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7. Kane lecture 11/15 and on
BrownMed
157
Business
Undergraduate 4
11/15/2010

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Term
what leads to production of inflammatory mediators? (4)
Definition
trauma, foreign body, infectious agents, necrosis (toxic, ischemic)
Term
2 inflammatory mediator groups
Definition
chemical mediators and chemotactic factors
Term
chemical mediators (3)
Definition
changes in blood flow > heat, redness. pain. increased permeability > swelling
Term
chemotactic factors > > (2)
Definition
recruitment and stimulation of inflammatory cells > acute inflammation and chronic inflammation
Term
acute inflammation cells (3)
Definition
neutrophils, mast cells, platelets
Term
chronic inflammation cells (3)
Definition
macrophages, lymphocytes, plasma cells
Term
inflammation is a _ host response
Definition
beneficial
Term
2 major components of inflammation
Definition
vascular reaction and mobilization of cells
Term
vascular reaction and mobilization of cells are mediated by _ derived from _ (2)
Definition
chemical messengers, plasma proteins or host cells
Term
t/f usually the outcome of acute inflammation is successful in killing and eliminating the invading microorganism
Definition
true. it usually resolves and the tissue returns to normal or is repaired.
Term
inflammation is one component of
Definition
the innate immune response
Term
wound healing cells (2)
Definition
fibroblasts, connective tissue matrix - structural and adhesive proteins
Term
connective tissue matrix made from
Definition
elastic fibers, collagen fibers and proteoglycans
Term
another name for a neutrophil
Definition
polymorphonuclear leukocyte
Term
the most important chemical mediators of inflammation are derived from (2)
Definition
either a cellular source or from the plasma
Term
2 types of chemical mediators derived from a cellular source
Definition
preformed mediators in secretory granules, newly synthesized mediators
Term
preformed mediators of inflammation in secretory granules (derived from a cellular source) (3)
Definition
histamine, serotonin, lysosomal enzymes
Term
newly synthesized chemical mediators of inflammation from a cellular source (6)
Definition
prostaglandins, leukotrienes, platelet-activating factors, activated oxygen species, nitric oxide, cytokines
Term
source of histamine
Definition
mast cells, basophils, platelets
Term
source of serotonin
Definition
platelets
Term
source of lysosomal enzymes
Definition
neutrophils, macrophages
Term
source of prostaglandins
Definition
all leukocytes, platelets, EC
Term
source of leukotrienes
Definition
all leukocytes
Term
source of platelet-activating factors
Definition
all leukocytes, EC
Term
source of activated oxygen species
Definition
all leukocytes
Term
source of nitric oxide
Definition
macrophages
Term
source of cytokines
Definition
lymphocytes, macrophages, EC
Term
major source of chemical mediators to the plasma
Definition
liver
Term
two types of plasma chemical mediators of inflammation
Definition
complement activation, factor XII (Hageman factor) activation
Term
(2) factor xii (hageman factor) activation
Definition
kinin system, coagulation/fibrinolysis system
Term
(4) complement activation
Definition
anaphylatoxins (bind neutrophils and macrophages): C3a, C5a. C3b (phagocytosis/opsonization), C5b-9 (MAC)
Term
the chemical mediators that are derived from plasma circulate as / act by
Definition
inactive precursors, activated by a cascad of proteases, and act by bindingto specific receptors on target cells
Term
plasma mediators are fast/slow
Definition
fast - don'tneed to be produced, just activted. have short lifespan
Term
activated factor XII =
Definition
Factor XIIa > kinin cascade (bradykinin, kallikrin>plasmin>complement cascade) and clotting cascade (thrombin>fibrin)
Term
bradykinin
Definition
causes increased vascular permeability and pain. created from HMWK in the kinin cascade of the kinin system
Term
a blood clot consists of
Definition
RBCs and platelets in a mesh of fibrin
Term
functions of plasmin in inflammation
Definition
cleaves and activates C3. results in clot lysis and release of fibrin-split products.
Term
fibrin split products
Definition
result in increased vascular permeability. are made because of plasmin.
Term
general principles of clotting cascade and fibrinolysis
Definition
amplification of response by positive feedback loops. release of secondary mediators that may dampen the response.
Term
3 pthways that activate the complement system
Definition
classical pathwy - IgG or IgM + C1. alternative pathway - direct activation of cell wall components of bacteria, fungi or toxins (cobra venom), lectin pathway - mannose binding lectin attaches to mannose on bacterial cell wall +C1
Term
bacteria that have evolved blocks to stop MAC (4)
Definition
salmonella, meningococcus, gonococcus, streptococcus (has C3b peptidase instead of physical block)
Term
resistance to phagocytosis example
Definition
pneumococcus - polysaccharide capsule
Term
resistance to complement activation examples (2)
Definition
menngitis- sialic acid inhibits C3 and C5 convertases. streptococcus - M protein blcks C3 and C3b binding
Term
release of histamine is triggered by
Definition
trauma, cold, igE receptors, C3a C5a, histamine-releasing actors, cytoknes IL1 IL8 and chemokines
Term
functions f histamine
Definition
vasodilation, increase vascular pereability,bnd to H1 reeptors in vessel wall. acts locally, quickly degradded.
Term
release o serotonin triggered by / function
Definition
thrombn, exposed subendothelial collagen, PAF Platelet Activating Factor / increases vascular permeabiliy like histamine and fibrin splits
Term
arachidonic acid metabolites (2)
Definition
prostaglandins, leukotrienes
Term
PAF
Definition
rapidly synthesized by mast cells, neutrophils, platelets, macrophages, endothelial cells. increases vascular permeability like serotonin, histamine and fibrin splits. also activates platelets and leukocyte adhesion, chemotaxis, and activation
Term
arachidonic acid cascade / major categories of these drugs
Definition
major target for drugs that alleviate pain and suppress inflammation. 1. corticosteroids 2. aspirin and NSAIDs 3. selective COX2 inhibitors
Term
what do corticosteroids do
Definition
inhibit phospholipase
Term
what do aspirin and non-steroidal anti-inflammatory drugs do
Definition
inhbit COX1 (constitutive) and COX2 (inducible) > inhibit prostaglandins specifically
Term
selective cox2 inhibitors
Definition
fewer gastric side effects, possible prothrombotic effect > inhibit prostaglandins specifically
Term
see diagram p. 13
Definition
Term
prostaglandin metabolits
Definition
PGI2 nd TXA2, lead to PGD2 and PGE2, vasodilation and increased vascular permeability
Term
lipoxins
Definition
anti inflammatory (inhibit neutrophil adhesion and chemotaxis). come from arachidonic acid but not the COX pathway ( came from lipoxygenase pathway)
Term
phospholipase A2
Definition
enzyme activity issupressed by steroids. isthe rate limiting enzyme for arachidonic acid synthesis
Term
CoX2
Definition
ajor target for anti inflammatory drugs
Term
the next gneration of anti inflammatory drugs
Definition
lipoxin analogues
Term
there is cell and tissue _ in expression of enzymes in synthesis of prostaglandins and leukotrienes
Definition
specificity
Term
phospholipase activation
Definition
PL A2 has a calcium channel that pulls PLs off cell membranes
Term
5 functions of arachidonic acid metabolites
Definition
vasoconstriction (TXA2, LTC4, LTD4, LTE4), vasodilation (PGI2, PGD2, PGE2) [die], incrased vascular permeability (LTC4, LTD4, LTE4), chemotaxis (LTB4, HETE), inhibition of chemotaxis (lipoxins)
Term
arachidonic acid metabolites fast/slow, act where
Definition
are rapidly synthesized, act locally at the site of synthesis, and are rapidly broken down
Term
prostaglandins and leukotrienes bind to
Definition
G-protein coupled receptors expressed on the surface of inflammatory cells. activation of these receptors is responsible for most of the key steps involved in acute inflammation.
Term
cytokines (2) / pathway (4)
Definition
IL-1, TNF-alpha. in the class of newly synthesized cell-derived mediators. / bacterial products, Ag-Ab complexes, toxins, physical injury > macrophage activation > IL1 and TNFa catalyze 1. leukocytes > cytokine secretion, 2. endothelial cells > cytokine secretion and leukocyte adhesion, 3. fibroblasts > wound healing, 4. systemic effects (fever, sleep)
Term
macrophages
Definition
are critical cells in acute inflammation. they mediate the transition between innate and adaptive immunity and also initiate tissue repair and wound healing.
Term
molecules produced in active macrophages
Definition
phagocyte oxidase> ROS, iNOS> NO, cytokines (TNF, IL12), INF-gamma > fibroblast growth factors+ angiogenic factors+ metalloproteinases, increased MHC molecules and costimulators
Term
effector functions of activated macrophages
Definition
ROS+NO= killing of microbes, cytokines= inflammation and enhanced adaptive immunity, fibroblast gf+angiogenic factors+ metalloproteinases=tissue remodeling, increased MHC molecules and costimulators= enhanced antigen presentation.
Term
toll-like receptors
Definition
different ones are activated by different microbes. PAMPs bind to them.
Term
DAMPs
Definition
damage associated molecular patterns: necrosis produces them > acute inflammation
Term
gram positive bacteria / example
Definition
stains purple on gram staining because peptidoglycan in the cell wall is on the outside and thus accessible to stain. / staphylococcus
Term
gram negative bacteria / what is released
Definition
stain pink / lipopolysaccharides (LPS) are released from gram negative bacteria when they replicate and invade into tissues.
Term
chemokines examples (6)
Definition
IL-8, MCP-1, MIP-1alpha, RANTES, eotoxin, lymphotactin
Term
chemokines
Definition
a family of small cytokines or proteins that are characterized by the presence of four cysteine residues in conserved domains that are important in their shape. all function to induce chemotaxis in nearby responsive cells = chemotactic cytokines. attract neutrophils, monocytes, basophils, eosinophils, and lymphocytes to the sites of inflammation.
Term
IL-8
Definition
chemotactic for neutrophils
Term
RANTES
Definition
Regulated upon Activation, Normal T cell Expressed and Secreted. released by CTLs and is a potent chemoattractant factor for monocytes and T cells.
Term
NO
Definition
rapidly synthesized by endothelial cells and activated macrophages. local mediator for vasodilation, reduced leukocyte adhesion, reduced platelet adhesion. together with ROS can kill bacteria. see diagram p. 18
Term
histologic landmark of acute inflammation
Definition
emigration of leukocytes (neutrophils, then macrophages) to the site of injury or infection
Term
etiologic agents of acute inflammation (5)
Definition
microorganisms (bacteria), physical agents (burns, radiation, trauma), chemical agents and microbial toxins, necrotic tissue, immunologic reactions (Ag-Ab complexes)
Term
stages of acute inflammation (3)
Definition
vascular changes, cellular responses: leukocyte recruitment and activation, resolution or repair
Term
vascular changes in acute inflammation (4)
Definition
vasodilation and increased blood flow, increased vascular permeability (edema) due to leakage of fluid and increased hydrostatic pressure, slowing of blood flow (stasis) due to increased viscosity, margination of leukocytes
Term
cellular responses (leukocyte recruitment and activation) in acute inflammation (4)
Definition
adhesion and transmigration, chemotaxis, activation, phagocytosis and killing
Term
what makes dilation of blood vessels remarkable in acute inflammation?
Definition
they are capillaries, so don't dilate and contract due to smooth muscle
Term
chemotaxis
Definition
the unidirectional movement of cells along a chemical gradient (in the interstitium)
Term
heat and redness at sites of acute inflammation
Definition
= vasodilation and increased blood flow
Term
key mediators of vasodilation (3)
Definition
prostaglandins, histamine, NO
Term
swelling and pain
Definition
= increased vascular permeability > accumulation of protein-rich fluid in the interstitium
Term
key mediators of increased vascular permeability (5)
Definition
histamine, bradykinin, C3a/5a, leukotrienes, PAF
Term
key mediators of pain (2)
Definition
bradykinin, prostaglandins
Term
defects in cellular responses in acute inflammation (3)
Definition
acquired - diabetes, alcoholism. congenital - rare.
Term
adhesion and transmigration (3)
Definition
attracting leukocytes and delivering them into the surrounding tissue. = extravasation: 1. margination, rolling and adhesion 2. transmigration or diapedesis, 3. migration in the interstitial tissues along a chemotactic gradient
Term
integrins on leukocytes
Definition
after rolling they enter a high-affinity state and bind to the integrin ligand (ICAM-1) on the vessel endothelium. = adhesion
Term
PECAM-1 and CD31
Definition
CD31 = protein on leukocyte that helps diapedesis, PECAM-1 = protein in the intercellular endothelial junction that helps diapedesis
Term
slowing of blood flow in dilated vessels causes
Definition
stasis and margination of leukocytes on the surface of endothelial cells
Term
selectins
Definition
stuff on endothelium that allows rolling of leukocytes on endothelium
Term
sialyl-lewis x
Definition
receptors on leukocytes - bind the selectins on the endothelium to permit rolling
Term
P-selectin is re-distributed to the surface of endothelial cells by (3) / how long does this take
Definition
local inflammatory mediators - histamine, thrombin and PAF / this occurs within minutes
Term
cytokines (IL-1 and TNF-alpha) are synthesized by macrophages when? and _ are released locally by macrophages, mast cells, and endothelial cells activated by cytokines.
Definition
after 1-2 hours into acute inflammation. / chemokines
Term
cytokines upregulate expression of
Definition
E-selectin, ICAM-1 = endothelial cell adhesion molecules
Term
chemokines
Definition
promote firm adhesion by making integrins high affinity (increasing the avidity of integrins). promote transmigration.
Term
transmigration
Definition
involves binding of CD31 on leukocytes to PECAM-1 in the intercellular junction. leukocytes secrete proteases locally to facilitate their migration across the basement membrane and into the extravascular CT.
Term
most important chemotactic factors in acute inflammation (3)
Definition
C5a/leukotriene B4, chemokines (IL8, MCP-1), bacterial products (N-formyl-methionyl peptides)
Term
general timeline of first three days of acute inflammation
Definition
edema peaks halfway through day 1. neutrophils peak at day 1. monocytes/macrophages peak at day 2 and make the transition to wound healing
Term
leukocyte activation is triggered by
Definition
binding of ligands to surface receptors of inflammatory cells. then production of ROS and phagocytosis of microbe into phagosome activates leukocytes.
Term
protein kinase C
Definition
creates an influx of calcium
Term
see diagram on p. 25 of inflammation
Definition
Term
when microbe is phagocytosed, what happens
Definition
it fuses with a lysosome, where the acidic pH starts breaking it down. then ROIs and NO kill it.
Term
chronic granulomatous disease
Definition
when NO/ROIs don't kill the microbe after it is phagocytosed and fuses with a lysosome
Term
2 mechanisms used to kill bacteria
Definition
oxygen-dependent and oxygen-independent
Term
oxygen-dependent bacteria killing
Definition
external COX > free radical within phagocytic vacuole
Term
oxygen-independent bacteria killing (5)
Definition
lysozyme, lactoferrin, bacterial permeability protein, major basic protein (eosinophils), defensins >>> make pores for lysis.
Term
after microbes are killed, they are degraded by
Definition
acidic hydrolases within phagolysosomes
Term
what has potential to damage host tissue? (4)
Definition
proteases, lysosomal enzymes, reactive oxygen metabolites and NO released from leukocytes
Term
abscess
Definition
dead tissue, dead neutrophils, and dead bacteria producing pus
Term
termination of acute inflammation (3)
Definition
breakdown of chemical mediators, restoration of normal vascular permeability, synthesis and release of endogenous anti-inflammatory agents
Term
endogenous anti-inflammatory agents (3)
Definition
lipoxins (arachidonic acid metabolites released by macrophages in late stages of inflammation), IL-10 (cytokine), TGF-beta (transforming growth factor beta)
Term
tissue damage is healed by
Definition
regeneration if CT framework remains intact; fibrosis or scarring in organs that cannot regenerate
Term
acute bacterial pneumonia
Definition
edema, accumulation of neutrophils in alveolar spaces
Term
key mediators responsible for acute inflammation? (7)
Definition
vasodilation, increased vascular permeability, chemotaxis, and leukocyte activation, pain, fever, tissue damage
Term
defects in leukocyte adhesion
Definition
(integrins LFA-1 and Mac-1 or sialyl-lewis x) > repeated bacterial childhood infections
Term
defects in leukocyte killing
Definition
(deficiency in NADPH oxidase subunits) > severe infections that do not resolve and cause granulomas (chronic granulomatous disease)
Term
defects in phagolysosome fusion
Definition
impaired innate and acquired immunity (Chediak-Higashi syndrome)
Term
acquired defects in acute inflammation (4)
Definition
secondary to chemo, diabetes, malnutrition, sepsis (severe systemic inflammation)
Term
excess fluid and dead neutrophils and stuff is cleaned by
Definition
lymphatics
Term
(2) cause fibrosis instead of resolution. t/f acute bacterial pneumonia resolves instead of fibroses
Definition
abscess, chronic inflammation / true
Term
acute inflammation is effective against (2)
Definition
extracellular bacteria, lytic viruses
Term
microorganisms that do not elicit acute inflammation / are controlled by
Definition
intracellular bacteria, non-lytic or persistent viruses / granulomatous inflammation
Term
normal functions of macrophages (3)
Definition
daily housekeeping (soot in lungs), cleaning up cell debris, killing microorganisms
Term
resident macrophages
Definition
dust cells, osteoclasts, kupffer cells, microglia
Term
activated macrophage
Definition
bigger, more diffuse contents and feet coming out. increased metabolic activity and lysosomal enzymes
Term
what activates macrophages
Definition
cytokine IFN gamma from activated T cell; also innate immunity like endotoxin, fibronectin, chemical mediators (TNF alpha)
Term
granuloma
Definition
cluster or aggregate of activated macrophages (multinucleated giant cells)
Term
activated macrophages screte a range of cytokines (5)
Definition
IL1beta, TNFa, IL6, CXCL8, IL12
Term
IL12
Definition
activates NK cells, induces the differentiation of CD4 t cells into TH1 cells
Term
CXCL8
Definition
chemotactic factor recruits neutrophils, basophils, and t cells to site of infection
Term
IL6
Definition
lymphocyte activation, increased antibody production > fever and systemic acute-phase protein production
Term
TNFa
Definition
increases vascular permeability and activates endothelium > 1. increased entry of IgG, complement, and cells to tissues and 2. increased fluid drainage to lymph nodes >> fever, shock, mobilization of metabolites
Term
IL1beta
Definition
activates vascular endothelium, activates lymphocytes, local tissue destruction increases access of effector cells >>> fever + production of IL6 (>antibodies)
Term
common properties of etiologic agents of granulomatous inflammation
Definition
foreign or endogenous materials that are poorly degradable, irritating, and persistent in the body for several weeks up to many years
Term
granulomatous inflammation is frequently potentiated by
Definition
an immune response to the stimulus, usually cell-mediated immunity
Term
examples of etiologic agents of granulomatous inflammation (5)
Definition
sutures (exogenous), keratin/lipids (endogenous materials), antigenic exogenous metals (beryllium), infectious agents (MYCOBACTERIUM TUBERCULOSIS), sarcoidosis (mechanism unknown)
Term
acid-fast bacilli
Definition
infection with mycobacterium tb
Term
host defenses against mycobacteria include (7)
Definition
TNF, IFN gamma, ROS, NO, Th1 (CD4 + T lymphocytes), activated macrophages. LOTS OF DESTRUCTION
Term
why don't dust cells kill mycobacteria
Definition
because they replicate within the phagosomes. phagosomes spread through lymph to blodd to spleen, marrow etc. = bacteremia
Term
what causes tuberculin positivity (hypersensitivity)
Definition
sensitized Th1 cells
Term
in granulomatous inflammation, infected macrophages produce / what kills mycobacteria
Definition
cytokines to recruit t cells > Th1 release cytokines to activate infected macrophages: free radicals and NO help to kill mycobacteria
Term
caseous necrosis
Definition
histologic appearance of NO, ROS and TNF all killing the infected macrophages in TB (lungs+kidneys)
Term
in most cases of TB
Definition
the immune system is succesfful and the infection remains latent
Term
coin lesions
Definition
nodules of healed, fibrosed, calcified granulomas. can be detected on chest xray.
Term
isoniazid
Definition
drug to treat TB through TNF response. (doesn't work if you have rheumatoid arthritis and are taking anti-TNF meds)
Term
HIV
Definition
kills CD4 T cells
Term
areas with most TB (3)
Definition
sub-saharan africa, SE asia, western pacific
Term
if you get a positive PPD test, what are the next steps in diagnosing TB?
Definition
use PCR machine with your spit. takes less than 2 hours
Term
host factors that favor reactivation or reinfection of TB (4)
Definition
HIV, exogenous corticosteroids, advanced age, malnutrition
Term
miliary tb
Definition
caused by massive hematogenous dissemination = progressive primary or secondary tb with low immunity. (spleen and liver)
Term
hallmark of CHRONIC inflammation
Definition
dense infiltration of tissues with lymphocytes, plasma cells, and macrophages.
Term
reciprocal interaction between lymphocytes and macrophages that prolong their activation (in chronic inflammation) via
Definition
release of INF gamma and IL 12, respectively
Term
"alternatively activated" macrophages in chronic inflammation (M2) release
Definition
TGF beta and other mediators that stimulate fibrosis
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