Inflammation - Yurchenco 4/5/16 Flashcards
inflammation definition
players involved
factors that can produce it
response to injury in which host…
- attempts to destroy causative agent
- sequester it to prevent further injury
symptoms: redness, edema, heat, loss of fx
involves both innate and adaptive immunity
→ fluid and leukocytes accumulate at injury site
can be caused by anything that adversely affects cell viability…
- heat
- ionizing radiation
- UV light
- microbial toxins
- anorexia
types of inflammation
- acute : occurs early, short duration
- mediated by polymorphic leukocytes
- afterwards, tissue returned to normal state
- chronic : can be more severe
- mediated by mononuclear infl cells (macrophages, lymphocytes)
- can have irreversible sequellae
- granulomatous : infl cells can’t control offending agent → try to sequester it again
*can have mixtures of all three types in various diseases!
state of affairs in general resting state of tissue and key players
arteriole → capillary → post-cap venule
mast cell : one infl cell (imp initiator of infl events)
parenchymal cells : main fxal cells of a given tissue
acute inflammation: summary of events
vascular dilation and plasma leakage into interstitium
bacterial infection → activates mast cells to release granules → arterioles will dilate, increase hydrostatic pressure → blood flow increases
- redness!
post-cap venules in particular will become “leaky” → some fluid will exit into interstitium [some will exit into lymphatics, establish a sort of steady state]
- edema!
at approx 12h (peaking at 24h): neutrophils line post-cap venule walls, migrate (diapedesis)
at 48h: neutrophilic response replaced by mononuclear infl response → mop up agents : eat remaining bacteria and neutrophils that have been there and played their part
mechanisms of acute inflammation
- innate vs. adaptive immunity
- cytokines, vasoactive amines, eicosanoids
- changes in microvascular permeability
- neutrophil adhesion, migration, diapedesis
- phagocytosis
innate immunity in relation to inflammation
defense mechs present before infection that monitor intra/extracellular compartments for infection or tissue injury
PRRs (TLRs, C-type lectin receptors, Nod-like receptors: “inflammasome”) bind antigens → gene transcription → production, activation, release of inflammatory cyokines
adaptive immunity
develops following exposure to antigens
- derived from lymphocytes and pdts (antibodies) with high diversity due to somatic hypermutation and recombination of antigen-binding regions
2 types:
1. humoral immunity: mediated by B lymphocytes via production of Ig
2. cellular immunity: mediated by T lymphocytes
mast cell degranulation : histamines, cytokines, eicosanoids
histamine (preformed and stored in granules) released in response to:
- physical injury/trauma/extreme temp
- immune resp involving antigen binding to mast cell - adaptive immunity
- complement C3a, C5a (“anaphylatoxins”) - adaptive immunity
- histamine-releasing proteins from leukocytes
cytokines and eicosanoids (synth’d de novo) secreted in response to:
- viruses, bacterial LPS, infection agents via TLRs - innate immunity
- immune rxns involding binding of antibodies to mast cells - adaptive immunity
activation of IgE receptor on mast cell → signaling cascade inducing…
- degranulation → histamine and other vasoactive amines → arterial dilation, venous leakage
- synthesis/release of cytokines
- synthesis/release of eicosanoids
eicosanoids
inflammatory agents synthesized and released by mast cells
- arachadonic acid derivatives
- anti-infl treatment often targets this pathway
steroids : membrane PLs → arachadonic acid [phospholipases]
- steroids inhibit phospholipases
NSAIDs (aspirin/indomethacin) : arachidonic acid → prostaglandin [cyclo-oxygenase]
- NSAIDS block cyclo oxygenase
lipoxygenase inhibitor : arachidonic acid → ….leukotrienes [lipoxygenase]
inflammatory cells have to make it form the vascular side of things to the interstitial side of things
how?
two barriers to be traversed:
- endothelium : active transport (pinocytotic vesicles)
- basal lamina : passive diffusion (across mesh-like sieve)
many processes exist to allow this to occur
- histamine-type response/leakage
- most regulated
- starts immediately, short duration (.5-1ish hour)
- mediated by inter-endothelial jx in response to induced endothelial shape change
- endothelial injury
- milder form → leakage. severe form → endo destroyed.
- limiting factor: thrombosis
-
increased transcytosis
* mediated by VEGF (vascular endothelial growth factor)
how does inflammation occur
i. e. how does fluid get from vasculature out into tissues
i. e. how do leukocytes get into tissues
regular mechanisms for fluid movement
- increased hydrostatic pressure
- decreased osmotic pressure
- removal of barrier to fluid and protein via openings at interendothelial jx
leukocyte exudation/extravasation
- margination & pavementing : leukocytes move to periphery of blood stream and stack up near interendothelial jxs
- migration → flattening & insertion → diapedesis → chemotaxis in interstitial space
molecules involved in endothelial-leukocyte adhesion prior
prior to diapedesis/chemotaxis, leukocytes have to be able to “stop” at appropriate site in the endothelium
rolling and adhesion mediated by molecules on both endothelium and leukocytes
P selectin / SialylLewis-modified proteins : ROLLING
- (monocytes, neutrophils, T lymphocytes)
E selectin / SialylLewis-modified proteins : ROLLING/ADHESION
- (monocytes, neutrophils, T lymphocytes)
GlyCam1, CD34 / L selectin : ROLLING
- mostly used by T lymphocytes for homing
ICAM1 / beta2 integrins (CD11/CD18; LFA1, Mac1) : ADHESION, arrest, transmigration
- neutrophils, monocytes, lymphocytes
VCAM / VLA4 (beta1) integrins : ADHESION
- eosinophils, monocytes, lymphocytes
how is leukocyte-endothelial binding activated?
3 ways
- inflammatory mediators (ex. P selectin) are stored in Weibel-Palade bodies in endothelial cells
* signaling by histamine, thrombin → fusion of WP bodies with cell membrane surface - cytokine signaling (ex. TNF, IL1) induces expression of new endothelial adhesion molecules
-
“inside out” signaling : integrins are “bent in” such that they cant bind selectins
* cytokines force subunits apart to extend them into binding conformation
neutrophil granules:
azurophil (primary)
specific (secondary)
azurophilic: large, dense granules containing…
- lysosomal enzymes
- peroxidase
- lysozyme (33%)
- cationic proteins
specific: smaller, less dense granules containing…
- alk phos
- lysozyme (67%)
- lactoferrin
opsonization factors → receptors
- IgG antibodies (heat stable) →Fc-gamma-R
- C3b (complement component) →
- CR1
- CR2
- CR3 (binds stable C3bi; beta2 integrin that also binds bacteria and things via LPS)
