1 Cell Injury

Tissue Hypoxia
Hypoxia
1. Hypoxia refers to inadequate oxygenation of tissue.
a. Oxygen (O2) is an electron acceptor in the mitochondrial oxidative
pathway.
b. Inadequate oxygen decreases synthesis of adenosine triphosphate
(ATP).
2. Several types of hypoxia produce O2-related changes reported with arterial
blood gas measurements
o

O2 diffuses from the alveoli, to plasma ( Pao2), and to red blood cells
(RBCs), where it attaches to heme groups ( Sao2).

Table 1-1. Terminology Associated with Oxygen Transport and

Hypoxia
Term Definition

Contributing Factors

PaO2

Pressure keeping O2
dissolved in plasma of
arterial blood

Percentage of O2 in inspired air, Reduced in hypoxemia

atmospheric pressure, normal
O2 exchange

SaO2

Average percentage of
O2 bound to Hb

PaO2 and valence of heme iron SaO2 < 80% produces

in each of the four heme groups cyanosis of skin and mucous
Fe2+ binds to O2; Fe3+does not membranes

O2
Total amount of O2
content carried in blood

Hb concentration in red blood

cells (most important factor),
PaO2, SaO2

Significance

Hb is the most important

carrier of O2

Fe2+, ferrous iron; Fe3+, ferric iron; Hb, hemoglobin; O2, oxygen; PaO2, partial pressure of arterial oxygen; SaO2,
arterial oxygen saturation.

Tissue
Hypoxia
Hypoxia
1. Hypoxia refers to inadequate oxygenation of tissue.
a. Oxygen (O2) is an electron acceptor in the mitochondrial oxidative
pathway.
b. Inadequate oxygen decreases synthesis of adenosine triphosphate
(ATP).
2. Several types of hypoxia produce O2-related changes reported with arterial
blood gas measurements
o

O2 diffuses from the alveoli, to plasma ( Pao2), and to red blood cells
(RBCs), where it attaches to heme groups ( Sao2).

Table 1-1. Terminology Associated with Oxygen Transport and

Hypoxia
Term Definition

Contributing Factors

PaO2

Percentage of O2 in inspired air, Reduced in hypoxemia

atmospheric pressure, normal
O2 exchange

Pressure keeping O2
dissolved in plasma of
arterial blood

Significance

SaO2

Average percentage of
O2 bound to Hb

O2
Total amount of O2
content carried in blood

PaO2 and valence of heme iron SaO2 < 80% produces

in each of the four heme groups cyanosis of skin and mucous
Fe2+ binds to O2; Fe3+does not membranes
Hb concentration in red blood
cells (most important factor),
PaO2, SaO2

Hb is the most important

carrier of O2

Fe2+, ferrous iron; Fe3+, ferric iron; Hb, hemoglobin; O2, oxygen; PaO2, partial pressure of arterial oxygen; SaO2,
arterial oxygen saturation.

Hypoxia
1. Hypoxia refers to inadequate oxygenation of tissue.
a. Oxygen (O2) is an electron acceptor in the mitochondrial oxidative
pathway.
b. Inadequate oxygen decreases synthesis of adenosine triphosphate
(ATP).
2. Several types of hypoxia produce O2-related changes reported with arterial
blood gas measurements
o

O2 diffuses from the alveoli, to plasma ( Pao2), and to red blood cells
(RBCs), where it attaches to heme groups ( Sao2).

Table 1-1. Terminology Associated with Oxygen Transport and

Hypoxia
Term Definition

Contributing Factors

PaO2

Pressure keeping O2
dissolved in plasma of
arterial blood

Percentage of O2 in inspired air, Reduced in hypoxemia

atmospheric pressure, normal
O2 exchange

SaO2

Average percentage of
O2 bound to Hb

PaO2 and valence of heme iron SaO2 < 80% produces

in each of the four heme groups cyanosis of skin and mucous
Fe2+ binds to O2; Fe3+does not membranes

O2
Total amount of O2
content carried in blood

Hb concentration in red blood

cells (most important factor),
PaO2, SaO2

Significance

Hb is the most important

carrier of O2

Fe2+, ferrous iron; Fe3+, ferric iron; Hb, hemoglobin; O2, oxygen; PaO2, partial pressure of arterial oxygen; SaO2,
arterial oxygen saturation.

Causes
of tissue
hypoxia
page 1
page 2

Patients with methemoglobinemia have chocolate-colored blood and

cyanosis. Skin color does not return to normal after administration of
O2. Treatment is methylene blue (activates metHb reductase) and
ascorbic acid (reduces Fe3+ to Fe2+).
page 2
page 3

At high altitudes, the atmospheric pressure is decreased; however,

the percentage of O2 in the atmosphere remains the same.
Hypoxemia stimulates peripheral chemoreceptors causing
respiratory alkalosis, which shifts the OBC to the left. However,
alkalosis activates phosphofructokinase in glycolysis causing
increased production of 1,3-BPG, which is converted to 2,3-BPG.
This brings the OBC back to normal or slightly to the right, leading to

increased release of O2 to tissue.

1. Ischemia
a. Decreased arterial blood flow or venous blood flow
b. Examples-coronary artery atherosclerosis, thrombosis of splenic vein
2. Hypoxemia
a. Decrease in Pao2
b. Causes
i.
Respiratory acidosis
Carbon dioxide (CO2) retention in the lungs produces
a corresponding decrease in Pao2.
Examples include depression of the medullary
respiratory center (e.g., barbiturates), paralysis of
diaphragm, chronic bronchitis.
ii.
Ventilation defects
Impaired O2 delivery to alveoli
Example-respiratory distress syndrome with
collapse of the distal airways
No O2 exchange in lungs that are perfused but not
ventilated
Produces intrapulmonary shunting of blood
Administration of 100% O2 does not increase
the Pao2.
iii.
Perfusion defects
Absence of blood flow to alveoli
Example-pulmonary embolus
No O2 exchange in lungs that are ventilated but not
perfused
Produces an increase in pathologic dead space
Administration of 100% O2 increases the
Pao2.
iv.
Diffusion defects
Decreased O2 diffusion through the alveolar-capillary
interface
Examples-interstitial fibrosis, pulmonary edema
3. Hemoglobin (Hb)-related abnormalities
a. Anemia
i.
Decreased Hb concentration
ii.
Causes
Decreased production of Hb (e.g., iron deficiency)
Increased destruction of RBCs (e.g., hereditary
spherocytosis)
Decreased production of RBCs (e.g., aplastic
anemia)
Increased sequestration of RBCs (e.g.,
splenomegaly)
iii.
Normal Pao2 and Sao2
b. Methemoglobinemia
i.
Methemoglobin (metHb) is Hb with oxidized heme groups
(Fe3+).
ii.
Causes
Oxidizing agents
Examples-nitrite- or sulfur-containing drugs,
such as nitroglycerin and trimethoprimsulfamethoxazole
Deficiency of metHb reductase
Reductase normally converts ferric iron, Fe3+,

to ferrous iron, Fe2+

iii.
Pathogenesis of hypoxia
Fe3+ cannot bind O2
Normal Pao2, decreased Sao2
c. Carbon monoxide (CO) poisoning
i.
Produced by incomplete combustion of carbon-containing
compounds
ii.
Caused by automobile exhaust, smoke inhalation, wood
stoves
iii.
Pathogenesis of hypoxia
CO competes with O2 for binding sites on Hb, which
decreases Sao2 without affecting Pao2.
It inhibits cytochrome oxidase in the electron
transport chain (ETC).
It causes a left shift in the O2-binding curve (OBC).
iv.
Clinical findings
Cherry-red discoloration of skin and blood
Headache (first symptom), coma, necrosis of the
globus pallidus
d. Factors causing a left shift in the OBC
i.
Decreased 2,3-bisphosphoglycerate (BPG)
Intermediate of glycolysis via conversion of 1,3-BPG
to 2,3-BPG
ii.
CO, alkalosis, metHb, fetal Hb, hypothermia
e. Enzyme inhibition of oxidative phosphorylation
i.
Synthesis of ATP is decreased.
ii.
CO and cyanide (CN) inhibit cytochrome oxidase in the ETC.
CN poisoning may result from drugs (e.g.,
nitroprusside) and combustion of polyurethane
products in house fires.
CN poisoning is treated with amyl nitrite (produces
metHb which combines with CN) followed by
thiosulfate (CN converted to thiocyanate).
f. Uncoupling of oxidative phosphorylation
i.
Uncoupling proteins carry protons pumped from the ETC into
the mitochondrial matrix.
Bypass of ATP synthase causes decreased synthesis
of ATP.
Examples include thermogenin in brown fat in
newborns, dinitrophenol used in synthesizing TNT.
ii.
Oxidative energy is released as heat rather than as ATP.

Danger of developing hyperthermia

Agents such as alcohol and salicylates act as mitochondrial toxins.

They damage the inner mitochondrial membrane, causing protons
to move into the mitochondrial matrix. Hyperthermia is a common
complication in alcohol and salicylate poisoning.

Tissues
susceptible
to hypoxia
Factors decreasing coronary artery blood flow (e.g., coronary artery
atherosclerosis) produce subendocardial ischemia, which is
manifested by chest pain (i.e., angina) and ST-segment depression
in an electrocardiogram (ECG). Increased thickness of the left
ventricle (i.e., hypertrophy) in the presence of increased myocardial

demand for O2 (e.g., exercise) can also produce subendocardial

ischemia.
1. Watershed areas between two blood supplies
a. The blood supply from the two vessels does not overlap.
b. Examples
i.
Area between the distribution of the anterior and middle
cerebral arteries
ii.
Area between the distribution of the superior and inferior
mesenteric arteries (i.e., splenic flexure)
2. Subendocardial tissue
a. Coronary vessels penetrate the epicardial surface.
b. Subendocardial tissue receives the least amount of O2.
3. Renal cortex and medulla
a. The straight portion of the proximal tubule in the cortex is most
susceptible to hypoxia.
b. The Na+/K+/2Cl- cotransport channel in the thick ascending limb of the
renal medulla is most susceptible to hypoxia.

Consequences
of hypoxic cell
injury
1. Decreased synthesis of ATP
2. Anaerobic glycolysis is used for ATP synthesis and is accompanied by several
changes:
a. Activation of phosphofructokinase caused by low citrate levels and
increased adenosine monophosphate
b. Net gain of 2ATP
c. Decrease in intracellular pH caused by an excess of lactate
d. Impaired Na+,K+-ATPase pump
Diffusion of Na+ and H2O into cells causes cellular swelling
(potentially reversible with restoration of O2).
3. Decreased protein synthesis due to detachment of ribosomes (potentially
reversible)
4. Irreversible cell changes
a. Impaired calcium (Ca2+)-ATPase pump
b. Increased cytosolic Ca2+, having two causes:
ii

iii

Enzyme activation
Phospholipase increases cell and organelle
membrane permeability.
Proteases damage the cytoskeleton.
Endonucleases cause fading of nuclear chromatin
(karyolysis).
Reentry of Ca2+ into mitochondria

Free
Radical
Cell
Injury
Definition of free radicals

Increases mitochondrial membrane permeability, with

release of cytochrome c (activates apoptosis

1. Compounds with a single unpaired electron in an outer orbital

2. Degrade nucleic acids and membrane molecules
a. DNA fragmentation and dissolution
b. Lipid peroxidation of polyunsaturated lipids in cell membranes

Definition
of free
radicals
1. Compounds with a single unpaired electron in an outer orbital
2. Degrade nucleic acids and membrane molecules
a. DNA fragmentation and dissolution
b. Lipid peroxidation of polyunsaturated lipids in cell membranes

Types of
free
radicals
1. O2-derived free radicals
a. Superoxides (
b. Hydroxyl ions (OH)
c. Peroxides (H2O2)
2. Drug and chemical free radicals
a. Free radicals are produced in the liver cytochrome P-450 system.
b. Examples include acetaminophen and carbon tetrachloride.

Neutralization
of free
radicals
1. Superoxide dismutase neutralizes superoxide free radicals.
2. Glutathione peroxidase (enhances glutathione) neutralizes peroxide,
hydroxyl, and acetaminophen free radicals.
3. Catalase neutralizes peroxide free radicals.
4. Vitamin antioxidants (ascorbic acid, vitamin E, -carotenes) block the
formation of free radicals and degrade free radicals.

Examples
of free
radical
injury
1. Acetaminophen free radicals
a. May cause diffuse chemical hepatitis
i.
Liver cell necrosis occurs around the central veins.
ii.
Treatment with N-acetylcysteine increases synthesis of
glutathione for neutralization of drug free radicals.
b. May cause renal papillary necrosis

ii

Necrosis occurs in association with the use of nonsteroidal

anti-inflammatory agents.
Carbon tetrachloride free radicals

o Produce liver cell necrosis with fatty change

2. Ischemia/reperfusion injury
a.
Occurs with restoration of blood flow to ischemic myocardium and cerebral
tissue
b.
and cytosolic Ca2+ irreversibly damage previously injured cells after restoration of
blood flow.
2. Retinopathy of prematurity
a.
Blindness may occur in the treatment of respiratory distress syndrome with an
O2 concentration > 50%.
3. Iron overload disorders
a.
b.

Examples include hemochromatosis and hemosiderosis.

Intracellular iron produces OH, which damage parenchymal cells.

Examples of injury include cirrhosis, exocrine/endocrine

pancreatic dysfunction, diffuse skin pigmentation.

Injury to
Cellular
Organelles
Mitochondria
1. Release of cytochrome c from injured mitochondria initiates apoptosis.
2. Injurious agents include alcohol, salicylates, and increased cytosolic Ca 2+.

Mitochondria
1. Release of cytochrome c from injured mitochondria initiates apoptosis.
2. Injurious agents include alcohol, salicylates, and increased cytosolic Ca 2+.

Smooth
endoplasmic
reticulum
(SER)
1. Induction of enzymes of the liver cytochrome P-450 system
a. Caused by alcohol, barbiturates, and phenytoin
b. Causes SER hyperplasia and increased drug detoxification, with
lower-than-expected therapeutic drug levels
2. Inhibition of enzymes of the cytochrome P-450 system
a. Caused by proton receptor blockers (e.g., omeprazole) and
macrolides (e.g., erythromycin)
b. Results in decreased drug detoxification, with higher-than-expected
therapeutic drug levels

Lysosomes
Inclusion (I)-cell disease is a rare inherited condition in which
lysosomal enzymes lack the mannose 6-phosphate marker.
Therefore, primary lysosomes do not contain the hydrolytic enzymes
necessary to degrade complex substrates. Undigested substrates
accumulate as large inclusions in the cytosol. Symptoms include
psychomotor retardation and early death.

1. Primary lysosomes
a. Hydrolytic enzymes destined for primary lysosomes are marked with
mannose 6-phosphate in the Golgi apparatus.
b. Marked enzymes are transferred to primary lysosomes.
c. Deficiency of lysosomal enzymes occurs in lysosomal storage
diseases.
i.
Complex substrates accumulate in lysosomes.
ii.
Example-Gaucher's disease with deficiency of
glucocerebrosidase causes accumulation of
glucocerebrosides in the lysosome.
2. Secondary lysosomes (phagolysosomes)
a. Arise from fusion of primary lysosomes with phagocytic vacuoles
b. Defective in Chdiak-Higashi syndrome (CHS)
CHS is an autosomal recessive disease with a defect in membrane
fusion. This results in fusion of azurophilic granules in the primary
lysosomes of leukocytes (giant granules) and inability of primary
lysosomes to fuse with phagosomes to produce secondary
phagolysosomes. There is increased susceptibility to infection
(particularly Staphylococcus aureus) due to defects in chemotaxis
(directed migration), degranulation, and bactericidal activity.

1. Mitotic spindle defects

o Examples-vinca alkaloids and colchicine bind to tubulin in
microtubules, which interferes with the assembly of the mitotic
spindle.
2. Intermediate filament defects
3. Ubiquitin binds to damaged intermediate filaments and marks them for
degradation in proteasomes in the cytosol.
4. Mallory bodies
o Damaged ("ubiquinated") cytokeratin intermediate filaments in
hepatocytes in alcoholic liver disease

5. Lewy bodies
Damaged neurofilaments in idiopathic Parkinson's disease
Eosinophilic cytoplasmic inclusions in degenerating substantia nigra
neurons
2. Rigor mortis
i.
ii.

Myosin heads become locked to actin filaments as a result of a lack

of ATP.

Table 1-2. Intracellular Accumulations

Substance

Clinical Significance

Endogenous
Accumulations
Bilirubin

Kernicterus: fat-soluble unconjugated bilirubin derived from Rh hemolytic

disease of newborn; bilirubin enters basal ganglia nuclei of brain, causing

permanent damage
Cholesterol

Xanthelasma: yellow plaque on eyelid; cholesterol in macrophages

Atherosclerosis: cholesterol-laden smooth muscle cells and macrophages
(i.e., foam cells); components of fibrofatty plaques

Glycogen

Diabetes mellitus: increased glycogen in proximal renal tubule cells (cells

are insensitive to insulin and become overloaded with glycogen)
Von Gierke's glycogenosis: deficiency of glucose-6-phosphatase; glycogen
excess in hepatocytes and renal tubular cells

Hemosiderin and
ferritin

Iron overload disorders (e.g., hemochromatosis): excess hemosiderin

deposition in parenchymal cells, leading to free radical damage and organ
dysfunction (e.g., cirrhosis); increase in serum ferritin
Iron deficiency: decrease in ferritin and hemosiderin

Melanin

Addison's disease: destruction of the adrenal cortex; hypocortisolism leads

to an increase in ACTH causing excess synthesis of melanin and diffuse
pigmentation of the skin and mucosal membranes

Triglyceride

Fatty liver: triglyceride in hepatocytes pushes the nucleus to the periphery

Exogenous
Accumulations
Anthracotic pigment Coal worker's pneumoconiosis: phagocytosis of black anthracotic pigment
(coal dust) by alveolar macrophages ("dust cells")
Lead

Lead poisoning: lead deposits in nuclei of proximal renal tubular cells (acidfast inclusion) contribute to nephrotoxic changes in the proximal tubule

ACTH, adrenocorticotropic hormone; GI, gastrointestinal.

1. Excess of exogenous or endogenous pigments

2. Excess of normal cell constituents
3. Excess of exogenous or endogenous abnormal substances
Table 1-2.
Intracellular
Accumulations
Substance

Clinical Significance

Endogenous
Accumulations
Bilirubin

Kernicterus: fat-soluble unconjugated bilirubin derived from Rh hemolytic

disease of newborn; bilirubin enters basal ganglia nuclei of brain, causing
permanent damage

Cholesterol

Xanthelasma: yellow plaque on eyelid; cholesterol in macrophages

Atherosclerosis: cholesterol-laden smooth muscle cells and macrophages
(i.e., foam cells); components of fibrofatty plaques

Glycogen

Diabetes mellitus: increased glycogen in proximal renal tubule cells (cells

are insensitive to insulin and become overloaded with glycogen)
Von Gierke's glycogenosis: deficiency of glucose-6-phosphatase; glycogen
excess in hepatocytes and renal tubular cells

Hemosiderin and
ferritin

Iron overload disorders (e.g., hemochromatosis): excess hemosiderin

deposition in parenchymal cells, leading to free radical damage and organ
dysfunction (e.g., cirrhosis); increase in serum ferritin
Iron deficiency: decrease in ferritin and hemosiderin

Melanin

Addison's disease: destruction of the adrenal cortex; hypocortisolism leads

to an increase in ACTH causing excess synthesis of melanin and diffuse
pigmentation of the skin and mucosal membranes

Triglyceride

Fatty liver: triglyceride in hepatocytes pushes the nucleus to the periphery

Exogenous
Accumulations
Anthracotic pigment Coal worker's pneumoconiosis: phagocytosis of black anthracotic pigment
(coal dust) by alveolar macrophages ("dust cells")
Lead

Lead poisoning: lead deposits in nuclei of proximal renal tubular cells (acidfast inclusion) contribute to nephrotoxic changes in the proximal tubule

ACTH, adrenocorticotropic hormone; GI, gastrointestinal.

1. Excess of exogenous or endogenous pigments

2. Excess of normal cell constituents
3. Excess of exogenous or endogenous abnormal substances
1. Cytosolic accumulation of triglyceride
2. Mechanisms of fatty change
a. Increased glycerol 3-phosphate (G3-P)
i.
Intermediate of glycolysis
ii.
Substrate for triglyceride synthesis
iii.
Metabolic intermediates of alcohol metabolism
Reduced nicotinamide adenine dinucleotide (NADH),
a product of alcohol metabolism, accelerates
conversion of dihydroxyacetone phosphate to G3-P.
b. Increased fatty acid synthesis

ii

Example-acetyl coenzyme A, the end product of alcohol

metabolism, is used to synthesize fatty acids.
b. Decreased -oxidation of fatty acids
Causes include alcohol, hypoxia, and diphtheria toxin.
c. Increased mobilization of fatty acids from adipose tissue
Causes include alcohol and starvation.
d. Decreased synthesis of apolipoprotein B-100
Causes include carbon tetrachloride and decreased protein
intake (e.g., kwashiorkor).
e. Decreased hepatic release of very low density lipoprotein
Causes include carbon tetrachloride and decreased protein
intake.
Morphology
a. Normal or enlarged liver with a yellowish discoloration
b. Clear space pushing the nucleus to the periphery

Iron
1. Ferritin
a. Major soluble iron storage protein
b. Stored in bone marrow macrophages (most abundant site) and
hepatocytes
c. Small amounts circulate in serum
Directly correlates with ferritin stores in the bone marrow
2. Hemosiderin
a. Insoluble product of ferritin degradation in lysosomes
b. Does not circulate in serum
c. Appears as golden brown granules in tissue
d. Appears as blue granules when stained with Prussian blue

Pathologic
calcification
1.

2.

Dystrophic calcification
a.

Deposition of calcium phosphate in necrotic tissue

b.

Normal serum calcium and phosphate

c.

Examples-calcified atherosclerotic plaque, calcification in pancreatitis

Metastatic calcification
a.

Deposition of calcium phosphate in normal tissue

b.

Due to increased serum calcium and/or phosphate

i.

Causes of hypercalcemia-primary hyperparathyroidism, malignancy-induced hypercalcemia

ii.

Causes of hyperphosphatemia-renal failure, primary hypoparathyroidism


c.

Excess phosphate drives calcium into normal tissue.

Examples of metastatic calcification

i.

Calcification of renal tubular basement membranes in the collecting ducts (nephrocalcinosis)

ii.

Basal ganglia calcification in hypoparathyroidism

Adaptation
to Cell Injury:
Growth
Alterations

Atrophy
Brown
atrophy is a
tissue
discoloration
that results
from
lysosomal
accumulation
of lipofuscin
("wear and
tear"
pigment).
Lipofuscin is
an
indigestible
lipid derived
from lipid
peroxidation
of cell
membranes,
which may
occur in
atrophy and
free radical
damage of
tissue.
1. Decrease in size of a tissue or organ
2. Causes of atrophy
a. Decreased hormone stimulation
Example-hypopituitarism causing atrophy of target organs,
such as the thyroid and adrenal cortex
b. Decreased innervation
Example-skeletal muscle atrophy following loss of lower
motor neurons in amyotrophic lateral sclerosis
c. Decreased blood flow
Example-cerebral atrophy due to atherosclerosis of the
carotid artery
d. Decreased nutrients
Example-total calorie deprivation in marasmus
e. Increased pressure
Example-atrophy of the renal cortex and medulla in
hydronephrosis
f. Occlusion of secretory ducts
Example-thick ductal secretions in cystic fibrosis cause

atrophy of exocrine glands

3. Mechanisms of atrophy
a. Shrinkage of cells due to increased catabolism of cell organelles
(e.g., mitochondria) and reduction in cytosol
ii
iii
iiii

Organelles and cytosol form autophagic vacuoles.

Autophagic vacuoles fuse with primary lysosomes for
enzymatic degradation.
Undigested lipids are stored as residual bodies.

b. Loss of cells by apoptosis

Atrophy
Brown
atrophy is a
tissue
discoloration
that results
from
lysosomal
accumulation
of lipofuscin
("wear and
tear"
pigment).
Lipofuscin is
an
indigestible
lipid derived
from lipid
peroxidation
of cell
membranes,
which may
occur in
atrophy and
free radical
damage of
tissue.
1. Decrease in size of a tissue or organ
2. Causes of atrophy
a. Decreased hormone stimulation
Example-hypopituitarism causing atrophy of target organs,
such as the thyroid and adrenal cortex
b. Decreased innervation
Example-skeletal muscle atrophy following loss of lower
motor neurons in amyotrophic lateral sclerosis
c. Decreased blood flow
Example-cerebral atrophy due to atherosclerosis of the
carotid artery
d. Decreased nutrients
Example-total calorie deprivation in marasmus
e. Increased pressure
Example-atrophy of the renal cortex and medulla in
hydronephrosis
f. Occlusion of secretory ducts

Example-thick ductal secretions in cystic fibrosis cause

atrophy of exocrine glands
3. Mechanisms of atrophy
a. Shrinkage of cells due to increased catabolism of cell organelles
(e.g., mitochondria) and reduction in cytosol

Organelles and cytosol form autophagic vacuoles.

Autophagic vacuoles fuse with primary lysosomes for
enzymatic degradation.
Undigested lipids are stored as residual bodies.

ii
iii
iiii

b. Loss of cells by apoptosis

Hypertrophy
1. Increase in cell size
2. Causes of hypertrophy
a. Increased workload
i.
Left ventricular hypertrophy in response to an increase in
afterload (resistance) or preload (volume)
ii.
Skeletal muscle hypertrophy in weight training
iii.
Smooth muscle hypertrophy in the urinary bladder in
response to urethral obstruction (e.g., prostate hyperplasia)
iv.
Surgical removal of one kidney with compensatory
hypertrophy (and hyperplasia) of the other kidney
b. Increased hormonal stimulation

ii

Example-enlargement of the gravid uterus due to smooth

muscle hypertrophy (and hyperplasia) from estrogen
stimulation
Mechanisms of cardiac muscle hypertrophy
a. Induction of genes for synthesis of growth factors, nuclear
transcription, and contractile proteins
b. Increase in cytosol, number of cytoplasmic organelles, and DNA
content

Hyperplasia
1. Increase in the number of normal cells
2. Causes of hyperplasia
a. Hypersecretion of trophic hormones
i.
Acromegaly due to an increase in growth hormone and
insulin growth factor-1
ii.
Endometrial gland hyperplasia due to hyperestrinism
iii.
Benign prostatic hyperplasia due to an increase in
dihydrotestosterone
iv.
Gynecomastia (male breast tissue) due to increased
estrogen
v.
Polycythemia due to an increase in erythropoietin
b. Chronic irritation

ii

Example-thickened epidermis from constant scratching

b. Chemical imbalance
Example-hypocalcemia stimulates parathyroid gland
hyperplasia
Mechanisms of hyperplasia
a. Dependent on the regenerative capacity of different types of cells
b. Labile cells (stem cells)

i.
ii.

Divide continuously
Examples-stem cells in the bone marrow, crypts of
Lieberkhn, and basal cells in the epidermis
iii.
May undergo hyperplasia as an adaptation to cell injury
b. Stable cells (resting cells)
i.
Divide infrequently, because they are normally in the Go
(resting) phase
ii.
Must be stimulated (e.g., growth factors, hormones) to enter
the cell cycle
iii.
Examples-hepatocytes, astrocytes, smooth muscle cells
iv.
May undergo hyperplasia or hypertrophy as an adaptation to
cell injury
c. Permanent cells (nonreplicating cells)
i.
Highly specialized cells that cannot replicate
ii.
Examples-neurons and skeletal and cardiac muscle cells
iii.
May undergo hypertrophy (only muscle)

Metaplasia
1. Replacement of one fully differentiated cell type by another
o Substituted cells are less sensitive to a particular stress.
2. Types of metaplasia
a. Metaplasia from squamous to glandular epithelium
i.
Example-distal esophagus epithelium shows an increase in
goblet cells and mucus-secreting cells in response to acid
reflux
ii.
This is called Barrett's esophagus.
b. Metaplasia from glandular to other types of glandular epithelium
i.
Example-pylorus and antrum epithelium shows an increase
in goblet cells and Paneth cells in response to Helicobacter
pylori-induced chronic atrophic gastritis
ii.
This is called intestinal metaplasia
c. Metaplasia from glandular to squamous epithelium
i.
Mainstem bronchus epithelium develops squamous
metaplasia in response to irritants in cigarette smoke.
ii.
Endocervical epithelium develops squamous metaplasia in
response to the acid pH in the vagina.
d. Metaplasia from transitional to squamous epithelium

Example-Schistosoma hematobium infection in the urinary

bladder causes transitional epithelium to undergo squamous
metaplasia.
2. Mechanism of metaplasia
ii Reprogramming stem cells in response to signals:
i.
Hormones (e.g., estrogen)
ii.
Vitamins (e.g., retinoic acid)
iii.
Chemical irritants (e.g., cigarette smoke)
b. Sometimes reversible if the irritant is removed

Dysplasia
1. Disordered cell growth
2. Risk factors for dysplasia
a. Hyperplasia (see section V)
b. Metaplasia (see section V)
c. Infection

Example-human papillomavirus type 16, causing squamous

dysplasia of the cervix
d. Chemicals
Example-irritants in cigarette smoke, causing squamous
metaplasia to progress to squamous dysplasia in the
mainstem bronchus
e. Ultraviolet light
Example-solar damage of the skin, causing squamous
dysplasia
3. Microscopic features of dysplasia
a. Nuclear features

ii
Increased mitotic activity, with normal mitotic spindles
iii
Increased nuclear size and chromatin
b. Disorderly proliferation of cells with loss of cell maturation as cells
progress to the surface
2. Dysplasia may or may not progress to cancer if the irritant is removed.

Cell Death

Cell death occurs when cells or tissues are unable to adapt to injury.

Necrosis
1-8 Acute myocardial infarction (MI) showing coagulation necrosis. This section of myocardial tissue is
from a 3-day-old acute MI. The outlines of the myocardial fibers are intact; however, they lack nuclei and
cross-striations. A neutrophilic infiltrate is present between some of the dead fibers.
Figure 1-9 Acute myocardial infarction (MI) showing a pale infarction of the posterior wall of the left
ventricle
Hemorrhagic infarction of the lung. There is a roughly wedge-shaped area of hemorrhage extending to the
pleural surface. The arrow shows an embolus in one of the pulmonary artery tributaries.

Dry gangrene of the toes in individuals with diabetes mellitus is a form of infarction
that results from ischemia. Coagulation necrosis is the primary type of necrosis
present in the dead tissue
Figure 1-11 Dry gangrene of the toes. Dry gangrene involves the first four toes. The dark black areas of
gangrene are bordered by light-colored, parchment-like skin
Figure 1-13 Caseous granuloma showing a central area of acellular, necrotic material surrounded by
activated macrophages (epithelioid cells), lymphocytes, and multiple multinucleated Langhans-type giant
cells.
Figure 1-14 Enzymatic fat necrosis in acute pancreatitis. Dark areas of hemorrhage are present in the
head of the pancreas (left side), and focal areas of pale fat necrosis (arrow) are present in the
peripancreatic fat.
page 20

1. Death of groups of cells, often accompanied by an inflammatory infiltrate

2. Coagulation necrosis
a. Preservation of the structural outline of dead cells
b. Mechanism of coagulation necrosis
i.
Denaturation of enzymes and structural proteins
Intracellular accumulation of lactate or heavy metals
(e.g., lead, mercury)
Exposure of cells to ionizing radiation
ii.
Inactivation of intracellular enzymes prevents dissolution
(autolysis) of the cell.
c. Microscopic features
i.
Indistinct outlines of cells within dead tissue
ii.
Absent nuclei or karyolysis (fading of nuclear chromatin)
d. Infarction
i.
Gross manifestation of coagulation necrosis secondary to the

sudden occlusion of a vessel

Usually wedge-shaped if dichotomously branching vessels
(e.g., pulmonary artery) are occluded
iii.
Pale (ischemic) type
Increased density of tissue (e.g., heart, kidney,
spleen) prevents RBCs from diffusing through
necrotic tissue
iv.
Hemorrhagic (red) type
Loose-textured tissue (e.g., lungs, small bowel)
allows RBCs to diffuse through necrotic tissue
3. Liquefactive necrosis
a. Necrotic degradation of tissue that softens and becomes liquified
b. Mechanisms
ii.

Lysosomal enzymes released by necrotic cells or neutrophils

cause liquefaction of tissue.
b. Examples
i.
ii.

Central nervous system infarction

Autocatalytic effect of hydrolytic enzymes generated
by neuroglial cells produces a cystic space
Abscess in a bacterial infection
Hydrolytic enzymes generated by neutrophils liquefy
dead tissue.

4. Caseous necrosis
b. Variant of coagulation necrosis associated with acellular, cheese-like
(caseous) material
c. Mechanism

Caseous material is formed by the release of lipid from the

cell walls of Mycobacterium tuberculosis and systemic fungi
(e.g., Histoplasma) after destruction by macrophages.
b. Microscopic features
i.
ii.

The acellular material in the center of a granuloma contains

activated macrophages, CD4 helper T cells, and
multinucleated giant cells
Some granulomas do not exhibit caseation (e.g.,
sarcoidosis).

5. Enzymatic fat necrosis

d. Peculiar to adipose tissue located around an acutely inflamed
pancreas
e. Mechanisms
i.
Activation of pancreatic lipase (e.g., alcohol excess) causing
hydrolysis of triglyceride in fat cells
ii.
Conversion of fatty acids into soap (saponification)
Combination of fatty acids and calcium
f. Gross appearance

c.

Chalky yellow-white deposits are primarily located in

peripancreatic and omental adipose tissue
Microscopic appearance

Pale outlines of fat cells filled with basophilic-staining

calcified areas
d. Traumatic fat necrosis
i.
ii.

Occurs in fatty tissue (e.g., female breast tissue) as a result

of trauma
Not enzyme-mediated

6. Fibrinoid necrosis
g. Limited to small muscular arteries, arterioles, venules, and glomerular
capillaries
h. Mechanism

Deposition of pink-staining proteinaceous material in

damaged vessel walls due to damaged basement
membranes
e. Associated conditions

Immune vasculitis (e.g., Henoch-Schnlein purpura),

malignant hypertension

Apoptosis
Figure 1-15 Apoptosis in the epidermis. The arrow shows a clear space in the epidermis containing an
intensely eosinophilic staining cell with a small, dense nucleus.

1. Programmed, enzyme-mediated cell death

2. Examples
a. Destruction of cells during embryogenesis
Example-loss of mllerian structures in a male fetus due to
Sertoli cell synthesis of mllerian inhibitory factor
b. Hormone-dependent atrophy of tissue
Example-endometrial cell breakdown after withdrawal of
estrogen and progesterone in the menstrual cycle
c. Death of tumor cells by cytotoxic CD8 T cells, corticosteroid
destruction of lymphocytes
3. Mechanisms of apoptosis
a. Signals initiate apoptosis by activating caspases:
Binding of tumor necrosis factor to its receptor
Withdrawal of growth factors or hormones
Injurious agents including viruses, radiation, free radicals that
damage DNA
ivi
BAX gene, cytochrome c
b. Genes regulating apoptosis
ii
TP53 suppressor gene
Temporarily arrests the cell cycle in the G1 phase to
repair DNA damage (aborts apoptosis)
Promotes apoptosis if DNA damage is too great by
activating the BAX apoptosis gene
iii
BCL2 gene family
Manufactures gene products that inhibit apoptosis
(i.e., antiapoptosis gene) by preventing mitochondrial
leakage of cytochrome c into the cytosol
c. Changes in the cell
ii
Activation of endonuclease leads to nuclear pyknosis ("ink
dot" appearance) and fragmentation.
iii
Activation of protease leads to the breakdown of the
cytoskeleton.
iiii
Formation of cytoplasmic buds on the cell membrane
ii
iii
iiii

Buds contain nuclear fragments, mitochondria, and

condensed protein fragments.
ivi
Formation of apoptotic bodies by the breaking off of
cytoplasmic buds
vi
Phagocytosis of apoptotic bodies by neighboring cells or
macrophages
2. Microscopic appearance of apoptosis
a. Cell detachment from neighboring cells
b. Deeply eosinophilic-staining cytoplasm
c. Pyknotic, fragmented, or absent nucleus
d. Minimal or no inflammatory infiltrate surrounding the cell

Enzyme markers of cell death

1. Tissues release certain enzymes that indicate the type of tissue involved and
extent of injury.
2. lists clinically significant enzyme markers.

Table 1-3. Enzyme Markers of Cell Death

Enzyme

Diagnostic Use

Aspartate aminotransferase
(AST)

Marker of diffuse liver cell necrosis (e.g., viral hepatitis)

Mitochondrial enzyme preferentially increased in alcohol-induced
liver disease

Alanine aminotransferase
(ALT)

Marker of diffuse liver cell necrosis (e.g., viral hepatitis)

More specific for liver cell necrosis than AST

Creatine kinase MB (CK-MB)

Isoenzyme increased in acute myocardial infarction or

myocarditis

Amylase and lipase

Marker enzymes for acute pancreatitis

Lipase more specific than amylase for pancreatitis
Amylase also increased in salivary gland inflammation (e.g.,
mumps)