PT4: Inflammation & Allergy in Asthma Flashcards
what is extrinsic asthma
atopic (allergic), young onset, hyperresponsive
what is intrinsic asthma
non-atopic (non-allergic), middle aged, hyperresponsive, more severe airflow limitation
what is allergy
changed reacticvity
usually used interchangably with immediate hypersensitivity (involves IgE mediated mast cell degeneration, synonymous with ‘atopy’ or ‘atopic diseases’)
what is atopy
allergy
what are allergens
antigens that elicit an allergic response
what is anaphylaxis
acute severe allergic reaction resulting in respiratory collapse
how is an allergy developed
strong genetic influence, allergenic potential, driven by T-helper lymphocyte subset and their products
what Th1 cytokines are involved in allergy
interferon-gamma
IL-12
what Th2 cytokines are involved in allergy
interleukin IL-4 and IL-3 (overlapping receptor usage with very similar actions)
IL-5, IL-9
what factors favour the Th1 phenotype
presence of older siblings, early exposure to day care, TB/measles/hep A infection, rural environment
what type of immunity does a Th1 phenotype give
protective immunity
what factors favour the Th2 phenotype
widespread use of antibiotics, western lifestyle, urban environment, diet, sensitisation to house-dust mites and cockroaches
what is the T-cell direction of allergic response
IL-4 and IL-13 switch B lymphocytes to make IgE antibody
IgE fixes onto FceR on the surface of tissue mast cells
what is IgE
relatively rare immunoglobulin in plasma
E= erythematous antibody
how is the IgE antibody used
Fc region binds with high affinity to FceR1 on mast cells and basophils
cross linking IgE (by antigen) bound to FceR1 on mast cell surface causes degranulation
what is the times course to develop allergy
initial sensitisation may take years; no or very limited symptoms during initial sensitisation and mast cell priming; sensitisation increases over years and re-exposure can trigger mast cell release
what are some examples of mast cell products
granule products (histamine)
TNF & other cytokines (inflammation and tissue growth)
proteases (tissue remodelling)
heparins (protective role)
membrane-derived lipid mediators of inflammation (leukotrines, prostanoids)
what level of histamine is found in the lungs
low level
what level of histamine is found in the skin
high level
what are some examples of H1 receptor antagonists
chlorpheniramine, astemizolem cetirizine
what are the uses of H1 receptor antagonists
(chlorpheniramine, astemizole, cetirizine)`
effective in allergic rhinitus, urticaria
no or little indication in asthma
astemizole and cetirizine have low lipophilicity and less CNS effect
what are cromones
disodium cromoglycate (DSCG), nedocromil mast cell stabalisers that inhibit mediator release from lung mast cells
when are cromones effective
effective in about half patients
effective against early and late phase asthma; antigen, irritant and exercise induced asthma; prolonged prophylaxis required
what are the other actions of cromones
inhibit eosinophil chemotaxis
inhibit sensory nerve fibre excitation and neural reflex
what is an example of an anti-IgE antibody
omalizumab
what is the anti-IgE antibody (omalizumab)
monoclonal antibody
binds Fc portion of IgE
prevents IgE binding to mast cells
protein drug (must be administered parenterally and very expensive)
approved for IgE mediated severe allergic asthma that is not responsive to glucocorticoids
how is immunotherapy used
escalating dose antigen under medical supervision, lisenced for use in allergy (not routine asthma), expensive
used for grass and pollen extracts, bee and wasp venom
what are the inflammatory mediators in asthma
smooth muscle, epithelium, bronchial venules, leukocyte chemotaxis and activation
what are some anti-inflammatory drugs used in asthma
glucocorticoids, mediator antagonists/inhibitors, cytokine inhibitors/antagonists
what are two examples of glucocorticoids
prednisolone, budesonide
how do glucocorticoids work
act mainly via regulating gene transcription (inhibit cytokine transcription, inhibit inflammatory leukocyte migration)
indirectly inhibit phospholipase A2 activity
what are mediator antagonists/inhibitors
orally active
leukotrine receptor antagonists
leukotrine synthesis inhibitors
what does LTRA stand for
leukotrine receptor antagonists
what are some examples of leukotrine receptor antagonists
montelukast, zafirlukast
what is an example of leukotrine synthesis inhibitors
zileuton
what leukotrines are active in asthma
LTC4 and LTD4 (cysteinyl leukotrienes); LTB4
what are the functions of LTC4 and LTD4 leukotrienes
potent constriction of airway smooth muscle, increase vascular permeability (oedema)
what is the function of the LTB4 leukoteiene
no direct bronchoconstriction, chemotactic for leukocytes
what is IL-5
growth factor, ‘primes’ and activates, chemotactic
what is non-allergic (intrinsic) asthma
many asthmatics not allergic, skin test negative (serum IgE levels still elevated), similar symptoms and tissue remodelling, innate immune system involvement
