inflammatory mediators Flashcards
what are inflammatory reactions characterised by
increased blood flow increased vascular permeability pain cellular infiltration loss of function
what type of molecules are inflammatory mediators labelled as and which molecules are they
local hormone/autacoid; since they are produced locally around the site of stimulus
histamine, 5HT, eicosanoids, kinins, platelet activating factor and cytokines
how is histamine produced, how is this inhibited
produced from histidine via the enzyme histidine decarboxylase
enzyme inhibitor: alpha methyl histidine
what might stimulate acute inflammation
infarction, bacterial infections, toxins, trauma
what happens during acute inflammation
vascular changes; vascular dilation, increased blood flow, increased permeability
neutrophil recruitment
release of inflammatory mediators
what might stimulate chronic inflammation
viral infections, chronic infections, persistant injury, autoimmune disease
which inflammatory mediators cause increased blood flow
histamine, 5HT, nitric oxide, bradykinin, platelet activating factor, PGE2 and PGI2
which inflammatory mediators lead to increased vascular permeability to allow cellular filtration
histamine, bradykinin, platelet activating factor, TNFalpha and IL-1, PGE2
what inflammatory mediators cause pain
substance P, bradykinin, calcitonin gene-related peptide
what inflammatory mediators cause loss of function
lipases, proteases, free radicals
how do neutrophils cross vasculature
(check immunology notes)
Rolling: neutrophils are attracted to vasculature via selectins and mucins; selectins P and E are expressed on endothelium, expression is caused by cytokines, sugar on neutrophil surface binds to these selectins
tight adhesion: after neutrophils bind to selectins it causes neutrophils to start expressing integrins such as LFA-1
LFA-1 allows neutrophil to bind to ICAM-1 on endothelium causing firm binding/ adhesion
ICAM-1 is caused by TNF and other inflammatory mediators
transmigration: after adhesion neutrophil can squeeze through since vasculature is more permeable due to cytokines, the process is called diapedesis
what role doe mast cells play in inflammation
they are activated by IgE and complement
release of inflammatory mediators: histamine, leukotrienes, prostaglandins, platelet activating factor, interleukins (IL4-6)
what is role of neutrophils in inflammation
first cells to migrate through vasculature (via ICAM-1)
function: phagocytosis and kill opsonised bacteria
neutrophils release leukotrienes, prostaglandin free radicals, proteases and interleukins: IL-1 and TNFalpha
what is role of eosinophils in inflammation
similar to neutrophils however they have more granules
aid in parasitic infections and in late phase asthma and allergic inflammation
release leukotrienes, prostaglandins, proteases, interleukins (1, 5, 6, 8 and TNFalpha)
what is role of macrophages in inflammation
antigen presentation, microbe killing, granuloma formation, angiogenesis, wound healing
what function do neurones have in inflammation
only in neurogenic inflammation; release of neuropeptides which is activated by bradykinin and 5HT
how is bradykinin synthesised
2 pathways:
one pathway:
low molecular weight kininogen is produced in glands, pancreas, kidney and neutrophils
low molecular weight kininogen is converted to kallidin by tissue kallikrein
kallidin (lys-bradykinin) is converted to bradykinin by aminopeptidase
other pathway:
high molecular weight kininogen is converted to bradykinin via plasma kallikrein
bradykinin and kallidin (lys-BK) are both metabolised by carboxypeptidases which add a des-Arg group to them, both metabolites are still active
describe the bradykinin receptors
B1 and B2 receptors, both GPCRs, both are Gq/i
B2: consitutive (always there)
acts through release of other mediators such as nitric oxide and prostaglandins, quickly desensitised through internalisation, agonists are bradykinin and kallidin, antagonist: HOE140
B1:
expression of B1 receptors is induced via cytokines
not internalised so is resistant to desensitisation
agonists: des-Arg kallidin (lys-des-arg bradykinin, a kallidin metabolite)
and des-Arg bradykinin (DABK) (a bradykinin metabolite)
(metabolites of B2 receptors are B1 receptor agonists)
antagonists: des-Arg HOE140
whre are bradykinin receptors located
endothelium, vascular smooth muscle, fibroblasts, epithelium, sensory nerves, leukocytes
how do ACE inhibitors affect bradykinin
ACE converts bradykinin into inactive peptides, so ACE inhibitors will increase bradykinin concentrations, also preventing angiotensin 2, a vasoconstrictor
how is complement activated
3 pathways: alternative pathway(activated by microbes), classical pathway( activated by antibody), lectin pathway( activated by manose, a bacterial sugar)
what is they key event in all pathways of complement
C3 convertase cleaves C3 into C3a and C3b
what are important complement molecules and what is their function
C3a: activates degranulation of mast cells
C3b: causes clearance of immune complexes, and opsonisation
C5a: causes degranulation of mast cells
MAC (membrane attack complex): (end product of complement cascade), causes pores to form in bacterial cell wall causing lysis
where is histamine found as what causes its release
mast cells (found in complex with acidic protein and heparin), basophils and histaminergic neurones
release is caused by; IgE, C5a and C3a, substance P, and morphine (exogenous)
how is histamine metabolised
it is oxidised by diamine oxidase (histamines)
N-methylation via N-methyltransferase
acetylation: via gut flora
oral doses of histamine are acetylated and oxidised (diamine oxidase is in gut and liver)
what is effect of kinins, including bradykinin
vasodilation, increase venular permeability, cause pain, contract smooth muscle
