1 cell injury

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 SignificancePaO2 Pressure keeping O2

dissolved in plasma of arterial blood

Percentage of O2 in inspired air, atmospheric pressure, normal O2 exchange

Reduced in hypoxemia

SaO2 Average percentage of O2 bound to Hb

PaO2 and valence of heme iron in each of the four heme groupsFe2+ binds to O2; Fe3+does not

SaO2 < 80% produces cyanosis of skin and mucous membranes

O2 content

Total amount of O2 carried in blood

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.

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










O2 content





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










O2 content





Causes of tissue hypoxia

page 1

page 2Patients 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 3At 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 trimethoprim-sulfamethoxazole

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:

.i Enzyme activation Phospholipase increases cell and organelle

membrane permeability. Proteases damage the cytoskeleton. Endonucleases cause fading of nuclear chromatin

(karyolysis). .ii Reentry of Ca2+ into mitochondria

Increases mitochondrial membrane permeability, with release of cytochrome c (activates apoptosis

Free Radical Cell Injury 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

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, β-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

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. Examples include hemochromatosis and hemosiderosis. b. 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 Ca2+.

Mitochondria 1. Release of cytochrome c from injured mitochondria initiates apoptosis.

2. Injurious agents include alcohol, salicylates, and increased cytosolic Ca2+.

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 Chédiak-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

i. Damaged neurofilaments in idiopathic Parkinson's disease ii. Eosinophilic cytoplasmic inclusions in degenerating substantia nigra

neurons 2. Rigor mortis

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

Table 1-2. Intracellular AccumulationsSubstance Clinical SignificanceEndogenous 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 macrophagesAtherosclerosis: 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 ferritinIron 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 (acid-fast 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

AccumulationsSubstance Clinical SignificanceEndogenous 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 macrophagesAtherosclerosis: 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 ferritinIron 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 (acid-fast 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

Example-acetyl coenzyme A, the end product of alcohol metabolism, is used to synthesize fatty acids.

b. Decreased β-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. Dystrophic calcification

a. Deposition of calcium phosphate in necrotic tissue

b. Normal serum calcium and phosphate

c. Examples-calcified atherosclerotic plaque, calcification in pancreatitis

2. Metastatic calcification

a. Deposition of calcium phosphate in normal tissue á

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

Excess phosphate drives calcium into normal tissue.

c. Examples of metastatic calcification

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

ii. Basal ganglia calcification in hypoparathyroidism

áAdaptation

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

.i Organelles and cytosol form autophagic vacuoles.

.ii Autophagic vacuoles fuse with primary lysosomes for enzymatic degradation.

.iii 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

.i Organelles and cytosol form autophagic vacuoles.

.ii Autophagic vacuoles fuse with primary lysosomes for enzymatic degradation.

.iii Undigested lipids are stored as residual bodies.

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

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

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. Divide continuously ii. Examples-stem cells in the bone marrow, crypts of

Lieberkühn, 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 .a 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

.i Increased mitotic activity, with normal mitotic spindles

.ii 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 ii. 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

Lysosomal enzymes released by necrotic cells or neutrophils cause liquefaction of tissue.

b. Examples

i. Central nervous system infarction Autocatalytic effect of hydrolytic enzymes generated

by neuroglial cells produces a cystic space ii. 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. The acellular material in the center of a granuloma contains activated macrophages, CD4 helper T cells, and multinucleated giant cells

ii. 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

Chalky yellow-white deposits are primarily located in peripancreatic and omental adipose tissue

c. Microscopic appearance Pale outlines of fat cells filled with basophilic-staining

calcified areas d. Traumatic fat necrosis

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

ii. 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-Schönlein purpura), malignant hypertension

ApoptosisFigure 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 müllerian structures in a male fetus due to

Sertoli cell synthesis of müllerian 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:

.i Binding of tumor necrosis factor to its receptor

.ii Withdrawal of growth factors or hormones

.iii Injurious agents including viruses, radiation, free radicals that damage DNA

v.i BAX gene, cytochrome c b. Genes regulating apoptosis

.i 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 .ii 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 .i Activation of endonuclease leads to nuclear pyknosis ("ink

dot" appearance) and fragmentation. .ii Activation of protease leads to the breakdown of the

cytoskeleton. .iii Formation of cytoplasmic buds on the cell membrane

Buds contain nuclear fragments, mitochondria, and condensed protein fragments.

v.i Formation of apoptotic bodies by the breaking off of cytoplasmic buds

v. 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 DeathEnzyme Diagnostic UseAspartate 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 pancreatitisLipase more specific than amylase for pancreatitisAmylase also increased in salivary gland inflammation (e.g., mumps)

1 cell injury

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