2.5 Inflammation and adhesion Flashcards Preview

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Flashcards in 2.5 Inflammation and adhesion Deck (87):
1

Stimuli for Inflammation

infection,
truama,
physical chemical agents,
necrosis,
foreign bodies,
immune reactions (foreign and auto)

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features of inflammation

complex,
nonspecific,
mostly vascular and connective tissue reaction to injury,
migration of leukocytes,
systemic reactions,
closely linked to immune system,
coagulation system and repair process

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Goal of inflammation

to eliminate, dilute or wall off injurious agent, but can be very harmful

4

inflammation overlaps with

immunity,
coagulation,
repair

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host resistance is divided into

innate and adaptive immunity

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coagulation system is divided into

dual function of clotting factors and factors as mediators

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usually inflammation leads to

induction of repair and repair inhibits inflammation. But not always resulting in disease

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inflammation time course can be

acute or chronic (granulomatous)

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5 cardinal signs of acute inflammation

rubor, tumor, calor, dolor, functio laesa

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rubor

redness

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tumor

swelling

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calor

heat

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dolor

pain

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functio laesa

loss of fn

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cells of inflammation

neutorphil, basophil, platelet, eosinophil, monocyte/macrophage, lymphocyte, plasma cell

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neutrophil

poly or PMN (many lobed nucleus) seen in acute inflammation

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basophil

accute/allergic - dark granules

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platelet

acute

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eosinophil

chronic/allergic

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monocyte/macrophage

chronic - kidney shaped nucleus

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lymphocyte

chronic - little bigger than a red cell

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plasmacell

chronic - eccentric nucleus filled with mrna for Ig

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difference btw eosinophil and mast cell

eosinophil will be red granules and mast cell will be purpleish

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band form

immature neutrophil looks like a wll defined horse shoe - not normal to have lots - tells you there is overproduction

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other cells also important for inflammatory process

fibroblasts

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simple demonstration of inflammatory response

wheal and flare reaction

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first thing when you scrape arm

goes white due to vasoconstriction of arteries and arterioles

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why does the white scratch turn red

you induced an inflammatory response so there is hyperemia as more blood rushes there

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what governs efflux and influx of fluid in vessels

mediators - inflammation gets things out of the vessels where you need them,
they don_t have to be damaged and leaky bc the mediators will direct them

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transudate

fluid accumulation in body cavity with low protein/specific gravity - ultrafiltrate - i.e. water squeezed out of vessels

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exudate

fluid accumulation in body cavity with high protei/ specific gravity

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edema

interstitial fluid accumulation (may be transudate or exudate)

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purulent

pus

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exudate in lungs

pneumonia

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transudate in lungs

heart failure

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duet to normal laminar flow and arterial and venou pressure

hydrostatic pressure forces fluid out and osmotic pressure draws fluid back in but only 80%. The other 20% goes to lymphatics

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with increased flow during vasodialation you get

increased hydrostatic pressure and transudate

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when endothelial cells get "leaky" you get

exudate - endothelial cells have increased permeability for proteins increasing the osmotic pressure

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hemoconcentration and stasis

loss of lamnar flow, rolling, attachment, transmigration

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factors affecting vascular permeability (leakage)

endothelial gap formation,
endothelial retraction,
increasaed trancytosis,
direct injury,
delayed prolonged leakage (like sunburn),
leukocyte-mediated damage,
leakage from new blood vessels

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Endothelial gap formation

most common mechnaism of non damage active vascular leakage

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endothelia gap formation is the major effecto of mediators such as

histamine, bradykinin, leukotrienes, substance P

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where does endothelial gap formation occur

exclusively in post capillary venules of 20 to 60 um in diameter (receptor density)

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how long does endothelia gap formation last

rapid and short lived - immediate transient response

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cytoskeletal reorganization/endothelial retraction

cytoskeleton changes and endothelial cells retract from one another

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how is endothelial retraction induced

by cytokines such as Il1 and TNF alpha or hypoxia and sublethal injury

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how long does cytoskeletal reorganization take

endothelial retraction is delayed 4-6 hrs and lasts longer up to 24 hrs

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is endothelial retraction localized

not perfectly localized bc injury can induce it

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increased trancytosis

movement of fluid and material across endothelial cytoplasm, occurs through clusters of uncoated vesicles and vacuoles called the vesiculovacular organelle

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how is trancytosis induced

vascular endothelial growht factor (VEGF) - also may be induced by histamine

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Direct endothelial injury resulting in necrosis results in

leakage from damaged vessels, immediate and long lasting (immediate sustained response), happens in small and large vessels, and is associated with platelet aggregation and thrombosis

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Delayed prolonged leakaged

2-12 hours lasting for hours to dayes, occurs at venules and capilaries

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how is delayed prolonged leakage induced

by mild thermal burns, ionizing and UV radiation (sunburn--get pain not just on skin but all over, chills..)

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delayed prolonged leakage mechanism

maybe apoptosis from DNA damage

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leukocyte mediated damage

leukocytes adhere to activated or damaged endothelium, secrete reactive and toxic products that damage self as well as microbes, location dependent on why and where leukocytes bind

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leakage from new blood vessels

during repair angiongenesis occurs and new vess are nleaky before new endothelial cells fully differentiate and form gap junctions, VEGF induces increased vascular permeability, new endothelium has an increased density of receptors for vasoactive signals

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what allows for pure collection of white exudate (pus)

mediators allowing collection of neutrophoils - so don't need vessel trauma for inflammation

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Margination

a hemodynamic effect where lamina flow of leukocytes changes to peripheral and contacto vascular wall duing stasis

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rolling-adhesion-extravasation occurs by

modulating various adhesion molecules on the surface of endothelial cells and leukocytes

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rolling-adhesion-extravasation is mediated by

secreated or formed inflammatory mediators

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rolling-adhesion-extravasation strategies are to

increase the number of receptors and increase affinity of receptors for ligands

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endothelium molecules

p-selectin,
e-selectin,
ICAM-1,
VCAM1,
CD 34/GlyCam,
CD31

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P-selectin

sialyl-lewis X and PSGL-1 (rolling: N, M, L)

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E -selectin

sialyl-lewis X (rolling adhesion: N, M, L)

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ICAM - 1

CD11/18 (beta2 integrins, aka LFA1 and Mac-1) (adhesion, arrest and transmigration: all leukocytes)

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Vcam-1

VLA4 (alpha4beta1) (integrins) and LPAM-1(alpha4beta7) (adhesion E,M,L)

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CD-34/GlyCam

L-selectin (rolling; lymphocyte homing: L)

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CD31 (PECAM)

CD31 (transmigration:all)

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Selectins

have an extracellular sugar binding domain similar to lectins. They bind sialyated oligosaccharides

70

knock out L selectin

poorly formed LNs and few t cells

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knock out either E or P selectin

mind effects bc the other compensates

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knock out both e and p selectin

severe effects

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immunoglobulin like molecules

ICAM-1, VCAM-1 (both bind integrins on leukocytes)

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integrins

transmembrane heterodimer glycoproteins with alpha and beta chains

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beta 2 integrins

LFA1 and MAC1 (bind ICAM1)

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beta 1 integrins

VLA4 and LPAM1 (bind to VCAM1)

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1. histamine, thrombin and PAF induce

the redistribution of P-selectin from intracellular sotres (weible-palade bodies) to the surface (takes minutes)

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2. Tnf and IL1 induce

the synthesis of E-selectin ICAM1, VCAM1 (takes 1-2 hours)

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3.luekocyte specific chemokines alter

conformation of LFA-1 and MAC-1 increasing the affinity of binding to ICAM 1.
requires ICAM1 and synthesis of chemokines by othercells (late response)

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4. early endothelial activation i.e.

rolling (selectins and sialyl-lewis X)

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5. later synthesis of

endothelial adhesion molecules and increased affinity of LFA1 and MAC1 --firm adhesion

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7. CD31, ICAM and integrins result in

transmigration

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genetic deficiency called leukocyte adhesion deficiency type 1 (LAD1)

def in LFA1 and Mac

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LAD2

def in sialyl-LewisX - big problem with leukocyte accumulation

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antibidies to adhesion molecules can block inflammation like

Natalizumab

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natalizumab

humanized monoclonal AB to VLA4 (alpha4beta1interin) to treat MS

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negative effect of natalizumab

bind up all the vla4? So no adhesion of leukocytes