PT 4 - Asthma inflammation and allergy

whats extrinsic (Atopic) asthma

70%

type 1 hypersensitivity reaction induced by exposure to extrinsic antigen

family history, develops early in life

whats intrinsic (non-atopic) asthma

30%

initiated by non-allergic mechanisms

no family history, occurs in older individuals

what does allergy mean

changed reactivity - type 1 hypersensitvity

involves IgE mediated mast cell degranulation

why do allergies develop

genetics

allergen properties - physiochemical characteristics, exposure dose, exposure timing

enviroment

what are allergic responses mainly driven by

Th2 cells - producde IL-4,5-13

whats allergic disease associated with

increased Th2:Th1 ratio

what do Th2 cytokines drive

IgE production

eosinophils

allergic inflammation

what factors favour Th2

antiboitcs

urban enviroment

western lifestyle

what do IL4 and IL-13 do

switch B lymphocytes to make IgE antibody

what does IgE bind to

FceR1 receptors on mast cell surface

what does cross linking of IgE on mast cells do

causes degranulation

how long might initial senstisation in allergy time course take

years

what happens during sensitisation

IgE levels rise and mast cells become armed

whats the final step in allergy time course

re-exposure - causes cross links of IgE, mast cell degranulation causing allergic symptoms

what are the 4 granule products

histamine - causes bronchoconstriction

TNF and other cytokines - promote inflammation

proteases - can cause tissue damage

heparins

what are the two membrane derived lipid mediators of inflammation

leukotrienes - cause strong bronchoconstriction

prostaglandins - inflammatory

what do mast cells recruit

eosinophils

neutrophils

creating late phase inflammation

what do eosinophils release

basic proteins

ROS

What do eosinophils produce

cytokines, leukotrienes and prostaglandins

what 4 things do inflammatory mediators do in asthma

cause smooth muscle contraction - bronchoconstriction

cause epithelial damage - more sensitivity

increased vascular permability - odema/swelling

leukocyte recruitment

what do Cysteinyl leukotrienes (LTC4 and LTD4) do?

very potent broncoconstrictors

increase mucus prodcution and vascular permability

what does the leukotriene LTB4 do?

no direct bronchoconstriction

chemotactic for leukocytes (recruits)

what does damage to epithelial cells of the lungs cause release of and what do they do?

alarmins - IL-25,33 and thymic stromal lymphopoietin

amplify Th2 responses and promote inflammaiton

what are the three main therapeutic targets in asthma

1. mast cells

2. eosinophils

3. inflammation

what an example of H1receptor antagonist? why is it not very effective in asthma

cetirizine (H1 receptor antagonists)

asthma involves many mediators not just histamine

what are chromoones

they are mast cell stabilisers - inhibit mediator release form lung mast cells

eg nedocromil

these are not rescue drugs

what are the two additional actions of chromones

inhibit eosinophil chemotaxis

inhibit sensory nerve fibre excitation and neural reflex

what bioloigc therapy targets mast cells

omalizumab - monoclonal antibody, binds Fc portion of IgE

prevents IgE binding to mast cells

what biologic therapy targets eosinophils

dupilumab - anti IL-4 receptor antibody -reduce Th2 receptor signalling

mepolizumab - anti-IL-5 antibodies -reduce eosinophils

how do corticosteroids target inflammation give 2 examples

act by modulating gene trascription - decrease proinflammatory molecules, increase anti-inflammatory molecules

eg budesonide, prednisolone