Inflammation - Yurchenco 4/5/16 Flashcards Preview

Immunity > Inflammation - Yurchenco 4/5/16 > Flashcards

Flashcards in Inflammation - Yurchenco 4/5/16 Deck (20):
1

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

2

types of inflammation

1. acute : occurs early, short duration

  • mediated by polymorphic leukocytes
  • afterwards, tissue returned to normal state

2. chronic : can be more severe

  • mediated by mononuclear infl cells (macrophages, lymphocytes)
  • can have irreversible sequellae

3. granulomatous : infl cells can't control offending agent → try to sequester it again

 

*can have mixtures of all three types in various diseases!

3

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

 

4

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

 

5

mechanisms of acute inflammation

1. innate vs. adaptive immunity

2. cytokines, vasoactive amines, eicosanoids

3. changes in microvascular permeability

4. neutrophil adhesion, migration, diapedesis

5. phagocytosis

6

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

7

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

8

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

9

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]

 

10

inflammatory cells have to make it form the vascular side of things to the interstitial side of things

 

how?

two barriers to be traversed:

1. endothelium : active transport (pinocytotic vesicles)

2. basal lamina : passive diffusion (across mesh-like sieve)

 

many processes exist to allow this to occur

1. 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

2. endothelial injury

  • milder form → leakage. severe form → endo destroyed.
  • limiting factor: thrombosis

3. increased transcytosis

  • mediated by VEGF (vascular endothelial growth factor)

 

11

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

12

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 proteinsROLLING 

  • (monocytes, neutrophils, T lymphocytes)

E selectin / SialylLewis-modified proteinsROLLING/ADHESION 

  • (monocytes, neutrophils, T lymphocytes)

GlyCam1, CD34 / L selectinROLLING

  • 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

13

how is leukocyte-endothelial binding activated?

3 ways

1. 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

2. cytokine signaling (ex. TNF, IL1) induces expression of new endothelial adhesion molecules

3. "inside out" signaling : integrins are "bent in" such that they cant bind selectins

  • cytokines force subunits apart to extend them into binding conformation

14

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

15

opsonization factors → receptors

1. IgG antibodies (heat stable) →Fc-gamma-R

2. C3b (complement component) →

  • CR1
  • CR2
  • CR3 (binds stable C3bi; beta2 integrin that also binds bacteria and things via LPS)

16

recognition and binding to a phagocyte induces 10fold increase in...

 

which pathway? why?

HMP pathway!

need NADPH to make the molecules needed to kill bacteria once phagocytosed!

  • NADPH oxidase : oxygen → superoxide which can go to H2O2, hypochlorite, etc → bacterial killing!

lack of NADPH oxidase activity  → chronic granulomatous disease

  • usually affects males (X linked)
  • not all bacteria affected equally in CGD

 

17

chart on diseases of leukocyte fx

18

chronic inflammation

DEFINITION

CHARACTERISTIC EFFECTS

complex, typically irreversible tissue changes initiated by...

  • parenchymal cell death, tissue destruction →
    • growth of new blood vessels
    • production of connective tissues

 

initial events: v similar to acute infl - vascular dilation, increased blood flow/hydrostatis pressure, increased leakage

  • effects later replaced by mononuclear infl cells
  • damaged parenchymal cells might also release cytokines and stuff
  • abscesses form : collection of pus (usually neutrophils) with tissue destruction and formation of a new cavity 
  • empyema : variant of an abscess → pus fills an existing cavity!
  • angiogenesis and granulation : stimulated by infl and hypoxia
    • chemokines bind to endothelial receptors → affect (promote/inhibit) migration and angiogenesis
    • VEGFA-VEGFR2 signaling pathways affect prolif, migration, survival
    • proliferation of fibroblasts, endothelial cells, fibrogenic cells → increased collagen synthesis; paired with decrased collagen breakdown...FIBROSIS

19

granulomatous inflammation

starts off like acute → transitions to circumscribed structure

  • new caps formed (chronic infl) + fibroblasts invade the field
  • macrophages/monocytes attempt to phagocytose material, but cant → become quiescent and just aggregate around the structure

called a GRANULOMA

 

types:

1. coccidioides immitus : 

2. sarcoidosis : 

3. foreign body (ex. suture granuloma)

20

double edged sword of inflammation

helpful to destroy or sequester pathogens

BUT

can also be part of disease processes (ex. silicosis, gout)