MoD Flashcards
BCL-2 function
Main anti-apoptotic protein
Bim, Bid, Bad function
BH3 proteins: activate Bax/Bak channels (cause loss of cytochrome C, activation of capsases), also block BCL-2/BCL-X
Describe the extracellular apoptotic pathway
FasL (on T cells) binds to Fas, causing activation of “death receptors” in TNF family, leading to activation of caspases that degrade structural components of nuclear matrix. Fas can also activated Bid, inducing the intrinsic pathway.
Define Pyknosis. What broad change is it associated with?
Shrunken, hyper chromatic nucleus; necrosis
Define Karyolysis. What broad change is it associated with?
Fading of the nucleus; necrosis
Define Karyorrhexis. What broad change is it associated with?
Fragmentation of the nucleus; necrosis
List all changes associated with irreversible cell injury
Karyolysis, pyknosis, karyorrhexis, myelin figures, dilation of mitochondria (last 2 on EM)
What type of cellular adaptation precludes cell division? Give examples
Hypertrophy; uterine changes during pregnancy, cardiac myocytes (response to incr. workload)
What can cause atrophy? Give examples
Decr. inn., blood flow, hormonal stimulation, workload, nutrition, incr. pressure; old brain
What can cause hyperplasia? Give examples
Incr. hormonal or GF stimuli; endometrial changes in response to estrogen and lactating breast
What type of necrosis is uniquely associated with TB?
Caseous necrosis
Give an example of Fat necrosis
Pancreas: lipases split triglycerides into fatty acids which react with calcium to undergo saponification
Describe the mechanism of reperfusion injury
Restoration of blood flow causes surge in ROS and nitrogen, also inflammation (d/t hypoxic tissues expressing cytokines and adhesion molecules) with activation of the complement system
Describe abnormal intracellular accumulations seen in reperfusion injury
Exogenous substances like minerals, infectious agents; abnormal synthesis or metabolism of endogenous substances like A1AT, Mallory’s hyaline, neurofibrillary tangles in Alzheimers, amyloidosis
Describe the effect of mercuric chloride on GI intestinal cells
Incr. membrane permeability; can cause leakage of enzymes
Intracellular accumulations associated with hepatic steatosis
Triglycerides in hepatocytes
Intracellular accumulations associated with proteinuria
Protein droplets in tubules
Intracellular accumulations associated with A1AT deficiency
A1AT globules in liver
Diseases and deposition areas associated with “metastatic calcification”
Endocrine diseases (e.g. hypercalcemia caused by renal disease or parathyroid excess); areas of acid secretion like lung, kidney, stomach, pulm veins and systemic arteries
Gross and histologic hallmarks of acute inflammation
Edema; neutrophils
Phospholipase A2 function
Cleaves arachidonic acid from phospholipid cell membrane
PGI2 function
Vasodilation, incr. vasc permeability, pain (peripheral nerve ending sensitization), decr. platelet aggregation, “maintain GFR”
PGE2 function
Fever, vasodilation, incr. vasc permeability, pain (CNS + peripheral nerve ending sensitization), “maintain GFR,” “hyperalgesic”
Where does PGD2 come from? Effects?
Mast cells; vasodilation, incr. vasc permeability, attracts neutrophils
LTB4 function
Attracts and activates neutrophils, also neutrophil adhesion (up regulates interns on leukocytes) and transmigration, produces ROS, release of lysosomal enzyme
LTC4 function
Vasoconstriction, bronchospasm, incr. vasc permeability (via pericytes)
LTD4 function
Vasoconstriction, bronchospasm, incr. vasc permeability (via pericytes)
LTE4 function
Vasoconstriction, bronchospasm, incr. vasc permeability (via pericytes)
Cardinal signs of inflammation? What causes these? What are the mediators?
“Rubor and calor” (redness and pain), but also swelling (mediated by histamine); vasodilation; histamine, prostaglandins, bradykinin
Bradykinin function
Vasodilation, incr. vasc permeability, pain (via peripheral sensitization)
What 2 substances “do” pain
Bradykinin and prostaglandins (NOT histamine)
Where does histamine come from? What is histamine’s function?
Mast cells, basophils and platelets; vasodilation (by binding to H1 receptors), incr. vasc permeability (causes swelling associated with acute inflammation), release of P-selectin from W-P bodies (“rolling”), bronchospasm, mucous secretion, dermal edema (“wheal” formation)
Describe the mechanism behind fever incidence as it relates to acute inflammation
Pyrogens stimulate IL-1 and TNF release from macrophages, in turn stimulating COX in perivascular cells of the hypothalamus, leading to increased PGE2, which itself raises the temp set point
Where does IL-1 come from? What is IL-1’s function?
Dendritic cells and macrophages; one of the “main inflammatory cytokines” - fever (incr. COX activity), mast cell degranulation (acute inflammation), induces E-selectins (rolling), induces CAMs (adhesion), attracts leukocytes (by inducing chemokines), causes “left shift,” causes acute phase secretion of plasma proteins from liver, incr. serum amylase A (SAA), implicated in septic shock and toxic shock syndrome
What mediates vasodilation in acute inflammation?
NO
What mediates incr. vasc permeability specifically in acute inflammation?
Histamine
What stimuli can cause mast cell degranulation, as it pertains to acute inflammation?
C3a, C5a, IL-1, IL-8, cross-linking of surface IgE by antigen, neuropeptides (substance P), cold, heat, tissue trauma
Differentiate between lymphangitis and lymphadenitis
Lymphangitis is inflammation of the lymphatic system, lymphadenitis is inflammation of lymph nodes
Define transudate and give an example
Edema with low protein concentration and low specific gravity; ascites from liver damage
Define exudate and give an example
Edema with high protein concentration and high specific gravity; “empyema,” or pus in pleural spaces from pneumonia
What substances induce chemokines? What do chemokines do?
IL-1, TNF, microbial products like LPS; guide leukocytes through tissues
Alpha chemokines’ acronym? What cells do they attract?
CXC chemokines; neutrophils
Beta chemokines’ acronym? What cells do they attract?
CC chemokines; monocytes, basophils, eosinophils, lymphocytes
Gamma chemokines’ acronym? What cells do they attract?
C chemokines; lymphocytes
What are CXCR-4 and CCR-5? What disease are they associated with?
Chemokine receptors; HIV
IL-8 function
Attracts neutrophils (CXC chemokine), macrophage degranulation, prolongs inflammation (with macrophages)
What step of inflammation are selectins important to? List them all.
Rolling; P-selectin (from Weibel-Palade bodies/platelets and endothelial cells), L-selectin (from leukocytes), E-selectin (from endothelium, induced by TNF and IL-1)
What 4 chemical messengers bring neutrophils into the tissue during acute inflammation?
c5a, LTB4, IL-8 and bacterial products
What intracellular process is associated with Leukocyte activation?
Increase in cytosolic Ca++
Describe the final step in acute inflammation with respect to the main cell type associated, and its potential effects
Macrophages; resolution and healing via IL-10 and TGF-b, prolonged inflammation via IL-8, abscess, chronic inflammation
Characteristics of serous inflammation? Give an example
Non-infected fluid from blood plasma or mesothelial cells; blisters
Characteristics of fibrinous inflammation? Give an example
Fibrinous exudate from extracellular deposition of fibrin, can be converted to scar tissue; meninges or pericardium
Characteristics of suppurative inflammation? Give an example
Purulent (pus), characterized by neutrophils, liquefied debris of necrotic cells, edema, fluid; abscess (if surrounded by neutrophils, also can become walled off and invaded by connective tissue)
What can prolong the neutrophil phase of acute inflammation?
Bacterial infections
What cell type is associated with hypersensitivity reactions?
Eosinophils
What cell type is increased by viral infections?
Lymphocytes
List effects of the acute phase response in acute inflammation
Fever (via IL-1 and TNF), leukocytosis, “left shift” (also via IL-1 and TNF), incr. pulse and BP, decr. sweating, chills, rigor, release of liver plasma proteins such as hepcidin, SAA, CRP, fibrinogen (via IL-1, IL-6 and TNF)
Clinical signs of septic shock? How is SIRS different?
Hypotension, diffuse intravascular coagulation (DIC), insulin resistance/hyperglycemia, metabolic acidosis; SIRS has similar presentation but no infectious cause
List all cells associated with chronic inflammation
Macrophages (most important), lymphocytes, plasma cells (Ab production), eosinophils (immune reaction mediated by IgE), mast cells (release histamine and prostaglandin granules)
Describe bi-directional action of lymphocytes and macrophages
Macrophages present antigens; activated T lymphocytes secrete chemokines that recruit macrophages
2 ways macrophages get activated
By T cells; IL-4
Difference between caseating and non-caveating granuloma
Non-caseating lacks central necrosis
Defining characteristic of a granuloma
Presence of epithelioid histiocytes
Examples of non-caseating granulomas
Crohn’s, sarcoidosis, foreign body, beryllium exposure
Examples of caseating granulomas
TB, fungi
What effect does serum Amyloid A (SAA) have in vivo? What is it stimulated by?
Severe chronic inflammation; IL-1 and TNF
Major chronic inflammation cytokines (broadly)
IL-12, IFN-gamma
Major acute inflammation cytokines (broadly)
IL-1, TNF
IL-10 function
“Suppressive” - resolution after acute inflammation, inhibits Th1 cells (by antagonizing IFN-gamma)
IL-4 function
Ig class switching/helps B cells make Ab (esp IgG1, IgE), incr. MHC II, T cell growth/survival, macrophage activation?
IL-6 function
One of the “main inflammatory cytokines” - incr. sed rate (by stimulating CRP, fibrinogen from liver during the acute phase response), stimulates B cell differentiation into plasma cells (produce Ab), stimulates T cells differentiation into Th (secrete IL-17)
IL-12 function
Converts CD4+ helper T cell to Th1 subtype in granuloma formation
List examples of labile tissues
Skin (basal stem cells), GU, intestine (stem cells in crypts), bone marrow (CD34+ hematopoietic stem cells)
List examples of stable tissues
Liver, kidney, lung, pancreas, adrenals
List examples of permanent tissues
Myocardium, skeletal muscle, neurons
Describe process/features of initial step of repair (wound healing)
Granulation tissue: fibroblasts, capillaries (nutrients), myofibroblasts (pull wound together), collagen III deposition which is replaced by collagen I (via collagenase, requires zinc cofactor)
Within what time frame are macrophages usually present in wound healing?
3-7 days
Within what time frame are neutrophils usually present in wound healing?
24 hrs
Give examples of parenchymal fibrosis. What is the cause? What mediates this process?
Scleroderma, liver cirrhosis, constrictive pericarditis; repeated injurious stimuli; TGF-beta and myofibroblasts (for collagen deposition)
What can cause delayed wound healing?
Bacterial infection (prolongs inflammation), vitamin C deficiency (required fro hydroxylation of proline), copper deficiency (Lysyl oxidase), zinc deficiency (cofactor for collagenase reaction)
TGF-beta function
Resolution s/p acute inflammation; scar formation: production of collagen and fibronectin, inhibits metalloproteases (otherwise degrade ECM); “pleiotropic” (fx can be conditional)
IFN-a function
Viral infection, incr. MHC I expression
IFN-b function
Viral infection, incr. MHC I expression
What cells produce IFN-gamma? What is IFN-gamma’s function?
Leukocytes and Th1 cells; “macrophage activation” (converts them to epithelioid histiocytes in granuloma formation), vasodilation, chronic inflammation, anti-bacterial, incr. expression of MHC I & II, inhibits Th2 proliferation
What is the role of Serotonin specifically with respect to inflammation? What cells release Serotonin?
Vasoconstriction; platelets and neuroendocrine cells
What does MCP-1 stand for? What kind of molecule is it?
Monocyte chemoattractant protein; chemokine
FGF (fibroblast growth factor) function
Tissue repair (scar formation), angiogenesis, skeletal development
What cells produce hepatocyte growth factor? What is its function? What receptor does it bind?
Mesenchymal cells, fibroblasts; cell migration, hepatocyte survival; MET (remember it’s over expressed in some tumors)
PDGF function
Stimulates fibroblasts, endothelial cell and smooth m. proliferation; also stimulates wound contraction
What conditions induce VEGF? What type of receptor does it bind? What effect does this have?
Hypoxia; tyrosine kinase; VEGF-A angiogenesis, VEGF-B embryonic angiogenesis, VEGF-C, -D, -E all do angiogenesis and lymphatics
IL-17 function
Recruits neutrophils
Factors in intrinsic (clotting) pathway and test used to assess function
II, V, VII, IX, XI, XII, fibrinogen; PTT
Factors in extrinsic (clotting) pathway and test used to assess function
II, V, VII, X, fibrinogen; PT
Thrombin function
Converts fibrinogen into cross linked fibrin
Clotting factor deficiencies
Moderate to severe bleeding: V, VII, VIII, IX, X
Mild bleeding: XI
Thrombotic state: XII
Incompatible with life: Prothrombin
Plasmin function (with respect to blood)
Breaks down fibrin (fibrinolytic cascade)
D dimer
Indicative of thrombotic state (fibrinolytic product)
Suppurative = ?
Supppurative = purulent = pus = pyogenic = dead neutrophils + liquefactive necrosis
What area of the brain undergoes necrosis d/t herpes (“herpes encephalitis”)?
Temporal lobe destruction
Supurative inflammation examples
Staphylococcal pneumonia, tissue abscesses (also strep, klebsiella)
Mononuclear examples
Syphillis, tropheryma whipplei
Cytopathic-cytoproliferative reactions examples
HPV, herpes
Tissue necrosis examples
Clostridium perfringens, hep B
Chronic inflammation/scarring examples
Liver cirrhosis
Granulomatous inflammation examples
Schistosomiasis, (mycobacterium) TB
What disease and clinical finding is associated with a pneumocytis Jiroveci infection?
AIDS (CD4+ helper T cell count < 200); diffuse bilateral infiltrates on CXR (fungal inf)
Examples of Type III hypersensitivity diseases
SLE, rheumatoid arthritis, membranous glomerulonephritis
Examples of T-cell mediated cytotoxicity diseases
Graft (and maybe transplant) rejection, viral infections, tumor surveillance
Examples of type I hypersensitivity reactiosn
Asthma, hay fever
What can cause an elevated sed rate?
If > 100 only neoplasm or temporal arteritis, but also elevated in RA, SLE, chronic inflammation, Sickle Cell Disease (really all anemia), and if elevated in stroke/CAD patients prognosis is poorer
Neutropenia causes
Decr. production: cytotoxic drugs, radiation, (bone) marrow infiltrate
Decr. survival: Hypersplenism, incr. utilization
Decr. both: Megaloblastic anemia, drug reaction, infection, alcohol
Lymphocytosis causes
Infectious: Pertussis, Brucellosis, viruses, fungus, TB, syphillis
Neoplastic: CLL causes wicked high levels
Lymphocytopenia causes
Immunodeficiency (e.g. AIDS) or immunosuppression (e.g. drugs)
Eosinophilia causes
Parasites, allergy, tumors, drug reactions
Eosinopenia causes
Severe infection
Monocytosis causes
Post-splenectomy, hematologic malignancies, TB, syphillis, endocarditis
Monocytopenia causes
Aplastic anemia (decr. production of WBCs), hairy cell leukemia
Basophilia causes
Allergic disorder, myeloproliferative disorder, hypothyroidism
Basopenia causes
Hyperthyroidism (does it even exist?)
What can cause an eosinophilic leukemoid reaction?
Children with parasitic infections
Neutrophilic leukemoid reaction causes
Infection, hemolysis, hemorrhage, malignancy involving bone, burns, pregnancy
