Cell Injury I – Cell Injury and Cell
Death
Dept. of Pathology
Dr : Ameer Jarrar , MD
Key Concepts
• Normal cells have a fairly narrow range of function or steady state:
Homeostasis
• Excess physiologic or pathologic stress may force the cell to a new
steady state: Adaptation
• Too much stress exceeds the cell’s adaptive capacity: Injury
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CELL ADAPTATION
Normal cell is in a steady state “Homeostasis”
Change in Homeostasis due to stimuli - Injury
Injury - Reversible / Irreversible
Adaptation / cell death
CELLULAR ADAPTATION TO STRESS
Adaptations are reversible changes in the number, size, phenotype,
metabolic activity or functions of cells in response to changes in their
environment
Physiologic adaptations are responses of cells to normal stimulation by
hormones or endogenous chemical mediators
Pathologic adaptations are responses to stress that allow cells to
modulate their structure and function and thus escape injury
Hypertrophy
is an increase in the size of cells & consequently an increase in the
size of an organ.
the enlargement is due to an increased synthesis of
structural proteins & organelles
Occurs when cells are incapable of dividing
Types:
a) physiologic
b) pathologic
Causes:
a) increased functional demand
b) hormonal stimulation
Physiologic Hypertrophy of the Uterus During Pregnancy
Gravid Uterus Normal Uterus
Small spindle-shaped uterine Large, plump hypertrophied
smooth muscle cells from a smooth muscle cells from a
normal uterus gravid uterus
Heart hypertrophy in
hypertension
Hypertrophy after myocardial infarction
The mechanisms of cardiac
hypertrophy:
1. mechanical triggers, such
as stretch
2. trophic triggers, such as
activation of α-adrenergic
receptors
Hypertrophy in hypertension
Adaptive changes may not be completely benign;
they can also result in a dramatic change in the
cellular phenotype:
• Reactivation of certain genes.
• Switch of contractile proteins to a different type.
• Degenerative changes overtime leading to failure
of organ
Skeletal muscle
hypertrophy in body
building:
Hyperplasia
is an increase in the number of cells in an organ or tissue
an adaptive response in cells capable of replication
a critical response of connective tissue cells in wound healing
Types:
a) physiologic hyperplasia
1) hormonal
ex. Proliferation of glandular epithelium of the female
breast at puberty & during pregnancy
2) compensatory – hyperplasia that occurs when a portion of
a tissue is removed or diseased
e.g. partial resection of a liver > mitotic activity 12 hours
later
b) pathologic hyperplasia
Caused by excessive hormonal or growth factor
stimulation
Like skin warts , endometrial hyperplasia
HYPERPLASIA OF THE PROSTATE GLAND
Hyperplasia
Gravid uterus
Physiologic hypertrophy of the
uterus during pregnancy. A,
Gross appearance of a normal
uterus (right) and a gravid
uterus (removed for
postpartum bleeding) (left). B,
Small spindle-shaped uterine
smooth muscle cells from a
normal uterus (left) compared
with large plump cells in gravid
uterus (right).
Hyperplasia
• Both hypertrophy and hyperplasia are reversible, if the stimulus is
removed.
• This differentiates these processes from cancer, in which cells
continue to grow despite the absence of hormonal stimuli.
• pathologic hyperplasia constitutes a fertile soil in which cancerous
proliferation may eventually arise. e.g. patients with hyperplasia of
the endometriumare at increased risk of developing endometrial
cancer e.g. papillomavirus infections predispose to cervical cancers
.*
Atrophy
Shrinkage in the size of the cell by the loss of cell substance
Results from decreased protein synthesis and increased
protein degradation
in cells
Is accompanied in many situations by increased autophagy
with resulting
Increases in autophagic vacoules
Causes:
Decreased workload
Loss of innervation
Diminished blood supply
Inadequate nutrition
Loss of endocrine stimulation
Aging (senile atrophy)
Causes of Atrophy
1) Physiological:
Øthymic involution, aging
Øloss of hormonal stimuli (menopause)
2) Pathological:
Ødecrease work load (immobilization of a limb to permit healing of a fracture)
Øloss of innervation (Denervation atrophy)
Ødiminished blood supply (ischemic atrophy)
Øinadequate nutrition
Atrophy of the brain in an Normal brain of a 25-year-old
82-year-old man man
ATROPHY IN OSTEOPOROSIS
These kidneys are from a patient who had
atherosclerotic stenosis of one renal artery
Normal
Metaplasia
a reversible change in which one adult cell type ( epithelial or mesenchymal) is
replaced by another adult cell type.
is cellular adaptation whereby cells sensitive to a particular stress
are replaced by other cell types better
able to withstand the adverse environment
Epithelial metaplasia
Examples
Squamos change that occurs in the respiratory epithelium in habitual cigarette
smokers ( normal columnar epithelial cells of trachea & bronchi are replaced by
stratified squamos epithelial cells
Vitamin A deficiency
Chronic gastric reflux, the normal stratified squamos epithelium of the lower
esophagus may undergo metaplasia to gastric columnar epithelium
Metaplasia
ØReplacement of one type of adult cell, whether epithelial or
mesenchymal, by another type of adult cell
ØAiming at replacing cells that are sensitive to certain stimuli by a
more resistant cell type.
ØThis happens through reprogramming of stem cells or
undifferentiated mesenchymal cells.
ØThe influences that induce metaplastic transformation, if persistent,
may induce cancer transformation in the metaplastic epithelium
Examples of Metaplasia
A.Schematic diagram of columnar to squamos epithelial
B. Metaplastic transformation of esophageal epithelium
Mesenchymal metaplasia Ex. Bone formed in soft
tissue particularly in foci of injury
METAPLASIA-ESOPHAGUS
METAPLASIA-LUNGS
CELLULAR INJURY
Cell Injury- pertains to the sequence of events when cells have no
adaptive response or the limits of adaptive capability are
exceeded
Types of Cell Injury
1. Reversible Injury- injury that persists within certain limits, cells
return to a stable baseline
2. Irreversible Injury- when the stimulus causing the injury persists
and is severe enough from the beginning that the affected
cells die
a. necrosis
b. apoptosis
Causes of Cell Injury
1. Hypoxia
Causes:
a. Ischemia
b. Inadequate oxygenation of the blood
c. Reduction in the oxygen-carrying capacity of the blood
2. Chemical Agents
a. glucose, salt or oxygen
b. poisons
c. environmental toxins
d. social “stimuli”
e. therapeutic drugs
3. Physical agents- trauma, extremes of temperature, radiation, electric
shock, & sudden changes in atmospheric pressure
4. Infectious agents
5. Immunologic reactions
Example: anaphylactic reaction to a foreign protein or a drug
reaction to self antigens
6. Genetic defects
Examples are genetic malformations associated with Down Syndrome,
sickle cell anemia & inborn errors of metabolism
7. Nutritional Imbalances
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Reversible Injury
• Mitochondrial oxidative phosphorylation is disrupted first
Decreased ATP
• Decreased Na/K ATPase gain of intracellular Na cell swelling
• Decreased ATP-dependent Ca pumps increased cytoplasmic Ca
concentration
• Altered metabolism depletion of glycogen
• Lactic acid accumulation decreased pH
• Detachment of ribosomes from RER decreased protein synthesis
• End result is cytoskeletal disruption with loss of microvilli, bleb
formation, etc
Irreversible Injury
• Mitochondrial swelling with formation of large amorphous densities in
matrix
• Lysosomal membrane damage leakage of proteolytic enzymes into
cytoplasm
• Mechanisms include:
• Irreversible mitochondrial dysfunction markedly decreased ATP
• Severe impairment of cellular and organellar membranes
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Cell Injury
• Membrane damage and loss of calcium homeostasis are most
crucial
• Some models of cell death suggest that a massive influx of calcium
“causes” cell death
• Too much cytoplasmic calcium:
• Denatures proteins
• Poisons mitochondria
• Inhibits cellular enzymes
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Clinical Correlation
• Injured membranes are leaky
• Enzymes and other proteins that escape through the leaky
membranes make their way to the bloodstream, where they can be
measured in the serum
Free Radicals
• Free radicals have an unpaired electron in their outer orbit
• Free radicals cause chain reactions
• Generated by:
• Absorption of radiant energy
• Oxidation of endogenous constituents
• Oxidation of exogenous compounds
Examples of Free Radical Injury
• Chemical (e.g., CCl4, acetaminophen)
• Inflammation / Microbial killing
• Irradiation (e.g., UV rays skin cancer)
• Oxygen (e.g., exposure to very high oxygen tension on ventilator)
• Age-related changes
Mechanism of Free Radical Injury
• Lipid peroxidation damage to cellular and organellar membranes
• Protein cross-linking and fragmentation due to oxidative
modification of amino acids and proteins
• DNA damage due to reactions of free radicals with thymine
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Morphology of Cell Injury –
Key Concept
• Morphologic changes follow functional changes
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Irreversible Injury – Nuclear Changes
• Pyknosis
• Nuclear shrinkage and increased basophilia
• Karyorrhexis
• Fragmentation of the pyknotic nucleus
• Karyolysis
• Fading of basophilia of chromatin
Karyolysis & karyorrhexis -- micro
Types of Cell Death
• Apoptosis
• Usually a regulated, controlled process
• Plays a role in embryogenesis
• Necrosis
• Always pathologic – the result of irreversible injury
• Numerous causes
• Apoptosis : programmed cell death
• Necrosis : abnormal cell death
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FEATURES OF NECROSIS AND APOPTOSIS
Feature Necrosis Apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis → karyorrhexis Fragmentation into
→ karyolysis nucleosome size fragments
Plasma Disrupted Intact; altered structure,
membrane especially orientation of
lipids
Cellular Enzymatic digestion; may Intact; may be released in
contents leak out of cell apoptotic bodies
Adjacent Frequent No
inflammation
Physiologic or Invariably pathologic Often physiologic, means of
pathologic (culmination of eliminating unwanted cells;
role irreversible cell injury) may be pathologic after
some forms of cell injury,
02.03.2008 Dr. Mohannad KHADER especially DNA damage
Apoptosis
• Involved in many processes, some physiologic, some pathologic
• Programmed cell death during embryogenesis
• Hormone-dependent involution of organs in the adult (e.g., thymus)
• Cell deletion in proliferating cell populations
• Cell death in tumors
• Cell injury in some viral diseases (e.g., hepatitis)
Apoptosis – Morphologic Features
• Cell shrinkage with increased cytoplasmic density
• Chromatin condensation
• Formation of cytoplasmic blebs and apoptotic bodies
• Phagocytosis of apoptotic cells by adjacent healthy cells
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