Pathoma Chapter 1B Flashcards
What happens to Bcl2 in the intrinsic mitochondrial pathway?
Cellular injury, DNA damage, or loss of hormonal stimulation leads to inactivation of Bcl2
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.
What is the extrinsic receptor-ligand pathway?
FAS ligand binds to (CD95) FAS death receptor and TNF binds TNF receptor (both activate caspases)
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
Cytotoxic CD8+ T cell-mediated pathway releases what?
perforins and granzyme ex CD8+ T-cell killing of virally infected cells is an example.
Perforins
secreted by CD8+ T cell create pores in membrane of target cell
Granzyme
secreted from CD8+ T cell enters pores and activates caspases
Free radicals are what?
chemical species with an unpaired electron in their outer orbit.
When does physiologic generation of free radicals occur?
it occurs during oxidative phosphorylation
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.)
Pathologic generation of free radicals arises with?
Ionizing radiation, inflammation, metals, drugs and chemicals
Ionizing radiation and Pathologic generation of free radicals
water hydrolyzed to hydroxyl free radical
Inflammation and Pathologic generation of free radicals
NADPH oxidase generates superoxide ions during oxygen dependent killing by neutrophils.
Metals and Pathologic generation of free radicals
(e.g., copper and iron) Fe generates hydroxyl free radicals (Fenton reaction).
Drugs and chemicals and Pathologic generation of free radicals
P450 system of liver metabolizes drugs (e.g acetaminophen), generating free radicals.
Free radicals cause
cellular injury via peroxidation of lipids and oxidation of DNA and proteins; DNA damage is implicated in aging and oncogenesis.
Elimination of free radicals occurs via what?
Antioxidants, Enzymes, Metal carrier proteins
Elimination of free radicals via Antioxidants
glutathione and vitamins A , C, and E
Elimination of free radicals via Enzymes
SOD, glutathione peroxidase, catalase
Superoxide dismutase
(in mitochondria) superoxide (O2.?>H202)
Glutathione peroxidase
(in mitochondria) GSH + free radical GSSH and H202
Catalase
(in peroxisomes) H2O2 ?> O2 and H202
Elimination of free radicals via Metal carrier proteins
transferrin and ceruloplasmin
Free Radical Injury
Carbon tetrachloride (CCl4) and Reperfusion Injury
Carbon tetrachloride - What is it used for?
Organic solvent used in the dry cleaning industry
How is CCl4 metabolized?
Converted to CC14 free radicals by P450 system of hepatocytes
CCl4 results in what?
cell injury with swelling of RER, ribosomes detach, impairing protein synthesis. Decreased apolipoproteins lead to fatty change in the liver
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
What is an amyloid?
It is a misfolded protein that deposits in the extracellular space, thereby damaging tissues.
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,
What is primary amyloidosis?
It is systemic deposition of AL amyloid, which is derived from immunoglobulin light chain
What is primary amyloidosis associated with?
plasma cell dyscrasias (e.g multiple myeloma)
Secondary amyloidosis is?
systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA).
What is SAA?
It is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean Fever (FMF).
What is FMF due to?
a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin.
What does FMF present with?
episodes of fever and acute serosal inflammation
FMF can mimic what?
appendicitis, arthritis, or myocardial infarction
How does FMF result in AA amyloid deposition in tissues?
High SAA during attacks deposits as AA amyloid in tissues
What is the most common organ involved in systemic amyloidosis?
kidney
What are the clinical findings of systemic amyloidosis?
Nephrotic syndrome, Restrictive cardiomyopathy or arrhythmia, Tongue enlargement, malabsorption, and hepatosplenomegaly
Diagnosis of systemic amyloidosis requires what?
tissue biopsy, Abdominal fat pad and rectum are easily accessible biopsy targets.
Damaged organs of systemic amyloidosis must be…
transplanted. Amyloid cannot be removed.
What is localized amyloidosis?
Amyloid deposition that is usually localized to a single organ
What is senile cardiac amyloidosis?
Non-mutated serum transthyretin deposits in the heart. Usually asymptomatic; present in 25% of individuals > 80 years of age
Familial amyloid cardiomyopathy
Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy, 5% of African Americans carry the mutated gene.
Non-insulin-dependent diabetes mellitus (type II)
Anylin (derived from insulin) deposits in the islets of the pancreas,
Alzheimer disease
amyloid beta (derived from J-amyloid precursor protein) deposits in the brain forming amyloid plaques
Gene for J-APP is present on…
chromosome 21.
Downs syndrome and Alzheimers?
Most individuals with Down syndrome (trisomy 21) develop Alzheimer disease by the age of 40 (early-onset).
Dialysis-associated amyloidosis
B-microglobulin deposits in joints,
Medullary carcinoma of the thyroid
Calcitonin (produced by tumor cells) deposits within the tumor (‘tumor cells in an amyloid background’).
