Inflamm Flashcards
What are the 4 cardinals signs of inflammation?
redness
swelling
heat
pain
+/- loss of fct
What are the sensors of cell damage?
- TLR (DAMPs, PAMPs)
- Cytosolic-R = NLR (uric acid = DNA breakdown, ATP = damage mito, reduced K+, DNA)
- Leucocytes express R for Fc tails of AC and for complements = recognize opsonized microbes
- Mannose-binding lectin = recognize microbial sugars = active complement
How is contraction of endothelial cells elicited?
By histamine, bradykinin, leukotriene
15-30 min = transitoire
How do leucocytes get out of vessels?
- Paracellular transport 2n retraction of endo cells (histamine, NO)
- Transcytosis in venules upregulated by VEGF = important to cross blood-brain-barrier
- Endothelial injury
What is the immediate transient response in acute inflammation? mediation?
Contraction of endothelial cells that increase permeability
Mediated by histamine (pre-formed really to be released at any time)
The cytoskeletal reorganisation permitting transcellular leakage is mediated by :
IL1, IL6, TNFa
Steps involved in margination of leucocytes
- Microbes in tissue
- Tissue resident macrophages bind PAMPs/DAMPs -> release IL1, IL6, TNFs -> activate endothelial cells
- Activated endothelial cells upregulate preformed P-selectin (later E- L-selectin) = ROLLING
- Selectins binds glycosylated molecules (PSGL-1, Sialyl-Lewis X) for transient low affinity binding -> Hausse affinity for integrins
- Integrin high affinity state (ICAM-1) = stable adhesion
- Migration through endothelium via CD31 (PECAM-1)
Where are P-selectin stored?
Exists preformed in Weibel-Palade body
What binds to L-selectin?
Receptor for leucocytes extravasation
1. GlyCAM-1 = high endothelial venules in lymphoid tissue
only binds selectin
2. MadCAM = expressed on MALT in TGI
also binds integrins (VLA4, a4B7)
3. CD34 = endothelial cells
The expression of selectin is mediated by
TNF, IL1, chemokine
Histamine, thrombin stimulate P-selectin
Molecules involved in migration
CD31, PECAM1
How do leucocytes pierce basement membrane?
By secreting collagenase
What are exogenous chemoattractants?
Bacterial producst = peptide with N-terminal, aa, lipids
What are endogenous chemoattractants?
Cytokine = IL8
Complement = C5a
Arachidonic acid (AA) metabolits = leukotriene B4
What allows leucocytes to move following binding of chemotactic agents to GPCR?
extension of flipodia
actin = leading edge
myosine = back of leucocytes
Steps of phagocytosis
- recognition
- engulfment
- killing and degradation
Properties of neutrophils
1. Origin
2. lifespan in tissue
3. response
4. ROS
5. NO
6. Degranulation
7. Cytokine production
8. NET
9. Enzymes lysosomal
- Origin = HSC in bone marrow
- lifespan in tissue = days
- response = short, fast
- ROS = rapidly induced by phagocyte oxidase
- NO = low or none
- Degranulation = major
- Cytokine production = low or none
- NET = rapide
- Enzymes lysosomal =prominent
Properties of macrophages
1. Origin = HSC in bone marrow, tissue-resident
2. lifespan in tissue = BM = days or week, tissue-resident = years
3. response = prolonged, slower
4. ROS = less prominent
5. NO = induced after transcriptional activation of iNOS
6. Degranulation = not prominent
7. Cytokine production = major
8. NET = no
9. Enzymes lysosomal = less
- Origin
- lifespan in tissue
- response
- ROS
- NO
- Degranulation
- Cytokine production
- NET
- Enzymes lysosomal
Elements allowing destruction of microbes in phagocytes
O2, H2O2 + azurophilic granules(MPO) -> HOCl = halogenation (hyalide bound) or oxidation (lipids peroxydation)
In macrophage, NO interacts with O2 = ONOO-
Neutrophils granules
Small = lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, alkaline phosphatase
Larger azurophil = MPO, defensin, acid hydrolase, neutral protease
Macrophages content
acid hydrolase
collagenase
elastase
phospholipase
plasminogen activator
Action of a1-antitrypsin on neutrophils
major inhibitor of neutrophils elastase
NET formation
ROS-dependant activation of arginine deaminase converts arginine to citrulline = chromatin decondensation
What is frustrated phagocytosis?
inability to ingest (immune complex deposit on large surface) = triggers activation/release of lysosomal enzyme EC
How do LT contribute to acute inflammation?
produce IL17 inducinf secretion of chemokines to recruit leucocytes
What are the termination mechanisms of acute inflammation?
Termination begins by switching the type of AA metabolite to antiinflammatory lipoxins = liberation of antiinflamm cytokines TGFB and IL10
Principal mediators of inflammation source and action :
1. Histamine
2. Prostaglandine
3. Leukotriene
4. Cytokines (TNF, IL1, IL6)
5. Chemokines
6. PAF
7. Complement
8. Kinins
- Histamine
Mast cell, basophils, platelets
VasoD, permeability, endo activation - Prostaglandine
Mast cells, leukocytes
VasoD, pain, fever - Leukotriene
Mast cells, leukocytes
Permeability, chemotaxis, leuco adhesion/activation - Cytokines (TNF, IL1, IL6)
macro, masto, endocells
endo activation, fever, metabolism, shock hypotensive - Chemokines
leuco activated macro
chemotaxis, leuco activation - PAF
leucocytes, masto
vasoD, permeability, leuco adhesion, chemotaxis, degranulation, oxidative burst - Complement
plasma (produced by liver)
leuco chemotaxis/activation, MAC, vasoD - Kinins
plasma (produced by liver)
permeability, smooth muscle contraction, vasoD, pain
When is histamin released?
Stored preformed in cells
physical injury
binding of IgE on AC of mastocytes
products of C3a, C5a
substance P, IL1, IL18 can cause release
Where is serotonin present?
platelets and neuroendocrine cells (GI)
AA derived mediators (eicosanoids) binds to what?
GPCR
Action of AA metabolites :
1. PGI2, PGE1, PGE2, PGD2
2. TxA2, LTC4, D4, E4
3. LT C4, D4, E4
4. LT B4, HETE
- PGI2, PGE1, PGE2, PGD2 = vasoD
- TxA2, LTC4, D4, E4 = vasoC
- LT C4, D4, E4 = increase permeability
- LT B4, HETE = chemotaxis, leucocyte adhesion
Why is COX-2 selectif inhibitor and interesting option?
Because COX2 generate PG involve only in inflamm rx vs COX1 involved in inflamm and physiologic protective effect
But inhibing COX2 can predispose to thrombosis
Source and actions of cytokines in acute inflammation :
1. TNF
2. IL1
3. IL6
4. Chemokines
5. IL17
- TNF
macro, masto, LT
stimule expression of endo adhesion and secretion of other cytokines - IL1
macro, endo cells, epi cells
similar to TNF, role in fever - IL6
macro and other cells
systemic effects - Chemokines
macro, endo cells, LT, masto
recruit other leucocytes, migration - IL17
LT
recruits neutro and monocytes
Source and actions of cytokines in chronic inflammation :
1. IL12
2. IFNy
3. IL17
- IL12
DC, macro
increase production of IFNy - IFNy
LT, NK cells
active macro - IL17
LT
recruits neutro and monocytes
Role and production of tumor necrosis factor (TNF)
Production of TNF signals by TLR and IL1
Roles :
- endo activation (adhesion, mediators)
- activation of leucocytes, IL1
- supress appetit (cachexia)
Role of C-X-C chemokines
act on neutro, IL8
secreted by macro, endo cells
inducers = microbial products, IL1, TNF
C-C chemokines (MCP-1, CCL2, CCL11, MIP-1, CCL3) role
attract monocytes, eosino, baso, lympho
C chemokines (lymphotactin, XCL1) role
relatively Sp for lympho
CX3C chemokines (CX3CL1) role
1 - cell surface bound on endo cells = promot adhesion of monocytes and LT
2- soluble form = potent chemoattractant
By what are triggered the 3 pathways of the complement system?
- Classical pathway = by binding C1 to IgM or IgG
- Alternative pathway = by microbial surface molecules
- Lectin pathway = plasma mannose-binding lectin binds carbohydrates on microbes = active C1
Role of DAF, factor H and CD59
DAF = prevent formation of C3 convertase
CD59 = inhibit formation of MAC
Factor H = promote cleavage and destruction of C3b = inhibits alternative pathway
Mediators of :
1. VasoD
2. Permeability
3. Chemotaxis/recruitment/activation
4. Fever
5. Pain
6. Tissue damage
- VasoD = histamine, prostaglandine
- Permeability = histamine, serotonin, C3a, C5a, LTC4,D4,E4
- Chemotaxis/recruitment/activation = TNF, IL1, C3a, C5a, LTB4
- Fever = IL1, TNF, PG
- Pain = PG, Bradykinin, substance P
- Tissue damage = lysosomal enzyme, ROS
Events in arteriole, capillary and venule
Arteriole = constriction, mast cell degranulation (chemotaxis, permeability, contraction endothelial) = fluid leakage
Capillary = platelet aggregation, emigration neutro, diapedesis or erythrocytes
Venules = emigration of lympho, infiltration of macro, fibrin deposition
Composition of eosinophilic granules
- Small granules (acid phosphatase, arylsulfatase) = inactive leukotriene
- Primary granule
- Large specific granule :
Major basic prot + Cationic prot = toxic parasites, histamine release
Eosinophil-derived neurotoxin = microbicidal
Eosinophil peroxidase = microbicidal
Catalase = inactive leukotriene
Enzymes and molecules in neutrophils
Specific granules :
- lactoferrin
- lysozyme
- alkaline phosphatase
- collagene 4
- leuco adhesion molecule, plasminogen activation, phospholipase A2
Azurophilic granules :
- MPO
- lysozyme
- cationic prots
- acid hydrolase
- elastase
- Non-sp collagenase
- BPI
- defensin, cathepsin
- phospholipase A2
To which cytokines respond neutrophils and monocytes
Neutro = IL8
Monocytes = CX3CL1, CXCL1, CCL2
Receptors of PAMPs
1. TLR6, TLR2, TLR1
2. TLR4-CD14, MD-2
3. TLR7-TLR8
4. TLR3
5. TLR5
6. TLR9
7. TLR10-11
- TLR6, TLR2, TLR1
- peptidoglycans G+
- lipoprotein
- mycobacterie
- LPS (lepto)
- GPI (trypanosoma)
- Zymosan (yeast) - TLR4-CD14, MD-2
- LPS G-
- Lipoteichoic acids G+
- RSV F protein - TLR7-TLR8
- ssRNA - TLR3
- dsRNA - TLR5
- Flagellin - TLR9
- Unmethylated CpG DNA - TLR10-11
- Uropathogenic bacteria
Activity of :
1. a defensin
2. B defensin
3. Cathelicidins
4. Surfactant prots A et D
- a defensin (entero, leuco)
microbidice, induce IL8, inhibe angiogenesis - B defensin (epithelia, leuco)
microbidice, chemotaxis (neutro, DC, leuco = prolif) - Cathelicidins (leuco, epithelia)
microbicide, cytokine/histamine release, cell prolif, angiogenesis, wound healing, prevent apopto (PR39) - Surfactant prots A et D (epithelia)
opsonize, macro activation
Th2 response
IL2-4-5-10-13-17-19
CCL3, 4, 5, 11
Th1 response
IL2-12-17-23, IFNy, TNF
CCL3,4,5 CCL2,3,4,5,7,8,12, CXCL9
What is the response with tissue macrophage activated by IFNy?
Inflammation and tissue injury = ROS, protease, cytokine, chemokines, coag factor, AA metabolites
What is the response with tissue macrophage activated by IL4?
Repair = growth factor (PDGF, FGF, TGFB), fibrogenic cytokines, angiogenic factor, remodeling collagenesis
How are classically activated macrophages induced?
By microbial products and cytokines (IFNy)
How are alternatively activated macrophages induced?
Cytokines (IL4, IL13) and in response to helminths
classically activated macrophage response
ROS, NO, lysosomal enzyme = microbidice
IL1, IL12, IL23, chemokines = inflamm
alternatively activated macrophages response
IL10 TGFB = antiinflamm
Arginase, proline, polyaminase, TGFB = wound repair, fibrosis
HIF-a in hypoxic or normal conditions
Normal :
HIF-a hydroxylation prevents binding to P300BP
Hypoxic :
HIF-a not hydroxylated = binds P300BP = gene transcription of the HRE (hypoxia response element) = angiogenesis, iron sequestration, hypoxia metabolism
Mechanism of TGF-B for collagene proliferation
TGF-B -> R-SMAD phospho = transcription for ECM depot, myofibroblast differenciation and fibroblast activation
regulated by SMAD 7
What does Th1 produce?
IFNy = active macro classical pathway
What does Th2 produce?
IL4, IL5, IL13 = recruit eosino, macro M2
What does Th17 produce?
IL 17 and other = secretion of chemokines, recruitment of neutrophils and monocytes
Formation of granuloma
M1 activated -> IL12 + present AG to CD4+ Th1 LT = epithelioid cell, giant cell, fibroblast, lympho, M1
FOREIGN BODY GRANULOMA = absence of LT immune response
IMMUNE GRANULOMA = peristent LT response (Th1 produce IFNy)
Proliferation of hepatocytes in response to injury
1- priming phase = IL6 produced by Kupffer act on hepatocytes to receive GF
2- GF phase = HGF, TGFa stimulate metabolism, DNA replication
3- termination phase = return to quiescence (TGFB)
Steps of angiogenesis
- VasoD (NO, VEGF)
- separation of pericytes (break basement membrane)
- migration of endothelial cell -> proliferation
- remodeling of capillary tubules
- recruitment of periendothelial cells (pericytes)
- suppression of endothelial proliferation
Notch pathway in angiogenesis
regulates sprouting and branching (stimulated by VEGF)
PDGF and TGFB in angiogenesis
STABILISATION
PGDF = recruit smooth muscle cell
TGFB = suppress endothelial prolif/migration
When can it heal by first intention?
When it involves only the epithelial layer
