Inflammation Flashcards
what does inflammation involve
interplay between leukocytes (WBCs), tissue cells (immune, structural), microvasculature, nerves, chemical mediators of inflammation
plasma derived
what are the cardinal signs of inflammation
heat, redness, swelling, pain, loss of function
what causes heat and redness
arteriolar dilation, increased blood flow to inflamed tissue
increased blood flow due to relaxation of artieries
what causes swelling
leakage of plasma from blood vessels into tissue (plasma extravasation)
more chronic swelling due to tissue remodelling, cellular accumulation
what causes pain
external physical or chemical injury; endogenous generation of chemical mediators of inflammation trigger sensory nerves
what causes loss of function
due to chronic inflammation dur to tissue remodelling (tissue destruction/fibrin disposition-scarring)
what are the cellular components of the inflammatory response
leukocytes (WBCs)
granulocytes (neutrophils, eosinophils, basophils), lymphocytes (T,B,NK cells), monocytes
what are tissue mast cells
widely distributed throughout connective tissue and mucosal surfaces, similarities with circulating basophils, contain synthesise and release inflammaotry mediators
what are stimuli of tissue mast cells
mechanical injury to skin, hypersensitivity, chemicals
what is the role of the endothelium in inflammatory response
blood vessels lined in epithelium
endothelial-derived NO causes arteriolar dilation; endothelial contraction makes venules leaky due to increased permeability
causes oedema
what are chemical mediators of inflammation
diverse molecules produced by the host in response to infection and immune reactions
low specificity (not antibodies)
effectors of the innate immune response but modulate the specific response
promote inflammation and hopefully initiate repair
what is the triple response of histamine
redness due to vasodilation, flare (neuropeptide release causing itching), wheal (swelling)
what is the action of histamine on blood vessels
relaxation of arteriolar smooth muscle
contraction of venular endothelium leading to increased permeability
what category of drug is chlorphenamine
H1 receptor antagonist
what are some chemical mediators in inflammation
PGE2 and PGI2 cause vasodilation
histamine and bradykinin increase venule permeability
what is bradykinin
inflammatory substance formed from plasma precursor
what is PGE2 (prostaglandin)
inflammatory substance formed from membrane lipid
what pre-formed mediators are released in response to local injury
histamine, mediators from membrane lipids (PGE2, PGI2), release of peptides from neurokinins
what mediators are produced during inflammatory response
following proteinase activation, bradykinin and complementing fragments are formed, as well as products of infiltrating cells
what mediators take hours to produce after inflammatory response
transcription and translation of proteins
why is inflammation beneficial
increased supply of cells and chemical mediators to site of inflammation (redness, swelling, removal of damaged tissue or infectious agents)
tells body to rest to relieve pain and loss of function
what are eicosanoids
oxidation products of 20-carbon fatty acids (arachidonic acid) classical eicosanoids (prostaglandins), non-classical eicosanoids
what is the process of prostaglandin biosynthesis
membrane phospholipids react with phospholipase A to form arachidonic acid which reacts with cyclo-oxygenase to form PGH2
then forms tissue specific isomerases
synthesis is low under basal conditions
profile and rate dramatically altered in inflammation
what are prostaglandin receptors
prostaglandins act via specific GPCRs on target cells
what are some examples of prostaglandin receptors
PGE2 receptors, prostacyclin, thromboxane, PGD2 receptors
what are the hysiological functions of PGs
initiation of labour, inhibition of gastric acid secretion/increased gastric mucous production, inhibition of platelet aggregation and vasodilation, platelet vasodilation and aggregation
what is EP2
pro-inflammatory receptor
Gs/AC mediated elevation of cAMP in smooth muscle vasodilates
can inhibit leukocyte function and have anti-inflammatory properties
what is the Von Frey pain perception test
prostaglandin receptors are on sensory nerves; EP1 receptors knock-out mice have decreased pain perception
it increases pain signals to the brain
what does an EP3 receptor do
activates leukocytes and mast cells (Gi linked receptor reduces AC/cAMP signalling; enhances function)
enhances oedema formation
how to prostaglandins act in fever
protective against infection, dangerous if prolonged or severe, regulated by production of PGE2 in the hypothalamus
what is cyclo-oxygenase
exists in two isoforms COX1 constitutive (products important in normal function of stomach, intestine, kidney and platelets) COX2 induced (especially during inflammation) COX3 splice variant of COX1 expressed in CNA
what is the target of aspirin
cyclooxygenase (enzyme that converts arachidonic acid into prostaglandin)
what binding effects does aspirin have
covalent binding, acetylates COX, irriversible inhibition of COX, releases salicylate
what binding effects does ibuprofen have
competitive inhibitor of arachidonate binding to COX
non-selective COX inhibitor
what are the side effects of aspirin like drugs
gastric irritation, bleeding, renal toxicity, bleeding due to COX1 inhibition and reducing cytoprotective effects of PGs
what are the anti-thrombotic actions of aspirin
irriversibly acetylates cyclo-oxygenase, thus platelet TXA2 production ceases; endothelial cells make new COX and so PGI2 is still released
what happens when aspirin is used for anti-thrombotic effect
COX inactivated by low dose aspirin
platelet COX1 inactivated for the life of the platelet; blood vessel COX rapidly resynthesised
PGI levels maintained and decreased thrombus formation
what is the action of leukotrienes
bronchoconstriction, oedema, chemotaxis, present in inflammation
what is the action of leukotrienes on bronchoconstriction
LTC4 and LTD4 constrict human bronchial smooth muscle which increases effects of other constrictor agents
what is the action of leukotrienes on oedema
LTC4 and LTD4 stimulate increased vascular permeability
LTB4 increases vascular permeability (neutrophil dependent)
what is the action of leukotrienes on chemotaxis
LTB4 potent chemotactic agent for inflammatory cells
BLT1 receptor
what is the action of leukotrienes in inflammation
high levels in synovial fluid of RA pts
how do glutocorticoids work
inhibit PLA2 so arachidonic acid is not produced
how does zileuton work
inhibits 5-lipoxygenase activity
how does montelukast work
inhibits leukotrienes
what action do glutocortecoids have on eicosanoids
inhibits PLA2 transcription, induces synthesis of endogenous PLA2 inhibitor ‘lipocortin’; inhibits COX2 synthesis
why are eicosanoids important
potent vasodilators, increase vascular permeability, pain, fever, synergy with other medications, modulators of cell function
what is leukocyte migration
leukocytes move from blood to sites of inflammation and immune activation
directional control is co-ordinated by tissue expression of adhesion molecules and chemical stimuli for leukocyte migration
on arrival at sites of inflammation, they precipitate in host defense, inflammation and repair/restoration
what is leukocyte diapedesis
- circulation 2. tethering/rolling 3. firm adhesion 4. transmigration
what happens in the tethering/rolling stage of leukocyte dispedesis
fast moving leukocytes tethered to blood vessel wall, guided by specific homing receptors and their ligands called selectins (binds carbohydrate structures with weak bonds)
most important stage is initial tethering of leukocytes to vascular cells
what are selectins
lectin-like adhesion molecules that weakly bind CHO molecules
where are L-selectins found
leukocytes
where are P-selectins found
platelets and endothelium
where are E-selectins found
endothelium
what is L-selectin
constitutive expression on leukocytes
leukocyte activation leads to transient increase in avidity (molecules cluster on surface)
rapid shedding by proteolytic cleavage
what is P-selectin
constituative in platelets and endothelium, stored in granules
rapidly translocated to cell surface on cell activation by thrombin or histamine
what is E-selectin
endothelial expression induced by cytokines or LPS
expression required de novo protein synthesis (slow)
expression inhibited by glutocortecoids
what is leukocyte adhesion deficiency II
patents suffer recurrent infections (no pus, neutrophilia)
normal phagocytosis and respiratory burst in vitro
defective fucose metabolism (leukocytes do not express selectin ligands)
decreased rolling response on E- or P-selectins
severely impaired neutrophil accumulation in skin inflammation
neutrophils stuck in vascular area (causes neutrophilia)
neutrophils do not escape circulatory system
what happens in the firm adhesion and flattening stage of leukocyte dispedesis
rolling along endothelial cell surface which activates integrins
subsequent to receiving signals from chemokines on the endothelial surfaces
what are integrins
firm adhesion occurs via integrins
heterodimeric proteins expressed on the surface of leukocytes and most other cells
how is adhesion regulated
basal expression of integrins, leukocyte activation induces conformational change which increases affinity and clustering of integrins
what is leukocyte adhesion deficiency I
patients suffer recurrant bacterial infection without pus
leukocytes do not adhere to extracellular material or endothelium in vitro
LAD I leukocytes are deficient in beta2 integrin
what are integrin ligands
intracellular adhesion molecule (ICAM)
ICAM2 basally expressed on endothelium
ICAM1 induced by cytokines
what is transmigration
involves CAMs and chemoattractants (chemotaxins)
what are examples of leukocyte adhesion blockers in therapy
anti VLA-4
anti alphaL beta2 in dry eye symdrome
what is natalizumab
monoclonal antibody against alpha4 integrin, inhibits T lymphocyte interactions with brain endothelium (decreased trafficking into the brain); trialled as therapy for MS
licenced in US for IBD
what is chemotaxis
leukocyte movement
what stimulates leukocyte movement (chemotaxis)
chemotaxins
they attract leukocytes - intigrin affinity and avidity change, movement
what is the source of chemotaxis
site of inflammaion
some are immobilised and ‘presented’ to leukocytes; endothelial cell surface presentation, bound onto extracellular matrix
what are some non-selective chemotaxins
LTB4, C3a, C5a, formyl peptides
what are some selective chemotaxins
chemokines (large family of proteins)
what are chemokines
structurally defined group of chemotaxins that are produced in response to IL-1, TNF and bacteria
G-protein coupled receptors
named according to ligand (-L) and receptor (-R)
what are CXC chemokines
mainly neutrophil and T cell attachments
target CXCL8 ligand and CXCL12 ligand
their targets are neutrophils, lymphocytes and stem cells
what are CC chemokines
not neutrophil attractants
ligands targeted are CCL2, CCL11 and targets are monocytes, eosinophil, activated T-cells
what rate does each WBC move at
neutrophils>monocytes>lymphocytes
neutrophil-acute inflammation
monocytes, lymphocytes - chronic inflammation
what is the tissue response in inflammation
different selectin and CAM expression, different chemokine expression
what is the leukocyte response to inflammation
different integrin expression, different chemokine receptor expression
where are integrins active
on CAM during adhesion part of leukocyte dispedesis
what happens during leukocyte transmigration
leukocytes escape from circulation and accumulate at sites of injury
selectins tether leukocytes on endothelium near inflammatory site
integrins are used for stronger adhesion on chemokine activation of leukocytes
CAMs expressed by endothelium are ligands for integrins
leukocyte movement directed by chemotaxis
what are proteases derived from
plasma zymogens, tissue cells, activated leukocytes
what do proteases have a central role in
host defense, removal of damaged tissue, initiating repair, inflammation
what are plasma proteins
interrelated systems activated by tissue injury, antibody complexes, foreign surfaces
generate inflammatory mediators from plasma precursors
kinins (vasodilation, increased permeability, pain)
complement (leukocyte activation, chemotaxis, mast cell degranulation, bacterial opsonisation and lysis)
clotting cascade (thrombosis, platelet activation)
what is angioedema
deep cutaneous and mucosal swelling; lasts days and most pts also suffer mast cell degranulation, responsive to H1 antagonists
histamine-independent forms may be drug induced (like ACE inhibitors) or hereditory
what proteases are involved in angioedema
angiotensin converting enzyme inhibitor (blocks bradykinin degredation so increases inflammation) hereditary angioedema (increases bradykinin, decreases protease inhibitors) trated with bradykinin receptor antagonist
what are the families of proteolytic enzymes
matrix metalloproteinases, serine proteinases, cysteine proteinases
what tissue damage occurs in RA
cartilage proteoglycans (matrix material) lost rapidly in RA so shock absorption impaired and loss of function proteoglycans have an open structre and are highly accessible and sensitive to breakdown by several proteinases collagen is lost more slowly which causes loss of function of cartilage as smooth surface
what are matrix metalloproteinases
break down collagen and other matrix proteins active at neutral pH, contains and requires Zn2+ major class of enzymes that degrade cartilage inhibited by endogenous TIMPS (tissue inhibitors of metallo-proteinases)
what activates metalloproteinases
removal of propeptide by other proteases
chemical modification of propeptide by RONS
active zinc site targeted by hydroxamate series of MMP inhibitors
what is the cysteine switch mechanism
propeptide maintains MMP in an inactive state; interaction between conserved cysteine residue in pro-domain and active site zinc ion is disrupted; active site becomes accessible and MMP is activated; pro-domain does not need to be removed of a proMMP to acquire activity; only disruption of the zinc-thiol interaction is absolutely required
what are peptidomimetics
synthetic MMP inhibitors used in inflammation
how do peptidomimetics work
small hydroxamic acid based molecules used in zinc binding, based on collagen structre, inhibit MMP ativity
they lack specificity and act on most metalloenzymes
how do non-peptide hydroxamates compare to peptidomimetica
they have better selectivity
what are other inhibitors of MMPs
tetracycline derivatives, antibody therapies, endogenous inhibitors (TIMPs)
what are some examples of serine and cysteins proteinases
neutrophil elastase - acive at neutral pH, breaks down matrix proteins like chondritin and proteoglycans
endogenous inhibition by serpins (serine protease inhibitors)
serpins are readily inactivated by oxidation
what are some adverse effects of MMP inhibitors
muscoskeletal inhibitors, lack of specificity, key role in homeostatic connective tissue turnover
what does RONS stand for
reactive oxygen and nitrogen species
what is the role of RONS
essential for host defence
how are RONS produced
infiltrating leukocytes and tissue resident cells
NADPH catalyses formation of O2- which forms H2O2 which is further metabolised to HClO (H+ and ClO-)
H2O2 inactivated by catalase
reactive nitrogen species formed from NOS derived NO- combining with oxygen species
what is respiratory burst
leukocytes phagocytose bacteria, yeast, immune complexes, damaged tissue
proteases and ROS generated as part of host defence
how do ROS’ cause joint damage
rheumatoid synovial tissue undergoes cycles of hypoxia and reperfusion (oxidative stress); immune complex formation in some diseases, generation of superoxide and RONS (tissue injury, modulation of cell function)
what are the effects of RONS
activation of inflammatory gene transcription; amino acid modifications; matrix modifications; DNA damage; cell apoptosis and necrosis
what are some resident RONS for inflammation
chondrocytes, osteoclasts, fibroblasts
