General Pathology

Question 1

Apoptosis:

- 4 morphologic steps?

Answer 1

Apoptosis: ATP-dependent, genetically-programmed cell death. NOT followed by acute inflammation.

(1) Dying cell detaches from neighboring cells
(2) Dying cell shrinks, leading to cytoplasm to become more eosinophilic (pink)
(3) Nucleus condenses (pyknosis) and fragments (karyorrhexis)
(4) APOPTOTIC BODIES are shed from the cell and are consumed by macrophages

Question 2

Intrinsic (mitochondrial) pathway of apoptosis:

• Gene family?
• Gene family - 3 genes?
• Chromosome on which gene family resides?

Answer 2

BCL gene family (chrom 18):

• Anti-apoptotic gene(s): BCL-2
• Pro-apoptotic genes(2): BAX, BAK

Question 3

Intrinsic (mitochondrial) pathway of apoptosis:

- Mechanism by which pathway is maintained in an inactive state in a normal cell (2)?

Answer 3

(1) Bcl-2 resides in the inner mitochondrial membrane, maintaining the membrane’s integrity and thereby preventing leakage of cytochrome c into the cytoplasm where it activates caspases and triggers apoptosis.
(2) Bcl-2 binds to and inhibits Apaf-1 (apoptotic protease activating factor 1), which when activated, induces the activation of caspases and triggers the apoptosis pathway.

Question 4

Intrinsic (mitochondrial) pathway of apoptosis:

• Mechanism by which pathway is activated 2/2 cell injury or DNA damage?
• Mechanism by which cytochrome c activates apoptosis?

Answer 4

(1) Activation of pro-apoptotic genes (BAX, BAK)
(2) Bax, Bak form channels/pores in the mitochondrial membrane (increases permeability) that cause leakage of cytochrome c into the cytoplasm where it activates caspases and triggers apoptosis.

Cytochrome c activates caspase-9 (INITIATOR CASPASE), which in turn activates EFFECTOR CASPASES (proteases, endonucleases) that mediate the execution phase of apoptosis

• Proteases destroy the cytoskeleton.
• Endonucleases destroy the nucleus.

Question 5

Intrinsic pathway of apoptosis:

- Classically functional in which developmental process?

Answer 5

Tissue remodeling in embryogenesis

Question 6

BCL-2 gene mutation:

• Mechanism by which contributes to tumorigenesis?
• A/w what cancer?

Answer 6

BCL-2 overexpression leads to the over-inhibition of Apaf-1, which decreases caspase activation and the potential for apoptosis in the neoplastic cells. Tumor is desensitized to apoptosis.

BCL-2 overexpression is a/w FOLLICULAR LYMPHOMA.

Question 7

Extrinsic (receptor-ligand) pathway of apoptosis:

- 2 receptors involved?

Answer 7

Death receptors are cell surface receptors that transmit signals for apoptosis when bound by specific ligands.

(1) TNF receptor 1 (TNFR1)
(2) FAS death receptor (CD95)

Question 8

Extrinsic (receptor-ligand) pathway of apoptosis - Signaling pathways:

• TNFR1?
• FAS (CD95)?

Answer 8

TNFR1:
- TNFα binding to TNFR1 activates initiator caspases (caspase-8 and caspase-10), which then activate effector caspases (proteases and endonucleases) that mediate the execution phase of apoptosis, leading to cell death.

FAS (CD95):

• Activate the extrinsic pathway of apoptosis through a cytoplasmic component known as the death domain.
• Upon Fas ligand (FasL) binding, FAS receptors trimerize, allowing their cytoplasmic death domains to form a binding site for an adaptor protein known as Fas-associated death domain (FADD).
• Receptor-bound FADD activates initiator caspases (caspase-8 and caspase-10), which then activate effector caspases (proteases and endonucleases) that mediate the execution phase of apoptosis, leading to cell death.

Question 9

FAS/FasL signaling:

• Functional unit of FAS receptor?
• A/w what immunologic process?
• Consequence of FAS (CD95) mutation or dysfunctional FAS-FasL interaction?

Answer 9

Functional unit of FAS receptor is cytoplasmic component (death domain).

FAS/FasL signaling pathway:

• Especially important in the negative selection of thymocytes, the immunologic process responsible for the clonal deletion of autoreactive T cells.
• Mutations in FAS, or dysfunctional Fas-FasL interactions, results in the excessive accumulation of autoreactive T cells and the development of autoimmune disease (e.g., SLE).

Question 10

Cytotoxic CD8+ T cell-mediated pathway of apoptosis:

- Mechanism by which pathway is activated 2/2 virally-infected cells or tumor cells?

Answer 10

(1) Foreign antigen expressed on the surface of infected host cells activate CD8+ T cells to secrete PERFORIN and GRANZYME B.
(2) Perforin creates pores in the plasma membrane of the infected cell, through which granzyme B enters the infected cell.
(3) Granzyme B cleaves initiates a caspase cascade that activates the extrinsic pathway (caspase-8 and caspase-10).

Question 11

DNA endonucleases:

• DNA site where endonucleases activated during apoptosis act?
• Base-pair size of the DNA fragments that they produce?
• Laboratory technique used as a sensitive indicator of apoptosis?

Answer 11

Endonucleases cleave DNA at INTERNUCLEOSOMAL REGIONS, yielding 180-bp fragments.

DNA laddering - During karyorrhexis (fragmentation), endonucleases cleave DNA at internucleosomal regions, yielding 180-bp fragments.

Question 12

Acetaminophen poisoning:

• Cytochrome P450 isoenzyme involved in the metabolism of acetaminophen at toxic levels?
• Toxic intermediate of acetaminophen metabolism at toxic levels?
• Where does liver necrosis initially occur (zone)?
• Mechanism by which normal levels of acetaminophen cause poisoning in alcoholics?

Answer 12

Toxic levels of acetaminophen metabolized by CYP2EI to toxic intermediate called NAPQI

Liver necrosis occurs initially around the central venules (zone3)

Alcohol induces synthesis of CYP2EI isoenzyme. Higher percentage of acetaminophen metabolized by CYPE2I, leading to higher levels of NAPQI (toxic metabolite).

Question 13

Acetaminophen poisoning:

• Treatment?
• Mechanism of treatment?

Answer 13

N-acetylcysteine

• precursor for the synthesis of glutathione. Replenishes glutathione levels.
• Decreases NAPQI levels and promotes its excretion in the kidneys.

Question 14

Carbon tetrachloride (CCl4):

• Mechanism by which causes free radical injury?
• Mechanism by which causes fatty liver?

Answer 14

CCl4 is an organic solvent used in the dry cleaning industry.

CCl4 is metabolized to CCl3 (free radical) by the cytochrome P450 system in the sER in the liver.

Accumulation of CCl3 in hepatocytes results in cell injury, including swelling of the rER, which causes ribosomes to dissociate, leading to reduced protein synthesis. Reduced synthesis of apolipoproteins (fatty acid carriers) leads to fatty change in the liver.

Question 15

Premature neonates with respiratory distress syndrome:

• Risk of developing what 2 conditions?
• Why?

Answer 15

Neonates with RDS are treated with artificial surfactant and O2 therapy.

O2-derived free radicals from O2 therapy may cause oxygen toxicity.

Superoxide (O2•-) free radicals may destroy the retinal cells and retinal vessels (RETINOPATHY OF PREMATURITY) and may damage the airways/lungs (BRONCHOPULMONARY DYSPLASIA).

Question 16

Iron poisoning:

• Mechanism by which iron poisoning generates free radicals?
• Signs/symptoms of acute poisoning?
• Signs/symptoms of chronic poisoning?
• Treatment?

Answer 16

Fenton reaction:
(Fe2+) + (H2O2) –> (Fe3+) + (OH-) + (OH•)

Acute iron poisoning: Free radicals target and damage the GI tract (lipid peroxidation of gastric mucosal cells), causing gastric bleeding, bloody diarrhea, and vomiting.

Chronic iron poisoning:
(Fe3+) + 3H2O –> Fe(OH)3 + 3H+
- Hydration of Fe3+ generates H+, causing metabolic acidosis. Chronic iron poisoning also causes pyloric scarring, which leads to GI obstruction.

Treatment: Iron chelation and dialysis

Question 17

Iron poisoning:

• IV chelator?
• PO chelator?

Answer 17

IV deferoxamine

PO deferasirox

Question 18

Hypoxia/ischemia:

• Cell types in brain susceptible to hypoxia/ischemia (3)?
• Sites in brain susceptible to hypoxia/ischemia (2)?

Answer 18

• Pyramidal cells of the hippocampus
• Purkinje cells in the cerebellum
• Neurons in the cerebral cortex

Watershed areas:

• Boundary area between anterior cerebral artery (ACA) and middle cerebral artery (MCA)
• Boundary area between middle cerebral artery (MCA) and posterior cerebral artery (PCA)

Question 19

Hypoxia/ischemia:

- Sites in colon susceptible to hypoxia/ischemia (2)?

Answer 19

(1) Splenic flexure (watershed area between the distribution of the superior mesenteric artery [SMA] and the inferior mesenteric artery [IMA]) –> Ischemic colitis
(2) Rectum

Question 20

Hypoxia/ischemia:

- Site in heart susceptible to hypoxia/ischemia? Why?

Answer 20

Subendocardium (particularly in the left ventricle).

Coronary vessels penetrate the epicardial surface. Therefore, the subendocardial tissues receive the LEAST amount of O2.

Question 21

Hypoxia/ischemia:

- Sites in kidney susceptible to hypoxia/ischemia (2)?

Answer 21

Straight portion of the proximal tubule

Thick ascending limb of the loop of Henle

Question 22

Hypoxia/ischemia:

- Site in liver susceptible to hypoxia/ischemia? Why?

Answer 22

Hepatocytes around the central venules (zone III)

In the portal triads, hepatic artery tributaries carrying oxygenated blood and portal vein tributaries carrying deoxygenated blood empty their blood into liver sinusoids (mixed oxygenated and deoxygenated blood), which drain blood into the central venules, which empty into the IVC. Hepatocytes closest to the portal triads (zone I) receive the most oxygen and nutrients, whereas those furthest from the portal triads (zone III around the central venules) receive the least amount of oxygen and nutrients. Production of free radicals from drugs (e.g., acetaminophen), tissue HYPOXIA, and alcohol-related fatty change of the liver initially damage hepatocytes in zone III, which, owing to their lack of O2, are more susceptible to injury.