inflammatory mediators

Question 1

what are inflammatory reactions characterised by

Answer 1

increased blood flow
increased vascular permeability
pain
cellular infiltration
loss of function

Question 2

what type of molecules are inflammatory mediators labelled as and which molecules are they

Answer 2

local hormone/autacoid; since they are produced locally around the site of stimulus

histamine, 5HT, eicosanoids, kinins, platelet activating factor and cytokines

Question 3

how is histamine produced, how is this inhibited

Answer 3

produced from histidine via the enzyme histidine decarboxylase

enzyme inhibitor: alpha methyl histidine

Question 4

what might stimulate acute inflammation

Answer 4

infarction, bacterial infections, toxins, trauma

Question 5

what happens during acute inflammation

Answer 5

vascular changes; vascular dilation, increased blood flow, increased permeability

neutrophil recruitment

release of inflammatory mediators

Question 6

what might stimulate chronic inflammation

Answer 6

viral infections, chronic infections, persistant injury, autoimmune disease

Question 7

which inflammatory mediators cause increased blood flow

Answer 7

histamine, 5HT, nitric oxide, bradykinin, platelet activating factor, PGE2 and PGI2

Question 8

which inflammatory mediators lead to increased vascular permeability to allow cellular filtration

Answer 8

histamine, bradykinin, platelet activating factor, TNFalpha and IL-1, PGE2

Question 9

what inflammatory mediators cause pain

Answer 9

substance P, bradykinin, calcitonin gene-related peptide

Question 10

what inflammatory mediators cause loss of function

Answer 10

lipases, proteases, free radicals

Question 11

how do neutrophils cross vasculature

Answer 11

(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

Question 12

what role doe mast cells play in inflammation

Answer 12

they are activated by IgE and complement

release of inflammatory mediators: histamine, leukotrienes, prostaglandins, platelet activating factor, interleukins (IL4-6)

Question 13

what is role of neutrophils in inflammation

Answer 13

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

Question 14

what is role of eosinophils in inflammation

Answer 14

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)

Question 15

what is role of macrophages in inflammation

Answer 15

antigen presentation, microbe killing, granuloma formation, angiogenesis, wound healing

Question 16

what function do neurones have in inflammation

Answer 16

only in neurogenic inflammation; release of neuropeptides which is activated by bradykinin and 5HT

Question 17

how is bradykinin synthesised

Answer 17

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

Question 18

describe the bradykinin receptors

Answer 18

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

Question 19

whre are bradykinin receptors located

Answer 19

endothelium, vascular smooth muscle, fibroblasts, epithelium, sensory nerves, leukocytes

Question 20

how do ACE inhibitors affect bradykinin

Answer 20

ACE converts bradykinin into inactive peptides, so ACE inhibitors will increase bradykinin concentrations, also preventing angiotensin 2, a vasoconstrictor

Question 21

how is complement activated

Answer 21

3 pathways: alternative pathway(activated by microbes), classical pathway( activated by antibody), lectin pathway( activated by manose, a bacterial sugar)

Question 22

what is they key event in all pathways of complement

Answer 22

C3 convertase cleaves C3 into C3a and C3b

Question 23

what are important complement molecules and what is their function

Answer 23

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

Question 24

where is histamine found as what causes its release

Answer 24

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)

Question 25

how is histamine metabolised

Answer 25

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)

Question 26

what is effect of kinins, including bradykinin

Answer 26

vasodilation, increase venular permeability, cause pain, contract smooth muscle