Airway smooth-muscle tone

Category: signaling

Overview

Bronchial smooth-muscle tone balances bronchoconstriction against bronchodilation. CONSTRICTORS: vagal acetylcholine → M3 muscarinic → Gq → PLC → IP3/Ca²⁺ → contraction + mucus; cysteinyl-leukotrienes (LTD4) → CysLT1; histamine. DILATORS: β2-adrenoceptor → Gs → adenylate cyclase → cAMP → PKA → relaxation. Therapeutics map onto these: β2 agonists — short-acting salbutamol (rescue), long-acting salmeterol / formoterol / vilanterol (maintenance); antimuscarinics — short-acting ipratropium, long-acting tiotropium (COPD mainstay); methylxanthine theophylline + PDE4 inhibitor roflumilast raise cAMP / cut inflammation; CysLT1 antagonist montelukast; and inhaled corticosteroids (budesonide, fluticasone) suppress the upstream eosinophilic inflammation that drives bronchial hyperreactivity. Cross-links: beta_2, muscarinic, cyslt1, pde4, asthma_th2_eosinophil_inflammation.

Organ Systems

• respiratory

Pathway Steps

1. beta2-adrenoceptor → bronchodilation — via β2 → Gs → adenylate cyclase → cAMP → PKA → ASM relaxation. β2-agonists raise airway smooth-muscle cAMP, relaxing it. SABA (salbutamol) for rescue; LABA (salmeterol, formoterol, vilanterol) for maintenance, always paired with an ICS in asthma. Cross-link: beta_2.
2. M3-muscarinic-receptor → bronchoconstriction — via ACh → M3 → Gq → PLC → IP3/Ca²⁺ → ASM contraction + mucus secretion. Vagal acetylcholine constricts airways via M3. Antimuscarinics block it — short-acting ipratropium and long-acting tiotropium (a COPD mainstay). Cross-link: muscarinic.
3. cysteinyl-leukotriene-LTD4 → bronchoconstriction — via LTD4 → CysLT1 → bronchoconstriction + mucus + microvascular leak. Cysteinyl-leukotrienes are potent bronchoconstrictors; the CysLT1 antagonist montelukast blocks them (asthma, exercise-induced bronchoconstriction, allergic rhinitis). Cross-links: cyslt1, mast_cell_leukotriene_axis.
4. airway-cAMP → bronchodilation — via PDE3/4 degrade cAMP; theophylline (non-selective PDE-i + adenosine antagonist) + roflumilast (PDE4-i) inhibit → ↑cAMP. Phosphodiesterases degrade airway cAMP. Theophylline raises cAMP and antagonizes bronchoconstrictor adenosine; roflumilast (PDE4 inhibitor) reduces inflammation in severe COPD. Cross-link: pde4.
5. airway-eosinophilic-inflammation → reduced-bronchial-hyperreactivity — via inhaled corticosteroid → glucocorticoid receptor → ↓Th2 cytokine transcription. Inhaled corticosteroids (budesonide, fluticasone) suppress the eosinophilic inflammation underlying bronchial hyperreactivity — the controller backbone of asthma. Cross-link: asthma_th2_eosinophil_inflammation.

Known Modulators

• salbutamol (activator) — β2-adrenoceptor → ↑cAMP → bronchodilation (SABA, rescue)
• salmeterol (activator) — β2-adrenoceptor (LABA, maintenance)
• formoterol (activator) — β2-adrenoceptor (LABA, fast-onset)
• vilanterol (activator) — β2-adrenoceptor (ultra-LABA, once-daily)
• ipratropium (inhibitor) — M3 muscarinic receptor → ↓bronchoconstriction (SAMA)
• tiotropium (inhibitor) — M3 muscarinic receptor (LAMA, COPD mainstay)
• theophylline (inhibitor) — phosphodiesterase + adenosine receptor → ↑cAMP, bronchodilation
• roflumilast (inhibitor) — PDE4 → ↑cAMP, anti-inflammatory (severe COPD)
• montelukast (inhibitor) — CysLT1 → blocks leukotriene bronchoconstriction
• budesonide (inhibitor) — GR (ICS) → ↓airway inflammation
• fluticasone (inhibitor) — GR (ICS) → ↓airway inflammation