CELLULAR ADAPTATION, CELL

INJURY AND CELL DEATH.

Dr. A. Kabir
Department of Human Pathology, College of
Medical sciences, UNIMAID
INTRODUCTION
 The cell is the basic living unit of an organism.

A living cell must maintain an organization capable of

producing energy.

 Thus,the most pressing need for a living cell is to

establish a structural and functional barrier between its
internal milieu and a hostile environment. i.e. it must
maintain a normal homeostasis.

 Atthe same time, to survive, the cell must be able to

adapt to adverse conditions such as changes in
temperature, solute concentrations, or oxygen supply,
the presence of noxious agents and so on.
Introduction cont’d
 Cells encounter many stresses as a result of the
changes in their internal and external environments
and it is their pattern of response to this stress that
constitutes the cellular basis for disease.

 If the adaptive capability is exceeded, cell injury

develops.

 Within certain limits, injury is reversible, and cells

return to a stable baseline; however, with severe or
persistent stress, irreversible injury results, and the
affected cells die by necrosis or apoptosis.
Stages in the cellular response to stress and injurious stimuli.

vier
CELLULAR ADAPTATION
 Adaptations are reversible changes in the size,
number, phenotype, metabolic activity, or functions
of cells in response to changes in their environment.

 Cellular adaptation can be physiological or

pathological.

The principal adaptive responses are:

 Atrophy (decrease in cell size)
 Hypertrophy (increase in cell size)
 Hyperplasia (increase in cell number)
 Metaplasia (change in cell type).
Cellular Responses to Injurious
Stimulus
Nature and Severity of Injurious Cellular
Stimulus Response
Altered physiologic stimuli:
Table 1-1. Cellular Responses to Injury Cellular
adaptations:
• Increased demand, increased trophic Hyperplasia,
stimulation (e.g. growth factors, hypertrophy
hormones)
• Decreased nutrients, stimulation Atrophy

• Chronic irritation (chemical or Metaplasia

physical)
Reduced oxygen supply; chemical Cell injury:
injury; microbial infection
HYPERTROPHY
 Refers to an increase in the size of cells, resulting in an
increase in the size of the organ.

 Occurs in non-dividing cells such as heart and skeletal

muscle.

 Hypertrophied organ has no new cells, but just larger cells.

 This increase in size is not due to cellular swelling but to the

synthesis of more structural components.

 Hypertrophy can be physiological or pathological.

Hypertrophy cont’d
PHYSIOLOGICAL:
→ Hormonal induced hypertrophy.
 1. Mass growth of uterus during pregnancy, with
hyperplasia

 2. Mass growth of Breast during lactation.

 3. In skeletal muscle due to heavy work like in weight
lifters, athletes

PATHOLOGICAL Hypertrophy
 – seen in Hearts and skeletal muscle
 1. In Heart due to chronic haemodynamic overload due to

hypertension or faulty valves – LVH.

Left ventricle (normal and hypertrophy)
Physiologic hypertrophy of the uterus during pregnancy
ATROPHY
 Shrinkage in the size of the cell by loss of cell substance
with resultant diminution in size of tissue or organ.

 Atrophy results from a reduction in the structural

components of the cell.

 Can be physiological or pathological.

PHYSIOLOGICAL atrophy is common during early

development e.g.
 i) Embryologic structures such as the NOTOCORD and

THYROGLOSSAL DUCT  undergo atrophy during foetal

development.

 ii) The uterus decreases shortly after parturition.

Common Causes of Pathological Atrophy
 i) Decreased workload (disuse atrophy)
 — immobilization of limb in POP or patient confined to bed rest
→ skeletal muscle atrophy.

 ii) Loss of innervation (denervation atrophy)

 — Damage to nerves as in polio → atrophy.
 NB: Normal function of skeletal muscle is dependent on its nerve
supply.

 iii) Diminished blood supply

 – Ischaemia to a tissue due to arterial occlusion → atrophy
because of progressive cell loss.
 In elderly, brain atrophy: atherosclerosis,

 iv) Pressure atrophy

 — Expanding benign tumour  atrophy in the surrounding
compressed tissue.
 — Severe Hydronephrosis  kidney parenchymal atrophy.
Common Causes of Pathological
Atrophy cont’d
 v) Loss of endocrine stimulation.
 Many endocrine glands, the breast and reproductive organs
depend on endocrine stimulation for normal function.
 loss of oestrogen stimulation after menopause →
physiological atrophy of endometrium, vaginal epithelium
and breast.

 vi) Aging (senile and brown atrophy)

 – Aging in associated with cell loss seen in tissues with
permanent cells e.g. Brain and Heart.

 vii) Inadequate nutrition

 – Marasmus is associated with use of skeletal muscle as a
source of energy after the reserves such as the adipose tissue
stores been depleted → marked muscle wasting.
TESTICULAR ATROPHY
senile atrophy
HYPERPLASIA
 Hyperplasia is an increase in the number of cells
in an organ or tissue, usually resulting in
increased volume of the organ or tissue.

 Hyperplasia frequently occurs with hypertrophy in

some organs especially in hormone-depended
organs e.g. uterus, breast.

 It occurs in tissues capable of replicating.

 Hyperplasia can be physiologic or pathologic.

HYPERPLASIA cont’d
PHYSIOLOGICAL
 1. Hormonal hyperplasia – increases the functional capacity of a tissue
when needed e.g. proliferation of the glandular epithelium of female
breast at puberty and during pregnancy Also in pregnant uterus.

 2. Compensatory hyperplasia → increases tissue mass after damage

or partial resection occurs e.g. after partial hepatectomy.

PATHOLOCIAL
 Mostly caused by excessive hormonal stimulation or growth factors

acting on target cells.

 1. Hormonally induced → endometrial hyperplasia. Potentiated by

Pituitary and ovarian hormones and imbalance between oestrogen with

progesterone.

 2. Prostatic hyperplasia

 3. Hyperplasia associated with viral infections HPV causing skin

warts (acanthosis, parakeratosis).
Endometrium (Normal and Hyperplasia)
METAPLASIA
 Is a reversible change in which one adult cell type is replaced by
another adult cell type ( Epithelial → epithelial; mesenchymal →
mesenchymal).

 Represents an adaptive substitution of cells that are sensitive to

stress by cell types better able to withstand the adverse
environment.

 Examples
Epithelial metaplasia
 → columnar to squamous as in respiratory tract in response to

chronic irritation
 (a) In habitual smokers, the normal columnar non ciliated epith →

stratified squamous → squamous cell carcinoma

 (b) Stones in the excretory ducts of the salivary gland, pancreas or

bile ducts may cause replacement of normal secretory columnar
epithelium → stratified epithelium.
Metaplasia of columnar to squamous epithelium in bronchus
Metaplasia cont’d
  Squamous to columnar as in Barrett oesophagitis in which
squamous epithelium is replaced by intestinal columnar cells →
Adenocarcinoma.

  Transitional to squamous as in urinary bladder where transitional

cell is replaced by squamous cell as a result of chronic inflammation
with schistosomiasis.

Connective Tissue metaplasia

– Is formation of cartilage, bone adipose tissue (mesenchymal tissues)
in tissues that normally do not contain these elements e.g. bone
formation in muscle (myositis ossificans) occurs after bone fracture.

Myeloid metaplasia
 – in Haemopoietic organ, such as adult spleen taking over production

of blood cells in severe Bone marrow disease  extramedullary

haematopoiesis.
Metaplasia of esophageal squamous epithelium
Mechanism of Metaplasia
 It is the result of a reprogramming of stem
cells that are known to exist in normal
tissues, -or of undifferentiated mesenchymal
cells present in connective tissue.

 These precursor cells differentiate along a

new pathway due to change in signals
generated by mixtures of cytokines, growth
factors and extracellular matrix.
Summary
 Cellular Adaptations are reversible changes in the size, number, phenotype,
metabolic activity, or functions of cells in response to changes in their
environment.

 ■ Hypertrophy: increased cell and organ size, often in response to increased

workload; induced by growth factors produced in response to mechanical
stress or other stimuli; occurs in tissues incapable of cell division.

 ■ Hyperplasia: increased cell numbers in response to hormones and other

growth factors; occurs in tissues whose cells are able to divide or contain
abundant tissue stem cells.

 ■ Atrophy: decreased cell and organ size, as a result of decreased nutrient

supply or disuse; associated with decreased synthesis of cellular building
blocks and increased breakdown of cellular organelles.

 ■ Metaplasia: change in phenotype of differentiated cells, often in response

to chronic irritation, that makes cells better able to withstand the stress;
usually induced by altered differentiation pathway of tissue stem cells; may
result in reduced functions or increased propensity for malignant
transformation.
CELL INJURY
 is defined as a variety of stresses that a cell
encounters as a result of changes in its
internal and external environment.

 All cells have in-built mechanisms to deal

with these changes to an extent. This is
known as cellular adaptation.

 Cell injury occurs when the limits of this

adaptation is exceeded by noxious stimuli.
Causes of cell injury
1. OXYGEN DEPRIVATION DUE TO
HYPOXIA/ISCHAEMIA
 Extremely important cause of cell injury

 May occur in clinical conditions like CCF,

COPD, SCD, CO poisoning, drowning, asphyxia.

 Ischaemia shuts up supply of both oxygen and

substrates- cells die faster.

 Targets cell’s oxidative respiratory apparatus

Causes of cell injury cont’d
2. PHYSICAL AGENTS:
 Mechanical trauma

 Extremes of temperature

 Sudden changes in atmospheric pressure

(decompression sickness, Caisson disease)

 Radiation

 Electric shock
Causes of cell injury cont’d
3. CHEMICAL AGENTS- drugs, poisons, alcohol
4. INFECTIOUS AGENTS – bacteria, viruses, fungi,
parasites
5. IMMUNOLOGIC REACTIONS- autoimmune Dxs like
SLE, RA, Hashimoto thyroiditis, type I DM etc
6. GENETIC DERANGEMENTS – SCD, inborn errors of
metabolism
7. NUTRITIONAL IMBALANCES- deficiencies or
excesses in normal cellular substrates e.g.
calories, proteins, CH2o, minerals, vitamins.
These can produce problems such as obesity,
malnutrition, scurvy, iron deficiency anaemia, etc
MOLECULAR TARGETS OF CELL INJURY

1. Aerobic respiration (mitochondria)

2. Maintenance of the integrity of cell membranes

3. Protein synthesis (endoplasmic reticulum )

4. The cytoskeleton

5. Preservation of the integrity of the genetic

apparatus.
Types of cell injury

 1. REVERSIBLE 2. IRREVERSIBLE

REVERSIBLE INJURY means that the cell recovers its function

when the noxious stimulus abates.

 The first point of attack of hypoxia is the cell’s

aerobic respiration and its oxidative
phosphorylation by mitochondria.

 As the oxygen tension decreases within the cell,
ATP production decreases through oxidative
phosphorylation
Morphology of reversible injury
Macroscopy
◦ Pallor, turgid tissue
◦ Increased weight
◦
Microscopy
◦ Cellular swelling; hydropic change or vacuolar degeneration
(Clear vacuoles in cytoplasm)
◦
Ultra structural changes
◦ Plasma membrane alterations: blebbing, blunting, and loss of
microvilli

◦ Mitochondrial changes: swelling and the appearance of small

amorphous densities

◦ Dilatation of ER: with detachment of polysomes; intracytoplasmic

myelin figures

◦ Nuclear alterations: clumping of chromatin

Irreversible injury
 Occurs when hypoxia/ischemia persists.
 Two features consistently characterise irreversibility:
◦ 1. Mitochondrial damage
◦ 2. Profound disturbances in membrane function

There is massive influx of calcium into the cell

Irreversible injury – cell death by necrosis:

◦ Due to release of lysosomal enzymes from damage to

lysosomal membranes
◦ Digest cellular components
◦ Loss of proteins, enzymes, ribonucleic acid and other
metabolites.

◦ Leakage of IC proteins into the circulation provides means of

detecting tissue specific-cellular injury and death using blood
serum samples e.g;
◦ Creatine kinase and troponin in myocardial infarction
◦ ALP & transaminases in liver disease
Characteristic of irreversible injury
 Rupture of lysosomes and autolysis
 Formation of myelin figures
 Lysis of E R
 Defects in cell membranes
 Formation of large densities
 Mitochondrial swelling
 Nuclear pyknosis, karyolysis or karyorrhexis
BIOCHEMICAL MECHANISM OF CELL
INJURY
Whatever the cause of injury, there are five
main foci of biochemical mechanisms
affected in the cell.

1- Decreased generation of ATP.

2- Mitochondrial dysfunction and damage
3- Increased production of free radicals
4- Intracellular accumulation of calcium and
loss of calcium homoeostasis
5- Defects in membrane permeability
Cellular and biochemical sites of damage in cell injury.

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© 2005 Elsevier
CELL DEATH

 This is the end result of irreversible cell injury

TYPES OF CELL DEATH
 1. NECROSIS 2. APOPTOSIS

 Necrosis
◦ Always pathologic – the result of irreversible injury
◦ Has numerous causes

 Apoptosis (programmed cell death)

◦ Usually a regulated, controlled process
◦ Physiological or pathological
NECROSIS
 This refers to the spectrum of morphologic changes
that follow cell death in living tissues.
Its most common manifestation is coagulative necrosis.

 The morphologic appearance of necrosis is the

result of two essentially concurrent processes:

1. Enzymatic digestion of the cell which can be

autolysis (self digestion) or heterolysis (enzymes
from lysosomes of leucocytes), and

2. Denaturation of proteins, with preservation of

basic tissue outline.
Types of Necrosis
 Coagulative necrosis
 Liquefactive (colliquative) necrosis
 Caseous necrosis
 Gangrenous necrosis
 Fat necrosis
 Fibrinoid necrosis.
Coagulative necrosis
 This form of necrosis occurs in all tissues
following hypoxic injury except in the brain. It
is exemplified in infarcts of solid organs such
as the heart, the spleen and the kidney.
 It results when the structural and enzymatic
proteins are denatured by acidosis that ensues
from the injury thus preventing enzymatic
digestion of the cells.
 This implies preservation of the basic outline of
the coagulated cells for a span of some days.
 The necrotic cells are removed by scavenger
white blood cells.
Coagulative necrosis cont’d
Macroscopy
 Following infarcts of solid organs, it appears as a
firm raised pale area, wedge-shaped with apex at the
centre and base towards the surface of the tissue.

Microscopy
 The cells retain their normal outlines.
◦ The nucleus shows one of two changes karyolysis and
karyorrhexis

◦ The cytoplasm becomes opaque and strongly eosinophilic

 EM shows disorganization and disintegration of the

cytoplasmic organelles and severe damage to plasma
membrane.
Liquefactive (Colliquative) necrosis
This occurs when the rate of dissolution of the
necrotic cells is faster than the rate of repair.
 In the brain following an infarct, there is rapid
dissolution of dead tissue due to the presence of
abundant lysosomal enzymes or different
hydrolases in the brain tissue.
 If extensive, cyst formation results that may
persist for life.
 Colliquative necrosis will also occur in area of
coagulative necrosis as a result of secondary
change, seen in
◦ Suppuration e.g. septic infarct
◦ Liquefaction of caseous material
Liquefactive necrosis of the brain
Caseous necrosis
 This is characteristic of Tuberculosis
 In caseous necrosis, the cells fail to maintain their outline
like in coagulative necrosis and they do not disappear by
lysis like in colliquative necrosis.

 Rather, the cells persist indefinitely as amorphous coarsely
granular eosinophilc material.

 Also unlike coagulative necrosis, the tissue architecture is

obliterated.

 Grossly, the debris appears as greyish while friable material

resembling clumpy cheese hence the name caseous necrosis.

 Microscopically, it appears as amorphous eosinophilic

material bordered by epithelioid cells, Langhan’s giant cells
and fibroblasts.
Fat necrosis
 This specifically affects adipose tissue and it is seen
following trauma and acute pancreatitis.

 This type of necrosis results from the presence of

trigylcerides in adipose tissue which are broken down by the
action of enzymes such as
◦ Phospholipases and proteases that attack plasma membrane of fat
cells releasing the TGs.

◦ Pancreatic lipases that hydrolyzes the TGs, producing free fatty acids.

 Precipitation of fatty acids as calcium soaps which

accumulate microscopically as amorphous basophilic
deposits at the periphery of irregular islands of necrotic
adipocytes.

Grossly, fat necrosis appears as irregular chalky white areas.

 Microscopically, amorphous basophilic deposits; a foreign

body giant cell reaction may be seen.
Gangrenous necrosis
 Most commonly applied to limbs that have lost
blood supply & have undergone coagulative
necrosis.

 Could be applied to necrotic strangulated

segments of intestines, testes, ovaries etc.

 When bacterial infection is superimposed,

coagulative necrosis is modified by the
liquifactive (putrefactive) action of the bacteria &
attracted leucocytes to form wet gangrene.
Gangrene - toes
Fibrinoid Necrosis
 Usually seen in the walls of blood vessels (e.g., in
vasculitides)
 Glassy, eosinophilic fibrin-like material is deposited
within the vascular walls
APOPTOSIS

Definition: programmed cell death or individual

cell necrosis, designed to eliminate unwanted
host cells through activation of a coordinated
internally programmed series of events
effected by dedicated set of gene products.
 Involves “step-by-step” gradual disassembly
& phagocytosis of cellular components,
designed to eliminate unwanted or potentially
harmful cells.
 It is an important process in both health and
disease.
Causes of Apoptosis
PHYSIOLOGIC APOPTOSIS
 Embryogenesis- implantation, organogenesis, developmental
involution.

 Hormone-dependent involution in adults – endometrial cell

breakdown during menstrual cycle, ovarian follicular atresia
during menopause, regression of lactating breast after
weaning; etc.

 Cell deletion in proliferating cell population e.g. intestinal crypt

epithelia.

 Death of host cells after they have served their useful

purposes- rbcs, neutrophils, macrophages.

 Clonal deletion of self reactive lymphocytes.

 Cell death induced by cytotoxic T lymphocytes

Causes of apoptosis cont’d
 PATHOLOGIC APOPTOSIS
◦ Cell injury with sub-lethal DNA damage
Virally infected cells
Cell death in tumours
Cell death due to chemotherapy and radiotherapy

STAGES OF APOPTOSIS
 During apoptosis, the cells go through the following
morphologic stages which can be categorized into:
A. The drying process
B. The elimination process.
The drying process
 Cell shrinkage.
 The cell is smaller in size, cytoplasm dense, organelles
relatively normal though more tightly packed.
 Chromatin condensation- most characteristic feature
of apoptosis.
 Chromatin aggregates under nuclear membrane.
 Nucleus may break up into fragments.
 Formation of cytoplasmic blebs and apoptotic bodies.
 The apoptotic cell shows extensive surface blebbing
then undergoes fragmentation into a number of
membrane bound apoptotic bodies composed of
cytoplasm and tightly packed organelles with or
without nuclear fragments.
A. Apoptosis of epidermal cells
B. Apoptosis of hepatocytes
The elimination process

 The apoptotic bodies are phagocytosed by

macrophages where they are readily
degraded in the lysosome.

 The adjacent cells migrate or proliferate to

replace the apoptotic cell.
Features of Necrosis and Apoptosis
 Cell size: Enlarged (swelling)  Cell size: Reduced (shrinkage)
 Nucelus: Fragmentation into nucleosome
size fragments
 Nucelus: Pyknosis, karyorrhexis,
karyolysis  Plasma membrane: Intact; altered
structure, especially orientation of lipids
 Plasma membrane: Disrupted
 Cellular contents: Intact; may be released
 Cellular contents: Enzymatic in apoptotic bodies
digestion; may leak out of cell  Adjacent inflammation: No
 Adjacent inflammation: Frequent  Physiologic or pathologic role: Often
physiologic, means of eliminating
 Physiologic or pathologic role: unwanted cells; may be pathologic after
Invariably pathologic (culmination of some forms of cell injury, especially DNA
irreversible cell injury) damage

NECROSIS APOPTOSIS
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