occurs

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B. Cell Injury

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 Causes of Cell Injury
• Excessive stressors • Alteration of osmotic homeostasis
• Enzyme denaturation, cofactor
• Deprivation of essential impairment
nutrients/substrates • Physical agents
• Oxygen deprivation • Infections
• Hypoxia vs Ischaemia • Immunologic reactions
• Nutritional imbalances • Genetic derangements
• Exposure to injurious
agents/stresses
• Chemical agents
• Alteration of membrane permeability

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 Reversible Cell Injury
• Sublethal cellular damage
• Functional and morphological
changes are reversible if the
damaging stimulus is removed
• Morphological features of
reversible cell injury:
• Cell and organelle swelling AKA
hydropic/vacuolar change
• Membrane blebs
• Swelling of ER
• Detachment of ribosomes from ER
• Loss of microvilli
• Clumping of nuclear chromatin
Source: Robbins Pathologic Basis of Disease, 10e 20
 Mechanisms of Cellular Injury
• Energy depletion (ATP)
• Loss of plasma membrane
integrity
• Defects in protein synthesis
• Cytoskeletal damage
• DNA damage
• Free radical damage
• Inflammation Source: Robbins Pathologic Basis of Disease, 10e

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 And then the point of no return…
• Beyond a certain point, cellular
injury becomes irreversible
• Irreversible cell injury is
characterised by
• Membrane damage/dysfunction
• Plasma membrane
• Lysosomal membranes
• Mitochondria
• Mitochondrial dysfunction

Source: Robbins Pathologic Basis of Disease, 10e 22

C. Cell Death

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 Morphological Alterations in Irreversible
Injury
• Cytoplasmic eosinophilia
• Nuclear degeneration
• Karyolysis
• Nucleus becomes pale and eventually disappears
• Due to the action of endonucleases
• Pyknosis
• Nucleus shrinks, chromatin condenses; becomes deeply basophilic
• Karyorrhexis
• Nucleus undergoes fragmentation
• Membrane rupture

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 Types of Cell Death
• Necrosis
• Pathological form of cell death
• Main characteristic is membrane damage (plasma membrane, mitochondria,
lysosomes)
• Cellular enzymes leak out and cause cellular damage
• Attendant inflammatory response
• Apoptosis
• Carefully orchestrated cascade that results in degradation of the cell and its
organelles
• Formation of apoptotic bodies which are ingested by phagocytes

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 26
Source: Robbins Pathologic Basis of Disease, 10e
 Morphologic Patterns of Necrosis
1. Coagulative necrosis
2. Colliquative necrosis
3. Caseous necrosis
4. Fat necrosis
5. Fibrinoid necrosis

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 1. Coagulative Necrosis
• Caused by blockage of action of most enzymes
• No dissolution of tissue
• Overall outline of dead tissue preserved and persists for some time
until inflammatory cells infiltrate the tissue
• The necrotic tissue appears paler than normal
• A localised area of coagulative necrosis is called an infarct

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Coagulative Necrosis – Myocardial Infarction

Gross, cross section: A pale, whitish infarct is surrounded by a zone of hyperemia (vascular dilatation).

Very low power glass slide: The area of coagulative necrosis is bright pink compared to the lighter pink
viable myocardium. The bluish areas on each side of the necrotic zone represent the granulation tissue
response to the necrosis.
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Coagulative Necrosis – Myocardial Infarction

• Here is myocardium in which the

cells are dying as a result of
ischaemic injury from coronary
artery occlusion
• This is early in the process of
necrosis
• The nuclei of the myocardial
fibres are being lost
• The cytoplasm is losing its
structure, because no well-
defined cross-striations are seen
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Dry Gangrene

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 2. Colliquative Necrosis
• AKA liquefactive necrosis
• Characterised by softening of the necrotic tissue into a paste-like
mush/watery débris
• Due to action of lytic enzymes released from dead cells or from
lysosomes of invading inflammatory cells
• Examples:
• Focal abscesses
• Brain infarct
• Wet gangrene

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2. Colliquative Necrosis

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2. Colliquative Necrosis

Cystic Brain Infarct

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2. Colliquative Necrosis

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 3. Caseous Necrosis
• In areas of caseous necrosis, cells die and form an amorphous
proteinaceous mass in which no resemblance to the original
architecture is discerned
• Typically seen in tuberculosis

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 4. Fat Necrosis
• Typically involves fat cells in and
around the pancreas, omentum
and abdominal wall
• Lipolysis due to lipase released
by the pancreas
• Triglycerides cleaved into fatty
acids which bind and precipitate
calcium ions forming insoluble
salts
• Deposition of calcium imparts a
chalky appearance
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5. Fibrinoid Necrosis
• Limited to small blood vessels
• Autoimmune diseases
• Malignant hypertension
• Necrosis of intima and media
• The walls of necrotic vessels are
impregnated with fibrin and
appear homogenously red on
H&E

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2. Apoptosis
• This is a controlled pathway of cell death in which cells activate enzymes
that degrade the cell’s own DNA and proteins
• Cell broken down into apoptotic bodies which are ingested by WBCs and
neighbouring cells
• Physiological
• Embryonic development
• Hormonal involution
• Normal cell turn-over
• Post-inflammatory “clean up”
• Pathological
• Virus-infected cells
• DNA damage
• Mitochondrial damage
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Robbins Basic Pathology

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 Necrosis vs Apoptosis
Feature Necrosis Apoptosis

Cell Size Enlarged (swelling) Reduced (Shrinkage)

Nucleus Pyknosis → Karyorrhexis → Karyolysis Fragmentation into small nucleosome-sized

fragments

Plasma Membrane Disrupted Intact; altered structure, especially

orientation of lipids

Cellular Elements Enzymatic digestion; may leak out of Intact; may be released in apoptotic bodies
cells

Adjacent Inflammation Frequent No

Physiologic or Pathologic Pathological Physiological

Pathological after certain forms of injury –
DNA damage

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4. Intracellular Accumulations

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Intracellular Accumulations
• Accumulation of abnormal • Carbohydrates – glycogen storage
disorders
amounts of various substances in
• Abnormal substance
a tissue • Endogenous
• Accumulations can be: • Amyloid
• Mutated α-1 antitrypsin protein
• Normal cellular constituent
• Exogenous
• Lipids
• Pneumoconioses
• TGs – Steatosis
• Tattoos
• Cholesterol – Atherosclerosis
• Xanthomas
• Proteins – reabsorption protein
droplets in renal tubules

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Fatty Liver

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Pigmented Intracellular Accumulations
• Exogenous • Endogenous
• Tattoo • Haemosiderin
• Anthracoses • Melanin
• Lipofuscin
• Bile

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Tattoo

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Anthracosis

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Haemosiderin

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5. Calcification

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Calcification
• Deposition of calcium salts within tissue
• 2 categories
• Dystrophic calcification
• Local deposition of calcium in dead or dying tissue
• Metastatic calcification
• Widespread tissue deposition of calcium salts
• Hypercalcaemia
• PTH- or PTHRP-producing tumours
• Increased bone destruction
• Renal failure

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Assignments
• Mechanism of Apoptosis

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The End

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