Chapter 2 - Cell Injury Flashcards
(227 cards)
0
Q
O2 diffusion
A
O2 in atmosphere → ↑PAO2 → ↑PaO2 → ↑SaO2
1
Q
Define hypoxia.
A
Inadequate oxygenation of tissue.
2
Q
O2 content equation
A
O2 content = (Hb g/dL × 1.34) × SaO2 + PaO2 × 0.003
3
Q
How does hypoxia affect ATP synthesis?
A
Hypoxia: ↓ATP synthesis by oxidation phosphorylation
4
Q
How does the pulse oximeter read if there is a dyshemoglobinemia present?
A
Pulse oximeter: falsely ↑SaO2 in metHb and COHb
5
Q
How does the co-oximeter read if there is a dyshemoglobinemia present?
A
Co-oximeter: accurately measures ↓SaO2 in metHb, COHb
6
Q
Clinical finding in hypoxia
A
Cyanosis
7
Q
Define ischemia.
A
Ischemia: ↓arterial blood inflow and/or venous outflow
8
Q
Ischemia consequences
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Ischemia consequences: atrophy, infarction, organ dysfunction
9
Q
Define hypoxemia.
A
Hypoxemia: ↓PaO2
10
Q
Define respiratory acidosis.
A
Respiratory acidosis: CO2 retention in lungs
11
Q
How does ↑Alveolar PCO2 affect Alveolar PO2, PaO2 and SaO2?
A
↑Alveolar PCO2 = ↓Alveolar PO2 = ↓PaO2 = ↓SaO2
12
Q
Define ventilation defect.
A
Ventilation defect: lung perfused but not ventilated
13
Q
Give an example of a diffuse ventilation defect.
A
RDS: diffuse ventilation defect
14
Q
What does a ventilation defect produce?
A
Ventilation defect: produces intrapulmonary shunting
15
Q
What is a perfusion defect?
A
Perfusion defect: lung ventilated but not perfused
16
Q
How does a perfusion defect affect dead space?
A
Perfusion defect: ↑dead space
17
Q
Define diffusion defect.
A
Diffusion defect: ↓O2 diffusion thru alveolar-capillary interface
18
Q
Give two examples of diffusion defect.
A
Diffusion defect: interstitial fibrosis, pulmonary edema
19
Q
Define anemia.
A
Anemia: ↓Hb concentration; ↓O2 content
20
Q
List four causes of anemia.
A
Anemia: ↓production Hb/RBCs; ↑destruction/sequestration RBCs
21
Q
How does anemia affect PaO2, SaO2, and O2 content?
A
Anemia: normal Pao2/Sao2; ↓O2 content
22
Q
Define methemoglobinemia.
A
MetHb: heme Fe3+; cannot attach to O2
23
Q
How is metHb reduced?
A
MetHb reduction: NADH electrons → cytochrome b5 → cytochrome b5 reductase → heme Fe2+
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List one cause of metHb.
MetHb: oxidant stresses (drugs, sepsis)
25
Describe the pathogenesis of hypoxia in methemoglobinemia.
MetHb: heme Fe3+; normal PaO2, ↓SaO2
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How does methemoglobin affect the oxygen binding curve?
MetHb: shifts OBC to left; lactic acidosis
27
How does oxygen administration affect cyanosis in methemoglobinemia?
MetHb: cyanosis is unresponsive to administration of O2
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What is the treatment for methemoglobinemia and how does it work?
MetHb Rx: IV methylene blue; accelerates NADPH-methemoglobin reductase
29
What is the leading cause of death by poisoning?
Carbon monoxide
30
List three causes of CO poisoning.
↑CO: car exhaust, smoke inhalation, wood stoves
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Describe the pathogenesis of hypoxia in carbon monoxide poisoning.
CO: high affinity for heme groups
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Describe the pathogenesis of hypoxia in CO poisoning.
COHb: inhibits cytochrome oxidase; left-shifted OBC; ↓SaO2
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List two clinical findings in CO poisoning.
CO poisoning: headache, cherry-red discoloration (usually postmortem)
34
List three lab findings in CO poisoning.
CO poisoning: normal PaO2, ↓SaO2, lactic acidosis (hypoxia)
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What is the treatment for CO poisoning?
Rx CO poisoning: 100% O2 via nonrebreather mask/endotracheal tube
36
What is 2,3-BPG and its role in the OBC?
2,3-BPG: glycolysis intermediate; stabilizes taut form Hb (↑release O2)
37
List six causes of left-shifted OBC.
Left-shifted OBC: ↓2,3-BPG, CO, alkalosis, metHb, fetal Hb, hypothermia
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How do COHb and MetHb affect SaO2, PaO2, and the OBC?
COHb and MetHb: ↓SaO2, normal PaO2, left-shifted OBC
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List four causes of right-shifted OBC.
Right-shifted OBC: ↑2,3-BPG, fever, acidosis, high altitude
40
How does high altitude affect atmospheric pressure of O2 and percentage of atmospheric O2?
High altitude: ↓atmospheric pressure; normal % atmospheric O2
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What is the acid-base disturbance when at a high altitude?
| How are 2,3-BPG levels and the OBC affected?
High altitude: hypoxemia/respiratory alkalosis; ↑2,3-BPG; right-shifted OBC
42
Name two electron donors in the oxidative pathway.
Oxidative pathway: transfer electrons from NADH, FADH2
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What does the phosphorylation pathway do?
Phosphorylation pathway: synthesis of ATP
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How do CO and CN affect the ETC?
CO and CN: inhibit cytochrome oxidase; ETC is shut down
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List two causes of CN poisoning.
CN poisoning: house fires (most common); excess nitroprusside
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What two types of poisoning are seen in house fires?
CO + CN poisoning: house fires
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Describe the pathogenesis of hypoxia common to CO and CN poisoning?
CO + CN poisoning: shutdown of ETC prevents diffusion of O2 from blood to tissue
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How does the mixed venous O2 content compare to the arterial O2 content in CN poisoning?
CN poisoning: mixed venous O2 content similar to arterial O2 content
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What enzyme is inhibited by CO and CN and what results?
CO and CN: inhibit cytochrome oxidase; lactic acidosis (hypoxia)
50
Describe the treatment for CN poisoning?
Rx CN poisoning: based on high affinity of CN for metHb and cobalt
51
List two uncouplers of oxidative phosphorylation.
Uncouplers: thermogenin (brown fat), dinitrophenol
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The presence of dinitrophenol may result in what?
Dinitrophenol: danger of hyperthermia
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What does thermogenin do?
Thermogenin: stabilizes body temperature in newborns
54
List two mitochondrial toxins. What do they do?
Mitochondrial toxins: alcohol, salicylates; act like “uncouplers”
55
List two watershed areas in the body.
Watershed areas: cerebral arteries, mesenteric arteries
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What is a complication of global hypoxia?
Watershed infarction in brain: complication global hypoxia
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Where does ischemic colitis occur?
Ischemic colitis: splenic flexure at junction of superior/inferior mesenteric artery
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ST-segment depression on ECG indicates what?
ST-segment depression ECG: subendocardial ischemia
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List two factors resulting in subendocardial ischemia.
Subendocardial ischemia: coronary artery atherosclerosis; cardiac hypertrophy
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List two locations in the nephron that are susceptible to ischemia.
Nephron locations susceptible to hypoxia: proximal tubule in cortex; thick ascending limb medulla
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Which is the most adversely affected cell in tissue hypoxia?
Neurons: most adversely affected cell in tissue hypoxia
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Which hepatocytes are most susceptible to hypoxia?
Zone III hepatocytes: most susceptible to hypoxia
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What is the primary source of ATP in hypoxia and what is the result?
Anaerobic glycolysis: primary ATP source in hypoxia; lactic acidosis
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What does increased intracellular lactate do?
↑Intracellular lactate: acid pH denatures structural/enzymic proteins
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What may lactic acidosis be a sign of?
Lactic acidosis: may be a sign of tissue hypoxia
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What results from an impaired Na+/K+-ATPase?
Na+/K+-ATPase pump impaired (reversible): intracellular swelling (↑Na+ and H2O)
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What results from an impaired Ca2+-ATPase pump?
Ca2+-ATPase pump impaired (irreversible): cannot pump Ca2+ out of cytosol
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What are four lethal effects of increased cytosolic Ca2+?
↑Ca2+ in cytosol: activates phospholipase, protease, endonuclease, caspases
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What is the effect of increased Ca2+ in mitochondria?
↑Ca2+ in mitochondria: ↑membrane permeability to cytochrome c → apoptosis
70
Define free radical?
FR: single unpaired electron in outer orbital
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What do free radicals do?
FRs: “steal” electrons from molecules, which become FRs
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What do free radicals primarily target?
FRs: damage membranes and nucleic acids
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Describe the relationship between free radical damage and age.
FR damage accumulates with age
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Describe two important roles of free radicals.
FRs important in microbial killing by leukocytes
| FRs important in reperfusion injury
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List two transitional metals that generate hydroxyl free radicals.
Iron, copper: transitional metals that generate hydroxyl FRs
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What is the most destructive free radical?
Hydroxyl FR: most destructive FR
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What produces superoxide free radicals?
Superoxide FRs: oxidase reactions; exposure to high O2 concentration
Superoxide FRs: NADPH oxidase in phagocyte cell membranes
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List two sources of nitric oxide free radical gas.
Nitric oxide FR gas: macrophages/endothelial cells; cigarettes
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Describe the importance of oxidized LDL.
Oxidized LDL: FR important in atherogenesis
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Describe the enzymatic reaction performed by SOD.
SOD: neutralizes superoxide FRs
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What does glutathione peroxidase do?
Glutathione peroxidase: neutralizes H2O2, hydroxyl, NAPQ1
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What does catalase do?
Catalase: neutralizes H2O2
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What does vitamin E do?
Vitamin E: prevents FR injury of cell membranes
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What is the best neutralizer of hydroxyl free radicals?
Vitamin C: best neutralizer of hydroxyl FRs
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What vitamin is reduced in smokers?
Smokers: ↓vitamin C levels
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What results from acetaminophen poisoning?
Acetaminophen poisoning: diffuse chemical hepatitis due to NAPQ1
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Alcohol induces the synthesis of which cytochrome P450 isozyme resulting in what?
Alcohol: induces synthesis CYP2E1 isoenzyme
Alcohol: ↑CYP2E1 synthesis; ↑metabolism of alcohol
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What is the treatment for acetaminophen poisoning and what does it do?
N-Acetylcysteine: Rx acetaminophen poisoning; provides cysteine for GSH synthesis
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What may result from use of acetaminophen and NSAIDs?
Acetaminophen + NSAIDs: FR injury of kidneys; renal papillary necrosis
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What is carbon tetrachloride and how does it become a free radical?
CCL4: solvent in dry cleaning; cytochrome P450 converts it into FR
91
List three factors involved in reperfusion injury.
Reperfusion injury: superoxide FRs + ↑cytosolic Ca2+ + neutrophils
92
Retinopathy of prematurity may result in the setting of RDS due to what?
Retinopathy prematurity in RDS: ↑superoxide FRs from O2 therapy
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How does iron overload affect free radical production?
Iron overload: ↑OH· FRs via Fenton reaction
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How does excess copper affect free radical production?
Excess copper: ↑OH· FRs via Fenton reaction; hepatotoxic/neurotoxic
95
Salicylates and alcohol affect which cellular organelle resulting in what?
Salicylates, alcohol damage mitochondria; megamitochondria in hepatocytes
96
Phenobarbital increases the synthesis of which cytochrome P450 isozyme resulting in what?
Phenobarbital: ↑CYP2B2 synthesis; converts drug to inactive metabolite
97
Phenytoin increases the synthesis of which cytochrome P450 isozyme resulting in what?
Phenytoin: ↑CYP3A4 synthesis in cytochrome P450 system; ↑metabolism of phenytoin
98
List two effects of SER hyperplasia.
SER hyperplasia: ↑drug metabolism; ↓drug effectiveness
99
List two SER inhibitors.
SER inhibitors: proton/histamine H2-receptor blockers; histamine receptor blockers
100
List two effects of SER inhibition.
SER inhibition: ↓drug metabolism; drug toxicity
101
Where are hydrolytic enzymes that are synthesized in the RER transported? Once there, what happens to these enzymes?
Hydrolytic enzymes undergo posttranslational modification in Golgi apparatus
102
Describe the posttranslational modification of hydrolytic enzymes.
Phosphotransferase attaches P to mannose residues on enzymes → mannose 6-P
103
Describe what occurs following posttranslational modification of lysosomal enzymes.
Mannose 6-P on lysosomal enzyme attaches to receptors on Golgi membrane
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Describe what occurs after vesicles containing receptor-bound lysosomal enzymes pinch off the Golgi apparatus.
Vesicles pinch off Golgi membrane → deliver enzymes to lysosomes; some vesicles return to Golgi
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What does the phagolysosome contain?
Phagolysosome: contains lysosomal enzymes
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What is inclusion-(I) cell disease and which enzyme is affected?
I-cell disease: defect in posttranslational modification lysosomal enzymes; deficient phosphotransferase
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What is lysosomal storage disease?
Lysosomal storage disease: ↓lysosomal enzymes; accumulation of complex substrates
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What is Chediak-Higashi Syndrome?
CHS: giant lysosomal granules (fusion defect); defect in formation of phagolysosomes
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What is the cytoskeleton composed of?
Cytoskeleton: microtubules, actin filaments, intermediate filaments
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Which two chemotherapeutic agents inhibit the synthesis of tubulin? What phase of the cell cycle is affected?
G2 phase defects: etoposide, bleomycin
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Name three compounds that cause mitotic spindle defects.
Mitotic spindle defects: vinca alkaloids, colchicine, paclitaxel
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What is ubiquitin?
Ubiquitin: marker for damaged intermediate filaments
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What are Mallory and Lewy bodies?
Mallory and Lewy bodies: ubiquinated keratin/neurofilament intermediate filaments, respectively
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What is the most common cause of fatty change in the liver?
Alcohol: most common cause of fatty change
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What is packaged in the VLDL fraction?
VLDL: liver-synthesized TGs
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What is the carbohydrate substrate for TG synthesis?
G3-P: carbohydrate substrate for TG synthesis
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What are the two functions of apoB-100?
ApoB-100: helps form VLDL and secrete VLDL from liver into blood
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How does kwashiorkor affect TG synthesis?
Kwashiorkor: ↑CHO → ↑DHAP → ↑G3-P → ↑TG synthesis
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How does alcohol affect TG synthesis?
Alcohol: ↑NADH → ↑conversion DHAP to G-3P → ↑synthesis TG
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How does alcohol affect FA synthesis in the liver?
Alcohol: ↑acetyl CoA → ↑synthesis FAs in liver
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List three effects alcohol has on FA.
Alcohol: ↑FAs → ↑synthesis, ↑mobilization from adipose; ↓β-oxidation FAs in mitochondria
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In kwashiorkor, how is apoB-100 affected and what results?
Kwashiorkor: ↓protein intake → ↓apoB-100 → ↓packaging/secretion of VLDL
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How does fatty liver affect TG and VLDL?
Fatty liver: ↑synthesis TG; ↓packaging/secretion VLDL
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What is ferritin?
Ferritin: soluble iron-binding protein in macrophages
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Where is ferritin synthesized?
Ferritin: synthesized in macrophages and hepatocytes
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What is a decrease in serum ferritin an indicator of?
Serum ferritin: ↓in iron deficiency anemia
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What is hemosiderin? What stains hemosiderin positive?
Hemosiderin: ferritin degradation product; Prussian blue positive
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What is dystrophic calcification?
Dystrophic calcification: calcification of necrotic (damaged) tissue
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What is the relationship between dystrophic calcification and serum calcium and phosphate levels?
Dystrophic calcification: serum calcium and phosphate are normal
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What is metastatic calcification?
Metastatic calcification: calcification of normal tissue
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What is the relationship between metastatic calcification and serum calcium and phosphate levels?
Metastatic calcification: ↑serum calcium and/or phosphate
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What is nephrocalcinosis and what does it produce?
Nephrocalcinosis: metastatic calcification of collecting ducts; produces diabetes insipidus
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What is atrophy?
Atrophy: ↓size/weight of tissue or organ
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List four causes of atrophy.
Atrophy: ↓hormone stimulation, ↓innervation, ↓blood flow, ↓nutrients
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What does increased luminal pressure result in? Which two organs may be affected?
Atrophy: ↑luminal pressure → compression atrophy (pancreas, kidney)
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What occurs during autophagy?
Autophagy: vacuoles with organelles fuse with lysosomes; enzyme degradation of organelles
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What is brown atrophy?
Brown atrophy: ↑lipofuscin in cells (undigested lipid)
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List two mechanisms of atrophy.
Atrophy: cell shrinkage (loss of cytosol/organelles); apoptosis
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What is hypertrophy?
Hypertrophy: ↑cell size
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What does cardiac muscle hypertrophy occur in response to?
Cardiac muscle hypertrophy: ↑preload (↑volume in ventricle) or ↑afterload (↑resistance ventricle must contract against)
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What occurs to the remaining kidney postnephrectomy?
Remaining kidney postnephrectomy: undergoes compensatory hypertrophy
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Why does CMV hypertrophy of the cell occur?
CMV hypertrophy of cell: due to ↑iron uptake causing ↑cell growth
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What is hyperplasia?
Hyperplasia: ↑number of cells
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Give an example of hyperplasia due to increased hormone stimulation.
↑Hormone stimulation: estrogen → endometrial hyperplasia
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Give an example of hyperplasia due to increased hormone sensitivity.
↑Hormone sensitivity: DHT → prostate hyperplasia
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Give three examples of chronic irritation resulting in hyperplasia.
Chronic irritation: skin thickening (scratching), bronchial mucous gland hyperplasia (smokers), regenerative nodules in cirrhosis (alcohol excess)
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List an example of chemical imbalance resulting in hyperplasia.
Chemical imbalance: ↓serum Ca2+ → parathyroid gland hyperplasia
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How does iodine deficiency affect the thyroid?
Iodine deficiency → goiter (hyperplasia/hypertrophy)
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Give an example of hyperplasia resulting from stimulating antibodies.
Hyperplasia stimulating antibodies: Graves disease
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Give an example of hyperplasia resulting from a viral infection.
Hyperplasia: HPV → epidermal hyperplasia (common wart)
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What must be true for hyperplasia to occur?
Hyperplasia only occurs if cells can enter the cell cycle
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What do labile cells do? Give an example of labile cells.
Labile cells: continuously divide; e.g., stem cells in bone marrow
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What are stable cells? Give two examples of stable cells.
Stable cells: resting cells in G0 phase cell cycle; e.g., hepatocytes, smooth muscle cells
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Permanent cells cannot do what? Give three examples of permanent cells.
Permanent cells: cannot divide; e.g., neurons, skeletal/cardiac muscle
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There is the risk of what in hyperplasia? Give two examples.
Cancer risk in hyperplasia: endometrial hyperplasia, regenerative nodules in cirrhosis
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What is metaplasia?
Metaplasia: one adult cell type replaces another
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Give an example of squamous to glandular epithelium.
Squamous to glandular epithelium: acid reflux distal esophagus (Barrett esophagus)
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Give an example of glandular to other glandular epithelium.
Glandular to other glandular epithelium: atrophic gastritis due to Helicobacter pylori
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Give two examples of glandular to squamous epithelium.
Glandular to squamous epithelium: bronchus in smoker; endocervix
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Give an example of transitional to squamous epithelium.
Transitional to squamous epithelium: Schistosoma haematobium infection of urinary bladder
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What is mesenchymal metaplasia?
Mesenchymal metaplasia: bone developing in area of muscle trauma
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What is the mechanism of metaplasia?
Mechanism: reprogramming stem cells to utilize progeny cells with different gene expression
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List three examples of stimuli for reprogramming in metaplasia.
Stimuli for reprogramming: hormones (estrogen), vitamins (retinoic acid), chemicals (cigarette smoke)
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There is the risk of developing what in the setting of metaplasia and hyperplasia? The risk greater in metaplasia or hyperplasia?
Metaplasia and hyperplasia: risk for developing dysplasia; metaplasia > hyperplasia
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What is dysplasia?
Dysplasia: disordered cell growth
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List two risk factors for developing dysplasia.
Risk factors: endometrial hyperplasia; Barrett esophagus
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List one risk factor for developing dysplasia related to infection.
Risk factor: HPV -> squamous dysplasia cervix
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List one risk factor for developing dysplasia related to chemicals.
Risk factor: cigarette smoke -> squamous dysplasia bronchus
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Name the type of dysplasia related to UV light.
Risk factor: UV light -> squamous dysplasia
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List one risk factor of dysplasia related to chronic skin irritation.
Risk factor: chronic skim irritation (3rd degree burn) -> squamous dysplasia
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What may dysplasia progress to?
Dysplasia may progress to cancer.
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How does dysplasia affect cell proliferation and mitotic activity?
Dysplasia: disorderly proliferation of cells;↑mitotic activity
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What three types of epithelium may be affected by dysplasia?
Dysplasia: may involve squamous, glandular, transitional epithelium
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What is necrosis?
Necrosis: death of groups of cells + inflammation
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What is coagulation necrosis?
Coagulation necrosis: preservation of structural outlines
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List three causes of coagulation necrosis due to denaturation of enzymes and structural proteins.
Coagulation necrosis: ↑intracellular lactic acid; ionizing radiation; heavy metals
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Name one microscopic feature of coagulation necrosis.
Coagulation necrosis: indistinct cell outlines in dead tissue
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What is an infarction?
Infarction: gross manifestation of coagulation necrosis
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Name two types of infarction.
Infarctions: pale and hemorrhagic types
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Pale infarctions are seen in what type of tissue? List three organs that may be affected by a pale infarction.
Pale infarctions: dense tissue; heart, kidney, spleen
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Hemorrhagic infarctions occur in what type of tissue? List three organs that may be affected by a hemorrhagic infarction.
Hemorrhagic infarctions: loose tissue; lung, bowel, testicle
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What type of necrosis is present in the setting of dry gangrene?
Dry gangrene: predominantly coagulation necrosis
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What is likely if a thrombus overlies an atherosclerotic plaque in a coronary artery?
Infarction likely if thrombus overlies atherosclerotic plaque in coronary artery
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Name two scenarios in which an infarction is less likely.
Infarction less likely: dual blood supply (lungs), collateral circulation (arcade system in superior/inferior mesenteric arteries)
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In what two scenarios are infarctions more likely?
Infarctions more likely: preexisting disease in tissue; end arteries
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Describe the mechanism by which liquefactive necrosis occurs.
Liquefactive necrosis: lysosomal enzyme destruction tissue by neutrophils
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What type of necrosis occurs in the setting of cerebral infarction?
Cerebral infarction: liquefactive not coagulative necrosis (exception to the rule)
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What type of necrosis occurs in a bacterial abscess?
Bacterial abscess: liquefactive necrosis
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Wet gangrene is predominantly what type of necrosis?
Wet gangrene: predominantly liquefactive necrosis
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Caseous necrosis is a variant of what type of necrosis?
Caseous necrosis: variant of coagulation necrosis
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What is responsible for the cheesy appearance of granulomas?
Lipid from cell wall Mycobacterium/systemic fungi → cheesy appearance in granulomas
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What is the most common cause of caseous necrosis?
Tuberculosis: most common cause of caseous necrosis
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Gummatous necrosis is what type of necrosis and is associated with what type of disease?
Gummatous necrosis: type of coagulation necrosis; associated with spirochetal disease (e.g., syphilis)
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What are the two most common sites for gummas?
Gummas: skin, bone most common sites
195
Acute pancreatitis is associated with what type of necrosis?
Enzymatic fat necrosis: acute pancreatitis
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What occurs during saponification? What commonly occurs in areas of saponification?
Saponification: calcium combined with fatty acids; dystrophic calcification
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Trauma of fat tissue is related to what type of necrosis? Is this type of necrosis enzyme-mediated?
Traumatic fat necrosis: related to trauma of fat tissue; not enzyme-mediated
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What mediates fibrinoid necrosis?
Fibrinoid necrosis: necrosis of immune-mediated disease
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What is apoptosis?
Apoptosis: programmed cell death
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List four examples of normal destruction of cells during embryogenesis.
Embryogenesis: MIS → apoptosis müllerian structures male Embryogenesis: lost tissue between fingers/toes; shaping inner ear; cardiac morphogenesis
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How does a drop in estrogen and progesterone affect endometrial tissue?
Drop in estrogen/progesterone → menses
202
How does a decrease in stimulating hormones affect the target tissue?
↓Stimulating hormones → atrophy of target tissue
203
What occurs to the thymus with increasing age?
Normal involution of thymus
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Cytotoxic CD8 T cells target which two cell types resulting in what?
death tumor cells/virus infected cells by cytotoxic CD8 T cells
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Corticosteroids destroys what two cell types? What is its role in acute inflammation?
Corticosteroid destroys B/T cells; removes acute inflammatory cells in acute inflammation
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List three things that damage DNA resulting in apoptosis.
DNA damaged by radiation/FRs/toxins
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Apoptosis is associated with the removal with what type of proteins?
misfolded proteins removed
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Defects in apoptosis can lead to what two types of diseases?
Defects in apoptosis → cancer, autoimmune disease
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What does the extrinsic pathway of apoptosis require?
Extrinsic pathway of apoptosis: requires TNF-α
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What does TNF-alpha activate?
TNFR1 is a death receptor activated by TNF-α
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What is the main source of TNF-alpha? What other cell types produce TNF-alpha?
TNF-α: produced by macrophages (main source); endothelial and cardiac cells, and neurons
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What does TNFR1 binding with TNF-alpha activate?
TNFR1 binding with TNF-α activates initiator caspases 8 and 10
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What do initiator caspases activate?
Caspases: initiator caspases activate effector caspases (proteases, endonucleases)
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Which is the most important of the two pathways of apoptosis?
Intrinsic pathway of apoptosis: most important of the two pathways
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Name the genes and gene types of the BCL gene family.
BCL gene family: antiapoptotic genes (BCL-2 gene) and antiapoptotic genes (BAX, BAK genes)
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What type of gene is BCL-2 and what does it do?
BCL-2 gene: antiapoptosis gene; protein maintains mitochondrial membrane integrity to prevent leakage of cytochrome c
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What does BAK/BAX activation result in?
BAX/BAK activation: mitochondrial channels in membrane leak cytochrome c into cytosol
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Once leaked into the cytosol, what does cytochrome c do?
Cytochrome c → activates caspases in cytosol → apoptosis
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Once activated, what is the role of effector caspases?
Proteases destroy cytoarchitecture, endonucleases destroy nucleus
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In apoptosis, what do cytoplasmic buds contain?
Cytoplasmic buds contain nuclear/mitochondrial/other organelle fragments
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What do cytoplasmic buds do and become?
Cytoplasmic buds separate from membrane → apoptotic bodies
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What happens to apoptotic bodies?
Apoptotic bodies phagocytosed by neighboring cells/macrophages
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Describe three microscopic features of apoptosis?
Apoptosis: deeply eosinophilic cytoplasm; pyknotic nucleus; minimal inflammation
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What is pyroptosis?
Pyroptosis: proinflammatory cell death using caspase-1
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In pyroptosis, what three cell types and what three microbial pathogens may be destroyed?
Pyroptosis: monocyte/macrophage/dendritic cell destruction Salmonella, Shigella, Legionella
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Pyroptosis has been implicated in the pathogenesis of what five diseases?
Pyroptosis: MI, neurodegenerative disease, IBD, cerebral ischemia, endotoxic shock
