Cellular adaptations to stress / cell

injury & death

 Pathology
Pathology is literally the study (logos) of
suffering (pathos) process as to:
 Etiology (its cause)

 Pathogenesis (mechanisms of its development)

 Morphologic changes (the structural alterations

induced in the cells and organs of the body )

 Clinical significance (functional consequences of the

morphologic changes )
 The goals of this course is to defined and
describe in general terms:

- physiological adaptations,
- reversibly and irreversibly injury
- cell death

 Virtually all forms of organ injury start with

molecular or structural alterations in cells
(Rudolf Virchow)

 Cellular dysfunction  tissue and organ injury 

clinical disease
 Cellular Responses to Stress

Adaptation, reversible injury, and cell death can be considered stages of

progressive impairment of the cell's normal function and structure
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Disease
Summary of tissue response to environmental change.
Adaptive responses allow cells to survive in the face of a
change in the cellular environment. Failure to adapt is
associated with cell damage or cell death.
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 Cellular Responses to Injury
Nature and Severity of Injurious Cellular Response
Stimulus
Altered physiologic stimuli: Cellular adaptations:
• Increased demand, increased trophic • Hyperplasia, hypertrophy
stimulation (e.g. growth factors, hormones)
• Decreased nutrients, stimulation • Atrophy
• Chronic irritation (chemical or physical) • Metaplasia
Reduced oxygen supply; chemical Cell injury:
injury; microbial infection
• Acute and self-limited • Acute reversible injury
• Progessive and severe (including DNA • Irreversible injury → cell death
damage)
Necrosis
Apoptosis
• Mild chronic injury • Subcellular alterations in various
organelles
Metabolic alterations, genetic or Intracellular accumulations;
acquired calcifications
Prolonged life span with cumulative Cellular aging
sublethal injury
 Various Types of Adaptations
 cells may undergo various adaptations in
physiological and pathological conditions

 controlled by complex molecular mechanisms

 common types of cellular adaptations

1. hypertrophy
2. hyperplasia
3. atrophy
4. metaplasia
5. dysplasia
6. intracellular accumulations
7. pathological calcifications
a. dystrophic calcification
b. metastatic calcification
 Mechanism of cellular adaptation
 up or down regulation of specific cellular receptors involved
in metabolism of certain components.

 induction of new protein synthesis by the target cell (ex:

response of muscle cells to increased physical demand)

 induction of cellular proliferation (responses of the endometrium

to estrogens)

 switch by cells from producing one type of a family of

proteins to another or markedly overproducing one protein
(cells producing various types of collagens and extracellular matrix
proteins in chronic inflammation and fibrosis).

These adaptations involve all steps of cellular metabolism of

proteins: receptor binding, signal transduction, transcription, translation,
or regulation of protein packaging and release.
 Cellular Adaptations

Size Number Type

Atrophy Hypertrophy Hyperplasia Metaplasia Dysplasia

1. Disuse
2. Loss of
endocrine Intracellular Calcifications
stimulation Accumulations
3. Denervation
4. Inadequate Dystrophic Metastatic
nutrition
5. Ischemia
 1. Hyperplasia
 Definition: increase the number of cells (proliferation)
in an organ or tissue --> increased volume of the
organ or tissue

 The increase of number is achieved not only by

proliferation of the existent cells but also by the
development of new cells from stem cells.

 may sometimes co-exist with hypertrophy

 Hyperplasia takes place if the

cellular population is capable of
synthesizing DNA, thus permitting
mitotic division
 Tissue

X
Epithelial Connective Nerve Muscle

Cartilage Bone Blood X X

Connective
Tissue Proper Skeletal Cardiac Smooth

Regenerating
Loose Dense Capability
Connective Connective
Good
Tissues Tissues

Moderate

Areolar Adipose Reticular Dense Dense Elastic Poor

regular Irregular
None
 Hyperplasia
 classified as:
 physiologic
- hormonal: increase the functional capacity
of a tissue (e.g., breast and uterus during
normal menstrual cycle and pregnancy)
- compensatory: increases tissue mass after
damage or partial resection (regeneration of
liver following partial hepatectomy or wound
healing)
 pathologic
- excessive hormonal stimulation (BPH,
endometrial hyperplasia) or growth factors
(hyperplastic epithelium in papillomaviruses
infections)
Normal breast

Breast in lactation
Normal Hyperplastic
Prostatic hyperplasia
Normal Achantosis

Achantosis
 2. Hypertrophy
 increase in the size of cells  enlargement of
the organs (the hypertrophied organ has no new cells,
just larger cells)  increase the function
 mostly seen in cells that cannot divide, i.e.,
- skeletal muscle (strength training)
- cardiac muscle (hypertension)
 changes usually revert to normal if the
stimulus is removed
 mediated by different mechanisms (increased
workload, hormonal stimulation and growth factors stimulation
 the synthesis of more structural components).
 Tissue

Epithelial Connective Nerve Muscle

Cartilage Bone Blood

Connective
Tissue Proper Skeletal Cardiac Smooth

Regenerating
Loose Dense Capability
Connective Connective
Good
Tissues Tissues

Moderate

Areolar Adipose Reticular Dense Dense Elastic Poor

regular Irregular
None
 Hypertrophy

Physiologic Pathologic

Exercise Adaptive Compensatory

Normal heart Hypertrophied heart Hypertrophied and dilated
heart
Hypertrophied heart
 Normal uterus Gravid uterus

Physiologic hypertrophy of the uterus during pregnancy. A,

gross appearance of a normal uterus and a gravid uterus
that was removed for postpartum bleeding,

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 3. Atrophy
 A shrinkage in the size of the cell due to decreased
synthesis or increase of chatabolism, with possible
reduction of functional capacity
 The cells are still alive and may return to original size
if are stimulated by correct signals or may culminate
with death
 Commonly, when atrophy occurs, the lost cells are
replaced by either adipose or fibrous tissue, often
maintaining the overall size of the organ.
 Should be distinguished by:
- hypoplasia = incomplete growth of an
organ
- agenesis= complete failure to grow
 Atrophy
Physiologic Pathologic

Denervation Inadequate Ischemia

Disuse Loss of
nutrition
endocrine
stimulation
Atrophy associated
with Alzheimer’s
Disease
Denervation Atrophy
Loss of endocrine
stimulation

http://www.wholewoman.com/newsletters/images/uterus_diagram.gif
Testicular
atrophy
 Atrophy associated
with Malnutrition

http://membres.lycos.fr/spe
edyz/billets/images/malnutri
tion.jpg

http://mazusy.blox.pl/resource/chuda.jpg
Atrophy of
myocytes
Normal Atrophy
 4. Metaplasia
 transformation or replacement of one adult cell type to
another adult cell type, the most common: columnar to
squamous

 also occurs in mesenchymal tissue (e.g., formation of

bone in skeletal muscle)

 metaplastic changes usually result from chronic irritation

 changes seem to precede the development of cancer, in

some instances

 thought to arise from reprogramming of stem or

undifferentiated cells that are present in adult tissue
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© 2004 Elsevier
 Metaplasia of
Respiratory Epithelium
Squamous metaplasia
in bronchis
 Collumnar to sq. ep
Bronchial metaplasia
Metaplasia of
Uterine Cervix
Metaplasia of
Uterine Cervix
At Higher
Magnification
 Metaplasia of
Esophagus Epithelium

Barrett’s Esophagus
Barrett’s
Esophagus
 5. Dysplasia
From Greek, roughly “bad formation”
 deranged cell growth  varying of size,
shape and organization of cells
 minor degrees are associated with irritation
or inflammation
 most commonly associated

with respiratory tract or

uterine cervix
 potentially reversible

 often a precursor for cancer

 the cells may undergo morphological
transformation in witch increase rate of division is
coupled with incomplete maturation of resultant
cells
 Dysplastic cells
 May show loss of normal architectural
relationship between the cells
 Tend to exhibit a high nuclear to cytoplasmic
ratio
 Nuclei: irregular contour, increase of size, of
hypercromasia
 Increase rate of mytotic activity
 Grading of dysplasia is notoriously
subjective and lacks intra- and inter-
observer reproducibility
 Different classification:
- in 3 categories: slight
moderate,
severe
- in 2 categories: low grade
high grade
Cervix dysplasia
Colonic adenomatous
polyp
 6. Intracellular accumulations

 develop when normal cellular constituents or

products (e.g., water, lipids -TGL,FL, Colesterol-
proteins, carbohydrates- Gn) occur in excess
- fatty changes in the liver, or heart

 genetic defects involving specific enzymes can

result in the massive accumulation of some
endogenous substances
- lysosomal storage diseases
 Accumulation of Pigments

 Exogenous
 carbon dust (anthracosis)

 Endogenous
 lipofuscin
aging pigment in liver, heart, neurons, etc.

 hemosiderin
lungs following congestive heart failure
called hemosiderosis when found in a number
of tissues and organs
 melanin
 bilirubin
jaundice
 Mechanisms of intracellular accumulations: (1) abnormal metabolism, as in fatty change in the liver; (2) mutations causing alterations in
protein folding and transport, as in alpha1-antitrypsin deficiency; (3) deficiency of critical enzymes that prevent breakdown of substrates
that accumulate in lysosomes, as in lysosomal storage diseases; and (4) inability to degrade phagocytosed particles, as in hemosiderosis
and carbon pigment accumulation.

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Anthracosis
Lipofuscin

Myocardial cells with lipofuscin

Icterus

http://www-medlib.med.utah.edu/WebPath/CINJHTML/CINJ049.html
Hemosiderin in the
liver
Liver congenital glycogenosis
 Sudan III

Liver steatosis
Fatty liver. A, Schematic diagram of the possible mechanisms leading to accumulation of triglycerides in fatty liver. Defects in any of the
steps of uptake, catabolism, or secretion can result in lipid accumulation. B, High-power detail of fatty change of the liver. In most cells,
the well-preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole. (B, Courtesy of Dr. James Crawford,
Department of Pathology, Yale University School of Medicine, New Haven, CT.)
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 Hyaline degeneration of the fibrous tissue

 thick, eosinophilic
collagen fibers
 few fibroblasts
 7. Pathological calcification
 abnormal tissue deposition of calcium salts, together
with smaller amounts of iron, magnesium, and other
mineral salts
 2 forms:

 dystrophic :
 in injured tissues, areas of necrosis
(atheroma in blood vessels, heart
valves in elderly individuals, old
tuberculosis lesion)
 normal serum levels of calcium and
absence of derangements in
calcium metabolism
 macro: as fine, white granules or
clumps, often felt as gritty deposits
 micro: basophilic, amorphous
granular, sometimes clumped,
appearance
 Metastatic
 deposition of calcium
salts in otherwise
normal tissues
 in hypercalcemic
states
 principally affects the
interstitial tissues of
the gastric mucosa,
kidneys, lungs,
systemic arteries, and
pulmonary veins.
nephrocalcinosis
 Cellular Responses to Injury
Nature and Severity of Injurious Cellular Response
Stimulus
Altered physiologic stimuli: Cellular adaptations:
• Increased demand, increased trophic • Hyperplasia, hypertrophy
stimulation (e.g. growth factors, hormones)
• Decreased nutrients, stimulation • Atrophy
• Chronic irritation (chemical or physical) • Metaplasia
Reduced oxygen supply; chemical Cell injury:
injury; microbial infection
• Acute and self-limited • Acute reversible injury
• Progessive and severe (including DNA • Irreversible injury → cell death
damage)
Necrosis
Apoptosis
• Mild chronic injury • Subcellular alterations in various
organelles
Metabolic alterations, genetic or Intracellular accumulations;
acquired calcifications
Prolonged life span with cumulative Cellular aging
sublethal injury
Reaction of cells to injury
Common
pathological
stimuli
causing cell
injury
 General principals regarding cellular
response to the injury
 Response depends on nature of injury, duration
and severity

 Consequences of injury depend on cell type

 Morphological changes detectable by MO may

occur much later than functional lesion

 Although different agents may have different

initial cellular targets, the final pathways are
ofen similar
 Targets of injurious stimuli
 Aerobic respiration
 Loss of ATP
 Sodium pump failure water enters cell  cell swells
 Membranes
 Defect in permeability water enters cell cell swells
and even death
 Synthetic mechanism
 Enzymatic and structural proteins are not
synthesized cell swells
 Genetic apparatus
 DNA and RNA changes
 Inherited or acquired
 If enzymes deficient substrate accumulates cell
swells
 Main cellular mechanism of cell injury

 ATP depletion
 Loss of calcium homeostasis
 Oxidative stress (excess Reactive Oxygen
Species - ROS)
 Damage of mitochondria and increase
permeability of membrane
Downloaded from: Robbins & Cotran Pathologic Basis of Disease
Reversibile cellular injury
 generalized swelling of
the cell and its
organelles
 blebbing of the plasma
membrane;
 detachment of
ribosomes from the
endoplasmic reticulum;
 and clumping of
nuclear chromatin
 Explain the differences between reversible
and irreversible cell injury.
.

REVERSIBLE IRREVERSIBLE

 Loss of ATP Irreversible mitochondrial damage

 Phospholipid breakdown Massive peroxidation due to due to

PLPase activation uncontrolled chain reaction

 Increase in ROS Uncontrolled ROS; inflammation

 Release of calcium from Uncontrolled calcium influx

storage site

 Altered metabolism Loss of amino acids

 Necrosis
 Gross irreversible cellular injury
 Passive process since does not require gene
involvement ore new protein synthesis
 Triggers or elicits a marked inflammatory
response (liberation of lysosomal enzymes,
digestion of cell mb., disruption of cells, influx
of macrphages due to release of chemotactic
factors an removal of debris)
 DNA fragmentation is haphazard with smudge
pattern on electrophoresis
 Must be differentiated by autolysis
 General and cellular characteristic
 Nuclear changes:
 Pyknosis –the shrinkage of the nucleus into a small
deeply basophylic or black clumps of chromatin
 Karyorrhexis – a fragmentation of the nucleus into
multiple small black dots or pieces
 Karyolysis – the fading of the nucleus, less and less
basophilic until it disappears
 Cytoplasmic changes:
 Increase pink cytoplasm (“eosinophilic”, “glassy”) –
less RNA
 Generalized swelling of organelles (ER, mitochondria)

 Disruption of ribosomes

 Autophagy (lysis of the cell’s own contents)

 Phagocytosis of deteriorating organelles by lysosomes

 Types of necrosis
 Coagulative necrosis
 Liquefactive
 Casseous
 Gangrenous
 Fibrinous
 Gummatous
 Fat
 1. Coagulative necrosis
 Most common type
 Cause is most often from sudden loss of blood supply
to an organ (ischemia)
 Heart an kidney (end arteries with limited collateral circulation)
 Adrenal glands
 Resuls of denaturation of proteins
 Early stages preservation of tissue architecture
 Histology
 General architecture well preserved
 Progressive nuclear condensation with eventual dissappearance of
stainable nuclei
 Increased pink cytoplasm (“eosinophilic”,”glassy”) with “ghost -like “
structures
Splenic infarct
 Adrenal gland

Acute myocardial
infarction
 2. Liquefactive necrosis
 Characterized by digestion of tissue

 Gross= affected tissue is liquified

 Histology: softening and liquefaction of tissue

 Typical of organs in which the tissues have a lot

of lipid (such as brain – cerebral infarct)

 Also in suppurative infections (pus formation)

 Liquefied tissue debris and intense inflammatory
response of PMN= abcess
abcess
Liquefactive necrosis
in the liver
 3. Caseous necrosis
 Gross – cheese-like (“caseous”) consistency
 Combines features of coagulative and
liquefactive necrosis
 Histology:
 Architecture not preserved
 Amorphous pink, granular material

 Few nuclei but no ghost-like appearance

 Occurs as a part of granulomatous

inflammation (most often seen in
tuberculosis)
tuberculosis lesions
 4. Gangrenous necrosis
 Extensive
 Most often due to interaction of blood supply to
lower extremities or bowel (secondary to
vascular occlusion)
 Most often associated with bacterial infections
 “Wet” gangrene (complicated by liquefaction
necrosis)
 “Dry” gangrene (coagulative necrosis without
liquefaction)
 “dry gangrene”

“wet gangrene”
 5. Fibrinoid necrosis
 Often associated with immune-mediated
vasculitis
 Connective tissue and muscle replacement
by homogenous pink material resembling
fibrin
 Ex: deposition of fibrin like material in the arterial
walls
 Histology:
 Smudgy pink appearance in vascular walls
 Necrosis may or may not be present
Fibrinoid necrosis
of placenta
 6. Gummatous necrosis

 Seen in granulomatous inflammation such

as tertiary syphilis
 Gross: rubbery
 Histology:
 No architecture
 Pink with few nuclei
Gumatous necrosis in
liver

Tertiary siphilis-
typical gumma
 7. Fat necrosis
 Traumatic type (following severe injury to
tissue with high fat content: breast)
 Hystology:
 Necrotic fat cells, acute inflammation, hemorrhage,
calcium soap formation, lipid-laden macrophages
 Enzymatic type
 Pancreas (complication of acute hemorrhagic
pancreatitis)
 Proteolytic and lipolytic enzymes diffuse into the
inflamed tissue of pancreatic parenchyma
 Can attract calciumfatty acids form calcium salts
(saponification – soap formation)
 Apoptosis
 Greek term meaning “falling away from”
(involutional process similar to physiological loss
of leaves from a tree).
 Programmed physiological cell death tha
removes unwanted cells
 Helps to maintain homeostasis and growth
in tissue
 Has subtle cellular damage (with enzymes
causes nuclear condensation and
fragmentation)
 Important mechanism for the removal of
cells with irreparable AND damage
 by free radicals, viruses, cytotoxic immune
mechanisms
 If fails then can lead to cancers, viral
infections and autoimmune diseases
 Plays a role in wound healing
 Also important mechanismm for
physiologic cell removal during
embryogenesis and in programmed cell
cycling (menstruation)
 Morphological features
 Tendency to involve single
isolated cells or small clusters

 Changes which lack inflammatory

response
 Blebbing of plasma membrane
 Cytoplasmic shrinkage and
increased pink staining
 chromatin condensation and
fragmentation
 Budding of cell and separation of
membrane-bound apoptotic
bodies
 phagocytosis of apoptotic bodies
by macrophages and adyacent
normal cells

 apoptosis is a dynamic process

energy dependent
Summary overview of apoptotic process
http://www-medlib.med.utah.edu/WebPath/CINJHTML/CINJ054.html
 Apoptosis of myocardial
cells

Apoptosis of liver cells

 Summary-differences between
apoptosis and necrosis

APOPTOSIS NECROSIS
 cells shrink cells swell and "explode"

 orderly DNA fragmentation disorderly DNA fragmentation

(ladders)

 caspase activation (cascade) no caspase activation

 no inflammation inflammation

 requires ATP caused by lack of ATP

 phagocytosis (no body) necrotic "corps" persists