Cell Injury, Death, and

Adaptation
The Cell and the Environment
● Adaptive Responses
– Atrophy
– Hypertrophy
– Hyperplasia
– Metaplasia
● Cell Injury
– Reversible (degeneration)
– Irreversible ( Cell death):

Necrosis
Apoptosis
 Causes of Cell Injury

● Hypoxia
● Physical Agents
● Chemicals and Drugs
● Microbiologic Agents
● Immunologic Reactions
● Genetic Defects
● Nutritional Imbalances
 Mechanisms of Cell Injury
● ISCHEMIC AND HYPOXIC INJURY
● FREE RADICAL MEDIATION OF CELL INJURY
– Radiation
– Inflammation
– Oxygen toxicity
– Chemicals
– Reperfusion injury
● CHEMICAL INJURY
 Ischemic and Hypoxic Injury

● Reversible Injury may show the followings:

1- Decreased oxidative phosphorylation
* reduced ATP
• increased cytosolic free calcium
* reduced activity of “sodium pump”
• accumulation of sodium by cell
• isosmotic gain of water (swelling)
• diffusion of potassium from cell
2- Increased Cytosolic Calcium
– Sources
* mitochondria
* endoplasmic reticulum
* external to the cell
– Consequences (activates enzymes)
* ATPase
• decreased ATP
* phospholipase
• decreased phospholipids
* endonuclease
• nuclear chromatin damage
3- Increased anaerobic glycolysis
* glycogen depletion
* lactic acid accumulation
* accumulation of inorganic phosphates
* reduced intracellular pH
4- Detachment of ribosomes
* reduced protein synthesis
5- Worsening mitochondrial function
6- Increasing membrane permeability
7- Cytoskeleton dispersion
* loss of microvilli
* formation of cell surface blebs
8- Swelling of mitochondria, endoplasmic reticulum,
and entire cells
8- Mitochondrial changes
* severe vacuolization
* amorphous calcium-rich densities
– Extensive plasma membrane damage
– Prominent swelling of lysosomes
– Massive influx of calcium (on reperfusion)
– Continued loss of cell proteins, coenzymes,
ribonucleic acids and other metabolites
– Leakage of enzymes measured in serum
– Injury to lysosomal membranes
* leakage of degradative enzymes
• activation of acid hydrolases due to
reduced intracellular pH with degradation
of cell components
– Prominent leakage of cellular enzymes
– Influx of macromolecules from interstitium
– “Myelin figures”-whorled phospholipid
masses
Mechanisms of Irreversible Injury
– 1- Phenomena characterizing irreversibility
A- inability to reverse mitochondrial
dysfunction
B- profound disturbances in membrane
function is a central factor
– 2- Potential causes of membrane damage
A- progressive loss of membrane
phospholipids
• activation of phospholipase
• reduced synthesis of phospholipids
 B- cytoskeletal abnormalities
• activation of proteases
• cell swelling
C- toxic oxygen radicals
• after restoration of blood flow (mainly from
polys)
D- lipid breakdown products
• from phospholipid degradation
• detergent effect on membranes
– 3- Ultimately a massive influx of calcium
Mechanisms of Cell Injury

FREE RADICAL MEDIATION OF

CELL INJURY
 Free Radical Mediation of Cell
Injury
● Free Radical Injury Contributes To:
– Chemical and radiation injury
– Oxygen and other gaseous toxicity
– Cellular aging
– Microbial killing by phagocytic cells
– Inflammatory damage
– Tumor destruction by macrophages
– Others
 Free Radical Mediation of Cell
Injury
● Definition Of Free Radicals
– Extremely unstable, highly reactive chemical
species with a single unpaired electron in an
outer orbital
● Examples Of Free Radicals
. . .-
– OH , H , O 2
● Source of Free Radicals
– Hydrolysis of water into OH. and H. by ionizing
radiation
– Redox reactions in normal physiology
* respiration
* intracellular oxidase action
* transition metal reactions
– Metabolism of exogenous chemicals
● Free Radical Injury Mechanisms
– Lipid peroxidation of membranes
* double bonds in polyunsaturated lipids
– Lesions in DNA
* reactions with thymine with single-strand
breaks
– Cross-linking of proteins
* sulfhydryl-mediated protein cross-linking
● Free Radical Degradation
– Unstable with spontaneous decay
– Decay accelerated by
* superoxide dismutase
* glutathione
* catalase
– Antioxidants (vitamin E, ceruloplasmin)
* block formation or scavenge
Mechanisms of Cell Injury

CHEMICAL INJURY
 Chemical Injury
● Mechanisms of Chemical Injury
– Direct combination with cell component
* mercury binding to sulfhydryl groups
– Conversion to reactive toxic metabolite
* principally involves liver
* usually by P-450 mixed function oxidases
* involves free radical formation
.
* CCl4 conversion to CCl3
Forms and Morphology of Cell
Injury
INTRACELLULAR ACCUMULATIONS
 Intracellular Accumulations

● General Principles
– Transient or permanent
– Harmless or injurious
– Cytoplasm (lysosomes) or nucleus
– Synthesized by the affected cell or produced
elsewhere
● General Principles
– Endogenous
* normal substance produced at normal or
increased rate/rate of metabolism
inadequate for removal (fatty liver)
* normal or abnormal substance cannot be
metabolized (storage diseases)
– Exogenous
• cell cannot degrade substance (carbon)
 Intracellular Accumulations

1- Fatty Change (Steatosis)

– Causes
* alcohol abuse, other toxins, anoxia,
obesity, protein malnutrition
– Pathogenesis
* various steps involved
* regress of hepatic triglycerides requires
complex with apoproteins to form
lipoproteins
 Intracellular Accumulations

● Fatty Change (Steatosis)

– Liver
* increased weight, yellow color
* fat vacuoles within cytoplasm of
hepatocytes
 Intracellular Accumulations

● Fatty Change (Steatosis)

– Heart
* focal fat deposits in myocardium (anemia)
* diffuse fat deposits in myocardium
(profound hypoxia, diphtheric myocarditis)
 Intracellular Accumulations

● Cholesterol and Cholesterol Esters

– Atherosclerosis
* macrophages and smooth muscle cells
filled with vacuoles
– Xanthomas
* macrophage accumulation/hereditary and
acquired hyperlipidemias
 Intracellular Accumulations

2- Proteins
– Renal tubular epithelium in proteinuria
– Plasma cells may accumulate
immunoglobulins (Russel bodies)
 Intracellular Accumulations

3- Glycogen
– Diabetes mellitus
* glycogen accumulation in renal tubular
epithelium, hepatocytes, cardiac myocytes,
pancreatic beta cells.
– Glycogen storage diseases (glycogenoses)
• enzymatic defects in synthesis or
breakdown of glycogen
 Intracellular Accumulations

4- Pigments:
A- Exogenous Pigments
– 1- Carbon (Anthracosis)
* Carbon is phagocytosed by alveolar
macrophages and transported by lymphatic
to lymph nodes
* Mild accumulations usually are of no
consequence--heavy accumulations may
induce a fibroblastic response
Intracellular Accumulations

– 2- Tattoos
* dyes phagocytosed
by macrophages
 Intracellular Accumulations

B- Endogenous Pigments
1- Lipofuscin (“wear and tear pigment)
* brownish yellow especially in heart, liver,
and brain--function of age or atrophy
(“brown atrophy”)
* represents complexes of lipid/protein
* derived from free radical peroxidation of
subcellular membranes
2- Melanin
* brown-black pigment
derived from tyrosine
in melanocytes
* may also accumulate in
basal keratinocytes
and dermal
macrophages
3- Hemosiderin
* hemoglobin derived iron containing golden-yellow
pigment
* represents large aggregates of ferritin micelles
* small amounts normal in phagocytic cells of
reticuloendothelial system.
* local excesses in focal hemorrhage
* systemic iron overload (hemosiderosis)
• in macrophages and parenchyma mainly in
liver, pancreas, heart, and endocrine organs
● Endogenous Pigments
– Hemosiderin
* systemic iron overload (hemosiderosis)
• increased absorption or impaired utilization of
iron; hemolytic anemias; transfusions
• extensive accumulation--- hemochromatosis &
organ fibrosis
Forms and Morphology of Cell
Injury
PATHOLOGIC CALCIFICATION
 Pathologic Calcification

● Dystrophic Calcification
– Normal serum calcium
– Areas of necrosis or injury
– Intracellular or extracellular
 Pathologic Calcification

● Metastatic Calcification
– Occurs in normal tissue
– Occurs with hypercalcemia
* hyperparathyroidism; bone catabolism with
tumors involving bone; vitamin D
intoxication; sarcoidosis; renal failure
– Primarily affects vessels, kidneys, lungs, and
gastric mucosa
 Amyloidosis

● Nature Of Amyloid
– Abnormal proteinaceous substance
– Deposited between cells
– Not a single chemical entity
– Appears as a pink translucent material on
H&E stain
 Amyloidosis
● Chemical Nature Of Amyloid
– AL (amyloid light chain)
* associated with B-cell dyscrasias
* produced by immunoglobulin-secreting cells.
– AA (amyloid associated)
* non-immunoglobulin
* derived from SAA (serum amyloid-associated
precursor protein)
* associated with chronic inflammatory diseases
 Amyloidosis
● Chemical Nature Of Amyloid
– Transthyretin (a normal serum protein)
* mutant form deposited in familial amyloid
polyneuropathies
– Beta-2-microglobulin (normal serum protein)
* deposits in long-term hemodialysis
– Beta-2-amyloid protein (derived from amyloid
precursor protein -APP)
* deposits in brain in Alzheimer’s disease
 Types

1- Immunocyte Dyscrasias With Amyloidosis

● Characteristics
– Complete immunoglobulin light chains (AL) produced
by aberrant monoclonal B-cells, such as in multiple
myeloma
– Serum M (myeloma) spike
– Bence Jones protein (either lambda or kappa light
chains)
2- Reactive Systemic Amyloidosis Characteristics
– AA protein deposits
– Occurs in setting of chronic inflammation

3- Heredofamilial Amyloidosis
– Familial Mediterranean fever
* AA protein-may be due to recurrent bouts of
inflammation of joints and serosal surfaces
– Familial amyloid polyneuropathies
* mutant transthyretins deposited
4- Localized Amyloidosis
– Heterogeneous chemical composition and clinical
presentation
– Often associated with local infiltration of plasma cells
(AL type amyloid)
– Medullary carcinoma of thyroid (amyloid chemically
related to calcitonin - a hormone secreted by the
tumor cells.
5- Amyloidosis Of Aging
– Senile cardiac amyloidosis
* transthyretin
– Senile cerebral amyloidosis (in Alzheimer’s disease)
* beta-2 amyloid protein
 Pathogenesis Of Amyloidosis

● Reactive Systemic Amyloidosis

– Elevated SAA (synthesized by liver in
response to IL-6 & IL-1)
– Abnormal breakdown of SAA.
● Immunocyte Dyscrasias
– AL synthesized by B-cells
– Abnormal degradation.
 Morphology Of Amyloidosis
● Generalizations
– Reactive systemic amyloidosis typically
affects kidneys, liver, spleen, lymph nodes,
adrenals, thyroid, and other tissues.
– Immunocyte-associated amyloidosis more
often involves heart, GI & respiratory tracts,
peripheral nerves, skin, and tongue.
* deposits may also occur in organs listed
for reactive systemic amyloidosis
 Morphology Of Amyloidosis

● Histologic Appearance
– Pink staining intercellular substance with
H&E stain
– Red-orange staining with Congo red
* green under polarized light
– Often causes parenchymal cell atrophy or
drop out
 Amyloidosis Of The Kidney

● Gross
– Unchanged or large and pale
● Microscopic
– Deposits mainly in glomeruli
– Also present in peritubular interstitium and
walls of blood vessels
 Amyloidosis Of Other Organs

● Spleen
– “Sago spleen”-splenic follicles
– “Lardaceous spleen”-splenic sinuses & pulp
● Liver, Heart, Endocrine glands
– Enlarged
– Interstitial deposits of amyloid
– Pressure atrophy
 Gaucher Disease

● Characteristics
– Glucocerebrosidase deficiency
– Accumulation of glucocerebrosides
– Involves phagocytic cells
– Predominantly affects liver, spleen and bone
marrow and maybe CNS at the end stage.
– Phagocytes enlarged with a fibrillar “wrinkled
tissue paper” cytoplasm
 Gaucher Disease

● Types
– Type 1 (99%) hepatosplenomegaly and
absence of CNS involvement-longevity
somewhat shortened
– Type 2 severe CNS involvement; secondary
involvement of spleen/liver--highly lethal
– Type 3 involves brain and viscera with a
course intermediate to types 1 and 2
Cell Death (Necrosis)
 Individual Cell Death
● Common event in some regenerating
tissues: such as skin and gut epithelium
and during embryogenesis
● Not a typical event in developed tissues
such as brain
● becomes a serious occurrence when
many cells are involved in such organs as
the liver
● Programmed cell death: Apoptosis
 What are the important factors on
the outcome of injury on cells?
Severity of injury and duration
have a major effect on the outcome
of injury
 Etiology of Tissue Necrosis
1) Hypoxia
2) Physical injury
a) Trauma
b) Radiation ‑ U.V., Cosmic, X‑ray
3) Chemicals ‑ variable
4) Biological toxins ‑ endotoxins
5) Immunological reactions
6) Inborn genetic disorders
7) Nutritional
 Mechanisms of Necrosis

Basic mechanisms:
1) Impaired oxidative phosphorylation
2) Membrane dissolution
3) Osmotic regulation
 Major Signs of Necrosis Similar to
Apoptosis
1) Nuclear degeneration
‑ Chromatin clumping
‑ Karyopyknosis (shrinking)
‑ Karyolysis (dissolution of chromatin)
‑ Karyorrhexis (fragmentation of chromatin)
2) Cytoplasmic changes
 Types of Necrosis
● Liquefactive necrosis: Necrosis in brain,
abscesses
● Coagulative necrosis: Necrosis of kidney,
liver, or heart muscle
● Caseous necrosis: Infection with
Mycobacterium tuberculosis
● Gangrene: Necrosis of an appendage,
usually limbs
● Fat necrosis
 Coagulative necrosis

● Caused by ischemia. Ischemia results in

decreased ATP, increased cytosolic Ca++,
and free radical formation, which each
eventually cause membrane damage.
● Example: Infarct: localized area of
ischemic necrosis as in myocardial
infarct.
 Liquefactive Necrosis
● Usually caused by focal bacterial infections,
because they can attract polymorphonuclear
leukocytes. The enzymes in the polys are
released to fight the bacteria, but also dissolve
the tissues nearby, causing an accumulation of
pus, effectively liquefying the tissue (hence, the
term liquefactive).
● Example: Abscess
 Caseation Necrosis
● Caseous: A distinct form of coagulative
necrosis seen in mycobacterial infections (e.g.,
tuberculosis), or in tumor necrosis, in which the
coagulated tissue no longer resembles the cells,
but is in chunks of unrecognizable debris.
Usually there is a giant cell and granulomatous
reaction, sometimes with polys, making the
appearance distinctive.
● Example: Tuberculosis.
 Fat necrosis

● Fat Necrosis: A term for necrosis in fat, caused either by

release of pancreatic enzymes from pancreas or gut
(Enzymatic fat necrosis) or by trauma to fat, either by a
physical blow or by surgery (Traumatic fat necrosis).
● The effect of the enzymes (lipases) is to release free
fatty acids, which then can combine with calcium to
produce detergents (soapy deposits in the tissues).
● Histologically, one sees shadowy outlines of fat cells
(like coagulative necrosis), but with Ca++ deposits,
foam cells, and a surrounding inflammatory reaction.
 Consequences of Necrosis

● Healing vs. permanent damage

● Local vs. systemic effects.
1) Type of tissue
2) Size of lesion
3) Location of lesion
 AUTOLYSIS

● Lysis of tissues by their own enzymes, following

the death of the organism. Therefore, the key
difference is that there is no vital reaction (i.e.,
no inflammation). Autolysis is essentially rotting
of the tissue.
● Early autolysis is indistinguishable from early
coagulative necrosis due to ischemia, unless
the latter is focal.