CH1 - Growth Adaptations, Cellular Injury, and Cell Death Flashcards Preview

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Flashcards in CH1 - Growth Adaptations, Cellular Injury, and Cell Death Deck (167):
1

What are the basic principles of growth adapdations?

An organ is in homeostasis with the physiologic stress placed on it. An increase, decrease, or change in stress on an organ can result in growth adaptations.

2

What leads to an increase in organ size?

An increase in stress

3

Hypertrophy occurs via what?

an increase in the size

4

Hyperplasia occurs via what?

an increase in the number of cells

5

What does hypertrophy involve?

gene activation, protein synthesis, and production of organelles.

6

What does Hyperplasia involve?

the production of new cells from stem cells.

7

Permanent tissues are... Do they undergo hypertrophy or hyperplasia?

cardiac muscle, skeletal muscle, and nerve, cannot make new cells and undergo hypertrophy only.

8

Pathologic hyperplasia leads to what?

(e.g., endometrial hyperplasia) can progress to dysplasia and,eventually cancer.

9

What is an exception to pathologic hyperplasia leading to cancer?

benign prostatic hyperplasia (BPH), which does notincrease the risk for prostate cancer,

10

What leads to a decrease in organ size?

A decrease in stress (e.g., decreased hormonal stimulation, disuse, or decreased nutrients/blood supply) (atrophy).

11

Atrophy occurs via?

a decrease in the size and number of cells

12

How does a decrease in cell number occur?

via apoptosis.

13

Decrease in cell size occurs via what?

ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular components.

14

What happens in ubiquitin-proteosome degradation?

intermediate filaments of the cytoskeleton are tagged with ubiquitin and destroyed by proteosomes.

15

What does autophagy of cellular components involve?

generation of autophagic vacuoles that fuse with lysosomes whose hydrolytic enzymes breakdown cellular components.

16

What happens in METAPLASIA?

change in stress on an organ leads to a change in cell type

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Metaplasia most commonly involves?

change of one type of surface epithelium (squamous, columnar, or urothelial) to another

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How do metaplastic cells handle the new stress?

they are better able to handle the new stress.

19

Esophagus is normally lined by what?

nonkeratinizing squamous epithelium (suited to handle friction of a food bolus)

20

Barrett esophagus

Acid reflux from the stomach causes metaplasia to nonciliated mucin-producing columnar cells (better able to handle the stress of acid

21

Metaplasia occurs via what?

programming of stem cells, which then produce the new cell type.

22

Is Metaplasia reversible?

with removal of the driving stressor.

23

Can metaplasia progress to cancer?

Under persistent stress, can progress to dysplasia and eventually result in cancer.

24

What is an exception to metaplasia leading to cancer?

apocrine metaplasia of breast, which carries no increased risk for cancer.

25

Vitamin A deficiency can result in what?

metaplasia,

26

Vitamin A is necessary for what?

differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye.

27

Keratomalacia

In vitamin A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium.

28

Myositis Ossificans

Mesenchymal (connective) tissues can undergo metaplasia. A classic example is myositis ossificans in which muscle tissue changes to bone during healing after trauma

29

DYSPLASIA is?

Disordered cellular growth

30

Dysplasia most often refers to?

proliferation of precancerous cells

31

Cervical intraepithelial neoplasia (CIN)

represents dysplasia and is a precursor to cervical cancer

32

Dysplasia often arises from?

longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus)

33

Is dysplasia is reversible?

yes, with alleviation of inciting stress.

34

In dysplasia what happens if stress persists?

dysplasia progresses to carcinoma irreversible)

35

What is aplasia?

it is failure of cell production during embryogenesis (e.g., unilateral renal agenesis)

36

What is hypoplasia?

it is a decrease in cell production during embryogenesis, resulting in a relatively small organ (e.g., streak ovary in Turner syndrome)

37

When does cellular injury occur?

when a stress exceeds the cells ability to adapt

38

The likelihood of injury depends on what?

the type of stress, its severity, and the type of cell affected.

39

What are highly susceptible to ischemic injury? As opposed to?

neurons whereas, skeletal muscle is relatively more resistant.

40

Slowly developing ischemia

eg: renal artery atherosclerosis, results in ATROPHY

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acute ischemia

eg: renal artery embolus, results in INJURY

42

What are common causes of cellular injury?

inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.

43

What is HYPOXIA?

Low oxygen delivery to tissue; important cause of cellular injury

44

What is the final electron acceptor in the electron transport chain of oxidative phosphorylation?

Oxygen

45

Decreased oxygen results in what?

impairs oxidative phosphorylation, resulting in decreased ATP production

46

What does a lack of ATP leads to?

cellular injury

47

What are some causes of hypoxia?

include ischemia, hypoxemia, and decreased 02 - carrying capacity of blood.

48

Ischemia is?

decreased blood flow through an organ

49

Ischemia arises with?

1. Decreased arterial perfusion (eg atherosclerosis) 2. Decreased venous drainage (eg Budd-Chiari syndrome) 3. Shock?generalized hypotension resulting in poor tissue perfusion

50

Hypoxemia is?

a low partial pressure of oxygen in the blood (Pao2< 60 mm Hg, SaO2<90%).

51

Hypoxemia arises with

1. High altitude 2. Hypoventilation 3. Diffusion defect 4. V/Q mismatch

52

High altitude to hypoxemia, how?

Decreased barometric pressure results in decreased PaO2

53

Hypoventilation to hypoxemia, how?

Increased Paco, results in decreased PaO2

54

Diffusion defect to hypoxemia, how?

PAO2 not able to push as much O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis)

55

V/Q mismatch to hypoxemia, how?

Blood bypasses oxygenated lung (circulation problem, eg: right-to-left shunt), or oxygenated air cannot reach blood (ventilation problem, eg: atelectasis)

56

Decreased O2-carrying capacity arises with what?

hemoglobin (Hb) loss or dysfunction

57

What are some examples of Decreased O2-carrying capacity?

1. Anemia 2. Carbon monoxide poisoning 3. Methemoglobinemia

58

Anemia leading to decreased O2 carrying capacity.

(decrease in RBC mass) PaO2 normal; SaO2 normal

59

Carbon monoxide poisoning

CO binds hemoglobin more avidly than oxygen

60

What is the PaO2 and SaO2 for carbon monoxide poisoning?

PaO2 normal; SaO2 decreased

61

Exposures for Carbon monoxide poisoning

include smoke from fires and exhaust from cars or gas heaters.

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Classic finding for Carbon monoxide poisoning

cherry-red appearance of skin.

63

Early sign of exposure for Carbon monoxide poisoning

headache; significant exposure leads to coma and death.

64

What is Methemoglobinemia?

Iron in heme is oxidized to Fe3+ which cannot bind oxygen

65

PaO2 and SaO2 for Methemoglobinemia?

PaO2 normal; SaO2 decreased

66

Methemoglobinemia is Seen with?

oxidant stress (eg sulfa and nitrate drugs) or in newborns

67

Classic finding for Methemoglobinemia?

cyanosis with chocolate-colored blood.

68

Treatment for Methemoglobinemia?

intravenous methylene blue, which helps reduce Fe3+ back to Fe2+ state.

69

Hypoxia results in low ATP how?

impairs oxidative phosphorylation resulting in decreased ATP.

70

Low ATP disrupts what?

key cellular functions including 1. Na/K pump 2. Ca2+ pump 3. Aerobic glycolysis

71

Disruption of Na/K pump results in what?

sodium and water buildup in the cell

72

Disruption of Ca2+ pump results in what?

Ca2+ buildup in the cytosol of the cell

73

Disruption of Aerobic glycolysis results in what?

switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DMA.

74

The hallmark of reversible injury is

cellular swelling.

75

Cytosol swelling results in

loss or microvilli and membrane blebbing.

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Swelling of the rough endoplasmic reticulum (RER) results in

dissociation of ribosomes and decreased protein synthesis.

77

The hallmark of irreversible injury is

membrane damage.

78

Plasma membrane damage results in

1. Cytosolic enzymes leaking into the serum {e.g cardiac troponin) 2. Additional calcium entering into the cell

79

Mitochondrial membrane damage results in

1. Loss of the electron transport chain (inner mitochondrial membrane) 2. Cytochrome c leaking into cytosol (activates apoptosis)

80

Lysosome membrane damage results in

hydrolytic enzymes leaking into the cytosol, which in turn, are activated by the high intracellular calcium.

81

The end result of irreversible injury is

cell death.

82

The morphologic hallmark of cell death is

loss of the nucleus,

83

loss of the nucleus occurs via

nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis)

84

The two mechanisms of cell death are

necrosis and apoptosis.

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NECROSIS

A. Death of large groups of cells followed by acute inflammation B. Due to some underlying pathologic process; never physiologic C. Divided into several types based on gross features

86

GROSS PATTERNS OF NECROSIS

A. Coagulative necrosis, B. liquefactive necrosis, C. Gangrenous necrosis D. Caseous necrosis E. Fat necrosis F. Fibrinoid necrosis

87

What is Coagulative necrosis?

Necrotic tissue that remains firm, cell shape and organ structure are preserved by coagulation of proteins, but the nucleus disappears

88

Coagulative necrosis is Characteristic of?

ischemic infarction of any organ except the brain

89

Area of infarcted tissue for Coagulative necrosis?

It is often wedge-shaped (pointing to focus of vascular occlusion) and pale.

90

What is Red infarction

arises if blood re-enters a loosely organized tissue (e.g. pulmonary or testicular infarction)

91

What is Liquefactive necrosis?

Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction.

92

Liquefactive necrosis is Characteristic of?

Brain infarction, abscess, pancreatitis

93

What type of necrosis for brain infarction?

Liquefactive necrosis - Proteolytic enzymes from microglial cells liquefy the brain.

94

What type of necrosis for abscess?

Liquefactive necrosis - proteolytic enzymes from neutrophils liquefy tissue

95

What type of necrosis for pancreatitis?

Liquefactive necrosis - Proteolytic enzymes from pancreas liquefy parenchyma.

96

What is Gangrenous necrosis?

Coagulative necrosis that resembles mummified tissue (dry gangrene)

97

Gangrenous necrosis is characteristic of?

ischemia of lower limb and GI tract

98

What is wet gangrene?

superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene).

99

What is Caseous necrosis?

Soft and friable necrotic tissue with cottage cheese-like appearance. It's a combination of coagulative and liquefactive necrosis

100

What is caseous necrosis characteristic of?

granulomatous inflammation due to tuberculous or fungal infection

101

What is fat necrosis?

Necrotic adipose tissue with chalky-white appearance due to deposition of calcium

102

What is fat necrosis characteristic of?

trauma to fat (eg. breast) and pancreatitis-mediated damage of peripancreatic fat

103

Fat necrosis and saponification

Fatty acids released by trauma (eg to breast) or lipase (eg pancreatitis) join with calcium via a process called saponification which is an example of dystrophic calcification in which calcium deposits on dead tissues.

104

dystrophic calcification

the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate

105

Dystrophic calcification vs metastatic calcification

high serum calcium or phosphate levels lead to calcium deposition in normal tissues (eg. hyperparathyroidism leading to nephrocalcinosis)

106

Fibrinoid necrosis

Necrotic damage to blood vessel wall, Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically

107

What is fibrinoid necrosis characteristic of?

malignant hypertension and vasculitis

108

What is apoptosis?

Energy (ATP)-dependent, genetically programmed cell death involving single cells or small groups of cells.

109

Examples of apoptosis include

1. Endometrial shedding during menstrual cycle 2. Removal of cells during embryogenesis 3. CD8+ T cell-mediated killing of virally infected cells

110

Morphology of apoptosis

1. Dying cell shrinks, leading cytoplasm to become more eosinophilic (pink) 2. Nucleus condenses (pyknosis) and fragments (karyorrhexis).

111

Apoptotic bodies

fall from the cell and are removed by macrophages; apoptosis is not followed by inflammation

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Apoptosis is mediated by

caspases that activate proteases and endonucleases

113

Proteases

break down the cytoskeleton.

114

Endonucleases

break down DNA,

115

How are caspases activated?

1. Intrinsic mitochondrial pathway 2. Extrinsic receptor-ligand pathway 3. Cytotoxic CD8+ Tcell-mediated pathway

116

What is the main molecule in the intrinsic mitochondrial pathway?

Bcl2

117

What happens to Bcl2 in the intrinsic mitochondrial pathway?

Cellular injury, DNA damage, or loss of hormonal stimulation leads to inactivation of Bcl2

118

In the intrinsic mitochondrial pathway lack of Bcl 2 results in what?

allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases.

119

What is the extrinsic receptor-ligand pathway?

FAS ligand binds to (CD95) FAS death receptor and TNF binds TNF receptor (both activate caspases)

120

What is an example of FAS ligand binding to FAS death receptor (CD95) on the target cell activating caspases

negative selection of thymocytes in thymus

121

Cytotoxic CD8+ T cell-mediated pathway releases what?

perforins and granzyme ex CD8+ T-cell killing of virally infected cells is an example.

122

Perforins

secreted by CD8+ T cell create pores in membrane of target cell

123

Granzyme

secreted from CD8+ T cell enters pores and activates caspases

124

Free radicals are what?

chemical species with an unpaired electron in their outer orbit.

125

When does physiologic generation of free radicals occur?

it occurs during oxidative phosphorylation

126

How are free radicals generated physiologically?

Cytochrome c oxidase (complex IV) transfers electrons to oxygen. Partial reduction of O2 yields superoxide (O2.) hydrogen peroxide (H202), and hydroxyl radicals (OH.)

127

Pathologic generation of free radicals arises with?

Ionizing radiation, inflammation, metals, drugs and chemicals

128

Ionizing radiation and Pathologic generation of free radicals

water hydrolyzed to hydroxyl free radical

129

Inflammation and Pathologic generation of free radicals

NADPH oxidase generates superoxide ions during oxygen dependent killing by neutrophils.

130

Metals and Pathologic generation of free radicals

(e.g., copper and iron) Fe generates hydroxyl free radicals (Fenton reaction).

131

Drugs and chemicals and Pathologic generation of free radicals

P450 system of liver metabolizes drugs (e.g acetaminophen), generating free radicals.

132

Free radicals cause

cellular injury via peroxidation of lipids and oxidation of DNA and proteins; DNA damage is implicated in aging and oncogenesis.

133

Elimination of free radicals occurs via what?

Antioxidants, Enzymes, Metal carrier proteins

134

Elimination of free radicals via Antioxidants

glutathione and vitamins A , C, and E

135

Elimination of free radicals via Enzymes

SOD, glutathione peroxidase, catalase

136

Superoxide dismutase

(in mitochondria) superoxide (O2.?>H202)

137

Glutathione peroxidase

(in mitochondria) GSH + free radical GSSH and H202

138

Catalase

(in peroxisomes) H2O2 ?> O2 and H202

139

Elimination of free radicals via Metal carrier proteins

transferrin and ceruloplasmin

140

Free Radical Injury

Carbon tetrachloride (CCl4) and Reperfusion Injury

141

Carbon tetrachloride - What is it used for?

Organic solvent used in the dry cleaning industry

142

How is CCl4 metabolized?

Converted to CC14 free radicals by P450 system of hepatocytes

143

CCl4 results in what?

cell injury with swelling of RER, ribosomes detach, impairing protein synthesis. Decreased apolipoproteins lead to fatty change in the liver

144

Reperfusion injury

Return of blood to ischemic tissue results in production of O2-derived free radicals, which further damage tissue. Leads to a continued rise in cardiac enzymes (troponin) after reperfusion of infarcted myocardial tissue

145

What is an amyloid?

It is a misfolded protein that deposits in the extracellular space, thereby damaging tissues.

146

What are the shared features of amyloid proteins?

beta-pleated sheet configuration, Congo red staining and apple-green birefringence when viewed microscopically under polarized light Deposition can be systemic or localized,

147

What is primary amyloidosis?

It is systemic deposition of AL amyloid, which is derived from immunoglobulin light chain

148

What is primary amyloidosis associated with?

plasma cell dyscrasias (e.g multiple myeloma)

149

Secondary amyloidosis is?

systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA).

150

What is SAA?

It is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean Fever (FMF).

151

What is FMF due to?

a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin.

152

What does FMF present with?

episodes of fever and acute serosal inflammation

153

FMF can mimic what?

appendicitis, arthritis, or myocardial infarction

154

How does FMF result in AA amyloid deposition in tissues?

High SAA during attacks deposits as AA amyloid in tissues

155

What is the most common organ involved in systemic amyloidosis?

kidney

156

What are the clinical findings of systemic amyloidosis?

Nephrotic syndrome, Restrictive cardiomyopathy or arrhythmia, Tongue enlargement, malabsorption, and hepatosplenomegaly

157

Diagnosis of systemic amyloidosis requires what?

tissue biopsy, Abdominal fat pad and rectum are easily accessible biopsy targets.

158

Damaged organs of systemic amyloidosis must be...

transplanted. Amyloid cannot be removed.

159

What is localized amyloidosis?

Amyloid deposition that is usually localized to a single organ

160

What is senile cardiac amyloidosis?

Non-mutated serum transthyretin deposits in the heart. Usually asymptomatic; present in 25% of individuals > 80 years of age

161

Familial amyloid cardiomyopathy

Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy, 5% of African Americans carry the mutated gene.

162

Non-insulin-dependent diabetes mellitus (type II)

Anylin (derived from insulin) deposits in the islets of the pancreas,

163

Alzheimer disease

amyloid beta (derived from J-amyloid precursor protein) deposits in the brain forming amyloid plaques

164

Gene for J-APP is present on...

chromosome 21.

165

Downs syndrome and Alzheimers?

Most individuals with Down syndrome (trisomy 21) develop Alzheimer disease by the age of 40 (early-onset).

166

Dialysis-associated amyloidosis

B-microglobulin deposits in joints,

167

Medullary carcinoma of the thyroid

Calcitonin (produced by tumor cells) deposits within the tumor ('tumor cells in an amyloid background').