Inflammation Flashcards
Cardinal signs of inflammation
Heat Redness Swelling Pain Loss of function
Heat/redness
Artery dialation
increased blood flow to tissue
Caused by endothelial NO
Swelling
Vascular leakage of plasma into tissue
Tissue remodelling can occur due to fibrin deposition
Pain
Chem mediators of inflammation cause pain by stim’ing nerves
Loss of function
Follows from swelling
tissure remodelling results in destruction and really fucks you up
Cells that cause inflammation
Granulocytes
Lymphocytes
Monocytes
Histamine receptors in inflammation
H1-stim’s phospholipase c
- vasodilates with NO
- Causes oedema via vascular contraction
- Pain/itch
H4- Leucocyte chemotaxis, pain/itch, activates PLC
Inflammatory mediators
BK- bradykinin formed from plasma precrusor, increases permeability
PGE2- Prostoglandin E2 from membrane lipid, increases blood flow
FMLP- activates neutrophils, increases permeability as a result
Eicosanoids
Oxidation products of 20 fatty acids- Arachidonic acid
Classic-Prostaglandins
Physiological functions of PG’s
- Initiate labour- PGF2alpha, PGE2
- Inhibit gastric secretion, increase Gast’ mucous production- PGE2
- Inhibit platlet aggregation/vasodilation- PGI2
- The opposite of 3- TXA2
Pro/antiinflammatory
PG’s can increases inflam’ via elevation of cAMP causing vasodilation
But it also inhibits leukocyte function
Fever
PGE2 in anterior hypothalamus activation can lead to fever as core temperature is elevated
Role for EP3 receptor
Cyclo-oxygenase
COX-1: GI, nephro and platelet maintenance
COX-2: Causes inflammation
COX-3: Possible target for paracetamol. It role in humans questionable.
Aspirin
acetylates COX
irreversible inhibition
Ibuprofen
competes with arachodonate for COX binding
Risks of COX selectivity
COX-1 selective: Causes GI bleeds
COX-2 selective: Causes strokes/blood clots
Low dose aspirin
Antithrombotic effect
Inhibits platelets COX-1 (No TxA2) which are prothrombotic
Endothelial COX-2 can now produce PGI2 which is antithrombotic
Leukotrines
LTC4/LTD4: ^ bronchoconstriction and oedema
LTB4:^Oedema, chemotactic for inflammatory cells
BLT1: chemotactic for inflammatory cells
Present in high levels for arthritis synovial fluid
Overall ^inflammation/bronchoconstriction/inflammatory cell migration
Glucocorticoid action
Inhibits transcription of PLA2
Induces synthesis of PLA2 inhibitor ‘lipocortin’
Inhibits COX-2 synthesis
EPA (Eicosapentaenoic acid)
Omega 3 fatty acid
COX metab’d to form:
PGI3- potent antiplatelet
TxA3- weak proplatelet
Leukocyte diapedesis
- Circulation
- Tethering/rolling-guided by selectins, thethers leukocyte to vascular cells
- Firm adhesion-guided by intergrins
- Transmigration- guided by chemoattractants and CAM’s
L, P and E selection
L-On leukocytes ^avidity
P-On platelets, translocated to surface by Hs (mins)
E-IL-1/TNF induce expression on endothelium (hours)
Integrins
Proteins expressed on leukocytes
Common beta2 chain +
alpha l/m/x
Making 3 heterodimers Al/B2, Am/B2, Ax/B2
Regulating adhesion
Leukocyte activation causes:
Conformational change in integrin-^affinity
Clustering-^avidity
Integrin ligand
Intercellular adhesion molecule (ICAM)
ICAM-2: Basally expressed on endothelium
ICAM-1: induced by cytokines IL-1, TNF
ICAM on endothelium binds to integrin on leukocyte
Chemotaxins
Attract and activate leukocytes
Source from site of inflammation
Sometimes immobilised and simply presented to leukocytes on:
Extracellular matrixes
endothelial cell surface
Chemokines
chemotaxins that are cytokines
Produced in response to bacteria, IL-1 and TNF
Is a g protein coupled receptor
Mainly attract neutrophils and t cells (CXC)
All chemokines are chemotaxins but not the other way round
Plasma proteases
Kinins
Complement
Clotting cascade
Angioedema
Long lasting
- responsive to H1 antagonists
- mast cell degranulation
If not responsive then caused by ACE inhibitors or is hereditary
MMP structure
4 parts- Propeptide, Catalytic Zn, hinge, c terminal
Propeptide bound to Zn by Cys residue keeping MMP inactive
Propeptide removed by proteases or chemically modified by RON
C terminal important for specificity and regulation
MMP (Metallo matrixproteinase)
Breaks down collagen
Requires Zn2+ and active at neutral pH
inhibited by TIMPS (Tissue inhibitors of metallo-proteinases)
Tissue damage in RA
Proteoglycans easily accesible to proteinases so quickly broken down
-results in loss of shock absorbtion and joint function
Cartilage made of collagen so broken down more slowly by MMP
MMP inhibition
Tetracyclines- reduces MMP synthesis/activity
-can have high specificity
Seriene/cysteine proteinases
Neutrophil elastase, cathepsin G Breaks down matrix proteins: elastin, laminin Endogenous inhibition by SERPIN -SERiene Protease INhibitors Serpins inactivated by oxidation
Reactive Oxygen and Nitrogen species (RONS)
Produced by leukocytes and tissue resident cells
NADPH catalyses formation of superoxide O2-
