CELLULAR ADAPTATION, INJURY

AND DEATH

By: Dr. Lalisa B. (MD, Pathology Resident)

Oct 20, 2023 By: Dr. Lalisa B. 1

Objectives:
 To know how cells adapt to stresses
 To know types of cellular adaptations to cell injury.
 To know the causes, mechanisms, and consequences of the
various forms of acute cell damage, including reversible cell
injury.

Oct 20, 2023 By: Dr. Lalisa B. 2

Introduction
• Cells are active participants in their environment, constantly adjusting their structure and
function to accommodate changing demands and extracellular stresses. This phenomenon is
called homeostasis.

• Different physiologic stimuli or pathologic stresses(e.g. hormones, growth factors, nutritional

deficiency, physical stresses, hypoxia, infections, poisons…) may induce cellular adaptations,
reversible injuries or irreversible injuries (death).

• Factors that determine the outcome include: the nature, severity and duration of the stress, the
metabolic state of the cells under stress, blood supply, and nutritional status of the cells under
the stress.
Oct 20, 2023 By: Dr. Lalisa B. 3
 Introduction…

NORMAL CELL
PHYSIOLOGIC STIMULI MINIMAL or BRIEF PATHOLOGIC STRESS

ADAPTATION
EXCESSIVE OR PROLONGED PATHOLOGIC STRESS

CELLULAR INJURY
REVERSIBLE INJURY IRRIVERSIBLE INJURY (CELL DEATH)

Oct 20, 2023 By: Dr. Lalisa B. 4

Oct 20, 2023 By: Dr. Lalisa B. 5
CELLULAR ADAPTATIONS
• Adaptations are reversible changes in the number, size,
appearance (phenotype), metabolic activity, or functions of
cells in response to changes in their environment.

• As cells encounter physiologic stimuli or pathologic stress, they

can undergo adaptation.

Oct 20, 2023 By: Dr. Lalisa B. 6

 CELLULAR ADAPTATIONS …
• Physiologic adaptations usually represent responses of cells to normal
stimulation by hormones or growth factors(e.g., the hormone-induced
enlargement of the breast and uterus during pregnancy).

• Pathologic adaptations are responses to stress that allow cells to

modulate their structure and function and thus escape injury.

• Such adaptations can take several distinct forms.

Oct 20, 2023 By: Dr. Lalisa B. 7

 Cellular adaptations …
• Adaptive responses are potentially reversible once the stress has been removed

• Some forms of adaptation may precede or progress to malignancy

• The principal adaptive responses are:

1. atrophy,
2. hypertrophy,
3. hyperplasia,
4. metaplasia.

Oct 20, 2023 By: Dr. Lalisa B. 8

1. Atrophy
• Definition: Decrease in cell size and functional ability by loss of its substance

• Causes: Decreased workload (e.g. disuse atrophy of skeletal muscles); Ischemia (diminished oxygen supply); Lack
of hormonal stimulation (e.g. postmenopausal atrophy of breast and uterus); Lack of neural stimulation (e.g.
denervation atrophy of skeletal muscles); Malnutrition (e.g. Marasmus); Aging (e.g. age related brain atrophy)

• Pathways: Ubiquitin-proteasome pathway, autophagy

• Mechanism: Decreased protein synthesis and increased protein degradation in cells.

• Morphology: Small shrunken cells with lipofuscin granules; decreased intracellular components, membrane
bound residual bodies and autophagosomes.

Oct 20, 2023 By: Dr. Lalisa B. 9

Autophagy
• Refers to lysosomal digestion of the cell’s own components;

• Autophagy is an adaptation to nutrient deprivation in which cells digest

their own organelles and recycle them to provide energy and substrates.

• If the stress is too severe for the process to cope with it, it results in cell
death by apoptosis.

Oct 20, 2023 By: Dr. Lalisa B. 10

2. Hypertrophy
• Definition: an increase in cell size and functional ability due to
increased synthesis of intracellular components

• Often occurs in tissues incapable of cell division.

– Can be physiologic (e.g. striated muscle hypertrophy of weight lifters) or pathologic

(e.g. cardiac muscle hypertrophy in hypertension patients)

Oct 20, 2023 By: Dr. Lalisa B. 11

Oct 20, 2023 12
 Hypertrophy…
• Causes: Physical stress (weight lifting, HTN), hormones (e.g. Gravid
uterus, Lactating breast)
• Mediators: Growth factors, cytokines, and other trophic stimuli
• Pathways: phosphoinositide 3-kinase (PI3K)/AKT pathway, downstream
of G-protein–coupled receptors
• Mechanism: Increased expression of genes and protein synthesis

Oct 20, 2023 By: Dr. Lalisa B. 13

3. Hyperplasia
• Definition: an increase in the number of cells in a tissue or organ

• occurs in tissues whose cells are able to divide or contain abundant tissue stem
cells (e.g. epithelial tissues, mesenchymal tissues)

• Some cell types are unable to exhibit hyperplasia (e.g., nerve, cardiac muscle
cells, skeletal muscle cells)

• It can be physiologic or pathologic

Oct 20, 2023 By: Dr. Lalisa B. 14
 Hyperplasia…
• Physiologic hyperplasia: Replacement of the shading epithelium of skin, GI…,
Compensatory hyperplasia after partial hepatectomy, breast development at
puberty and pregnancy, lymphoid hyperplasia and wound healing

• Pathologic hyperplasia: Endometrial hyperplasia, BPH, Warts

• Mediators: Hormones, Growth factors, cytokines, and other trophic stimuli

• Mechanism: Increased expression of growth-promoting genes (proto-

oncogenes); Increased DNA synthesis and cell division
Oct 20, 2023 By: Dr. Lalisa B. 15
 4. Metaplasia
• Definition: a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another
adult cell type. It has been suggested that the replaced cell is better able to tolerate the environmental stresses.

• Metaplasia is nearly always found in association with tissue damage, repair, and regeneration.

• Causes of metaplasia: Smoking, vitamin A def., GERD, hormonal effect, early sexual intercourse…

• Proposed mechanism: Thought to arise by genetic "reprogramming" of stem cells rather than trans-
differentiation of already differentiated cells.

• Metaplasia is usually a benign process that is reversible if the stimuli is removed but rarely some types of
metaplasia could be a precursor for cancers.

Oct 20, 2023 By: Dr. Lalisa B. 16

 Types of metaplasia
• Columnar to squamous epithelium: e.g. squamous metaplasia of bronchial epithelium in
response to the chronic irritation of tobacco smoke; squamous metaplasia of the endocervix in
response to hormonal effect or early sexual intercourse

• Squamous to columnar epithelium: e.g. lower esophagus in response to chronic reflux of gastric
acid to the esophagus (barrette esophagus). It is a risk for esophageal adenocarcinoma.

• Urothelial to squamous: Squamous metaplasia of the bladder urothelium in response to chronic

irritation by shitosomiasis, bladder stone…It is a risk for squamous carcinoma of the bladder.

• Mesenchymal metaplasia: e.g. osseous, chondroid

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 Squamous metaplasia of the enodcervix

Oct 20, 2023 By: Dr. Lalisa B. 18

 Consequences of metaplasia
NORMAL CELL

METAPLASIA

DYSPLASIA

ANAPLASIA

Oct 20, 2023 By: Dr. Lalisa B. 19

Dysplasia
• Dysplasia is a term that literally means “disordered growth” characterized by variation in cell
size and shape, and loss of cellular organization.

• It is encountered principally in epithelia.

• Dysplastic cells may exhibit considerable pleomorphism and often contain large hyperchromatic
nuclei with a high nuclear-to-cytoplasmic ratio.

• When dysplastic changes are marked and involve the full thickness of the epithelium, but the
lesion does not penetrate the basement membrane, it is considered a preinvasive neoplasm
and is referred to as carcinoma in situ.
Oct 20, 2023 By: Dr. Lalisa B. 20
 Anaplasia

• The term anaplasia literally means “backward formation”-

implying loss of the structural and functional
differentiation of normal cells.

• Anaplastic cells often display the following morphologic

features:
– Pleomorphism (i.e., variation in size and shape)
– Nuclear abnormalities: extreme hyperchromatism (dark-
staining), variation in nuclear size and shape, o
– Tumor giant cells may be formed.
– Loss of polarity

• Presence of anaplasia usually suggests aggressive cancer.

Oct 20, 2023 By: Dr. Lalisa B. 21

Oct 20, 2023 22
 CELLULAR INJURY
• If the adaptive capability is exceeded or if the external stress is
inherently harmful, cell injury develops.

• Within certain limits injury is reversible, and cells return to a stable

baseline; however, severe or persistent stress results in irreversible
injury and death of the affected cells.

• Cellular injuries and death are the fundamental underlying

mechanisms of any disease process.
Oct 20, 2023 By: Dr. Lalisa B. 23
 Factors that affect cellular response to injury

• The cellular response to injurious stimuli depends on the

nature of the injury, its duration, and its severity.

• And also the cell’s nutritional status, hormonal status and its
metabolic needs are important in its response to injury.

Oct 20, 2023 By: Dr. Lalisa B. 24

 Causes of Cellular Injury (the usual suspects)

1. Hypoxia (lack of oxygen)

2. Infections
3. Immunologic reactions
4. Genetic and developmental defects
5. Chemical injury e.g. free radicals
6. Physical injuries
7. Nutritional or vitamin imbalance
8. Aging
Oct 20, 2023 By: Dr. Lalisa B. 25
 Mechanisms of Cell Injury
• Cell injury results from functional and biochemical abnormalities in one or more of
several essential cellular components.

• The most important targets of injurious stimuli are

a. Mitochondria: the sites of ATP generation
b. Cell membranes, on which the ionic and osmotic homeostasis of the cell and its
organelles depends;
c. Rough endoplasmic reticulum: the site of protein synthesis
d. The cytoskeleton; and
e. The genetic apparatus of the cell.
Oct 20, 2023 By: Dr. Lalisa B. 26
 Mechanism of cellular injury…

Oct 20, 2023 By: Dr. Lalisa B. 27

 Reversible Cell Injury
• Reversible injury is the state of cell injury at which the
deranged function and morphology of the injured cells can
return to normal if the damaging stimulus is removed.

• MORPHOLOGY: Cell swelling, plasma membrane blebbing and

loss of micro-villi, mitochondrial swelling, dilation of the ER,
fatty change, eosinophilia (due to decreased cytoplasmic RNA)

Oct 20, 2023 By: Dr. Lalisa B. 28

 Morphology of cellular injury

Oct 20, 2023 By: Dr. Lalisa B. 29

 CELL DEATH
• Cell will die when the cell injury is irreversible

• Cell death is one of the most crucial events in the evolution of disease in any tissue or
organ.

• It results from diverse causes, including ischemia (lack of blood flow), infections, toxins,
and immune reactions.

• Cell death is also a normal and essential process in embryogenesis, the development of
organs, and the maintenance of homeostasis.
Oct 20, 2023 By: Dr. Lalisa B. 30
 patterns of cell death
• Apoptosis = programmed cell death

• Necrosis = unplanned cell death due to irreversible cell injury

Oct 20, 2023 By: Dr. Lalisa B. 31

 Apoptosis
• DEFINITION: Programmed cell death

• CAUSES: Physiologic (lack of GF, hormonal or neural stimulation, induction by other cells); pathologic (severe DNA damage,
accumulation of mis-folded proteins, certain viral infections)

• PATHWAYS: intrinsic (mitochondrial) pathway and extrinsic (the death receptor) pathway

• MECHANISM: activation of caspase enzymes cascade

• MORPHOLOGY: Cell shrinkage, cytoplasmic blebs, intensely eosinophilic cytoplasm , Chromatin condensation,
fragmentation in to apoptotic bodies (composed of cytoplasm and tightly packed organelles, with or without nuclear
fragments)

• ENDRESULT: Phagocytosis
Oct 20, 2023 By: Dr. Lalisa B. 32
 Pathways of apoptosis.

Oct 20, 2023 By: Dr. Lalisa B. 33

 Necrosis
• DEFINITION: Unplanned and uncontrollable form of cell death that has been called “accidental” cell death due to
irreversible cell injuries.

• Necrosis is a form of cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately
digest the cell.

• Necrosis is always pathologic.

• Causes of necrosis include: Hypoxia, Free radical injury, Cell membrane damage and Increased intracellular calcium level

• MORPHOLOGY: cellular swelling, increased eosinophilia; nuclear shrinkage (piknosis), fragmentation (karyorhexis), and
dissolution (karyolysis); breakdown of plasma membrane and organelle membranes; myelin figures; leakage and
enzymatic digestion of cellular contents; inflammatory cells.

Oct 20, 2023 By: Dr. Lalisa B. 34

 Patterns of necrosis
1. Coagulative necrosis: the basic tissue architecture is preserved but the nucleus disappears

2. Liquefactive necrosis: enzymatic digestion of a dead tissue resulting in liquidizing the tissue.

3. Gangrenous necrosis: interruption of blood flow to extremities result in darkening of the tissue; two types (arterial/dry
gangrene and venous/wet gangrene)

4. Caseous necrosis: friable yellow-white (cheese-like) appearance of the area of necrosis

5. Fat necrosis: focal areas of fat destruction; typically resulting from release of activated pancreatic lipases

6. Fibrinoid necrosis: is a special form of necrosis usually seen in immune reactions involving blood vessels appearing like fibrin.

Oct 20, 2023 By: Dr. Lalisa B. 35

 Coagulative necrosis
• Coagulative necrosis is a form of
tissue necrosis in which the
component cells are dead but the
basic tissue architecture is
preserved for at least several days.

Oct 20, 2023 By: Dr. Lalisa B. 36

 Liquefactive necrosis (BRAIN)

• Liquefactive necrosis is seen in focal

bacterial or, occasionally, fungal
infections, because microbes stimulate
the accumulation of inflammatory cells
and the enzymes of leukocytes digest
("liquefy") the tissue.

Oct 20, 2023 By: Dr. Lalisa B. 37

 Caseous necrosis ( LUNG)

• The term "caseous" (cheese-like) is

derived from the friable yellow-white
appearance of the area of necrosis.

• Caseous necrosis is encountered most

often in foci of tuberculous infection.

Oct 20, 2023 By: Dr. Lalisa B. 38

 Fat necrosis (PANCREASE)

• Fat necrosis refers to focal areas of fat

destruction, typically resulting from
release of activated pancreatic lipases
into the substance of the pancreas and
the peritoneal cavity.

Oct 20, 2023 By: Dr. Lalisa B. 39

 Fibrinoid necrosis

• Fibrinoid necrosis is a special form of

necrosis usually seen in immune
reactions involving blood vessels.

• This pattern of necrosis is prominent

when complexes of antigens and
antibodies are deposited in the walls of
arteries.

Oct 20, 2023 By: Dr. Lalisa B. 40

 Necrosis vs apoptosis

Oct 20, 2023 By: Dr. Lalisa B. 41

 I thank U !!
Thank You !!

October 20, 2023 42