Mechanisms of asthma + hyper reactivity Flashcards
What is definition of asthma?
Chronic inflammatory disorder of airways:
Usually associated with variable airflow obstruction + increased reactivity/responsiveness to variety of stimuli
(hyperreactivity/hyperresponsiveness).
Obstruction is often reversible - spontaneously or with treatment, but chronic asthma reversibility is poor.
Early response - bronchconstriction, then recovery.
Late response - secondary reduction via oedema, secretions + inflammation -
How is lung function tested?
PEFR - rate
FEV1 - volume in 1 sec.
Both decrease in asthma.
Severe asthmatics have hypersensitivity to bronchoconstrictor and greater decrease in FEV1 (max response)
What are the general mechanisms of hyper responsiveness?
Smooth muscle hyperplasia/hypertrophy - increased SM contractility.
- stimulated by inflammation - more and bigger muscles, greater contractility and reduced bronchiole diameter.
Increased excitatory nerve activity - ACh on M3 receptors in SM.
+ ENANC activity with Neurokin A, Neurokinin B and SP = act on NK receptors.
- stimulating elevated intracellular free Ca”+ and SM contraction.
Stimulation of sensory nerve pathways in airways + NKA activity on sensory afferent nerves - leads to increased vagal efferent output on airway SM = greater airway constriction.
(antidromitc response)
Decreased bronchodilator activity - circulating adrenaline acts on B-adrenoceptors - Bronchodilation.
iNANC - inhibitory:
Dilator neuropeptides like CGRP, VIP = activate AC = raise cAMP.
Neuronally-derived NO - acts on soluble GC = raise cGMP.
= act on epithelial cells - increases NO release from epithelial cells and released to cause SM relaxation.
Inflammation - epithelial damage, exposure of sensory nerves = hyper sensitivity…
Oedema and secretions (mucus plugging)reduce luminal diameter.
What drugs are used to treat initial response in asthma?a
B2 adrenoceptor agonists:
Gs coupled = AC = cAMP = PKA = inhibits MLCK + opens K+ channels and leads to Ca2+ sequestration.
Salbutamol - most commonly prescribed B2 agonist for bronchospasm in asthma.
Shortest acting, least lipophilic with rapid onset.
Interacts reversibly with b2 receptor and doesn’t dissolve in phospholipid membrane like others..
PDE inhibitors:
Aminophylline - a mixture of theophylline and ethylenediamine.
Lower potency and shorter acting.
Inhibiting PDE III and IV in airway SM…. increasing cAMP = leading to bronchodilation.
What are involved in secondary response?
Damaged epithlial lining exposes sensory nerves = hypersensitivity.
Oedema and secretions lead to decreased luminal diameter - mucus plugging.
- Increased permeability and vasodilation in venules from neuropeptide release, leading to eodema.
Inflammatory mediators and leukocyte recruitment
What WBCs are involved in secondary response?
Eleated eosinophils in blood, tissues and BAL of asthmatics.
Increased Th2 lymphocytes, macrophages and neutrophils (in BAL in severe asthma).
What is the role of eosinophils?
Production of inflammatory agents:
RONS - cause epithelial damage
Release of LTC4, TxA2 - bronchoconstrictor and pro-inflammatory.
(LTC4 and LTD4 are cysteinyl leukotrienes - potent bronchoconstrictors and increase vascular permeability, leading to oedema….
LTB4 - is Chemotactic and activates WBCs)
Cationic proteins - leading to further epithelial damage, like MBP, ECP..
Pro-inflammatory cytokines -
How to treat 2ndary response?
Glucocorticoids - prednisolone
PDE inhibitors - theophylline or Roflumilast
Leukotriene antagonists/synthesis inhibitors - Zileuton
How can Zileuton and Montelukast work?
ZIleuton inhibits 5-lipooxygenase - preventing synthesis of leukotrienes.
Montelukast - inhibits LTC4 and LTD4…
How can glucocorticoids help asthma?
Reduce secondary response driven by inflammation.
Indirectly inhibit PLA2 - decreasing LTB4, LTC4 and LTD4 synthesis as well as TxA2.
Mainstay second line alongside Beta agonists.
Inhibit inflammatory leukocyte migration and cytokine transcription.
