Substance P-induced airway hyperreactivity is mediated by neuronal M(2) receptor dysfunction

Area of Science:

• Neuroimmunology
• Respiratory Medicine
• Pharmacology

Background:

• Neuronal muscarinic M(2) receptors normally inhibit acetylcholine release from vagus nerves.
• Airway hyperreactivity in asthma models is linked to M(2) autoreceptor blockade by eosinophil major basic protein (MBP).
• Substance P, a neuropeptide, induces eosinophil degranulation and airway hyperreactivity.

Purpose of the Study:

• To investigate if substance P-induced airway hyperreactivity is mediated by MBP release and M(2) receptor dysfunction.
• To explore the role of neurokinin-1 (NK(1)) receptors in this process.

Main Methods:

• Anesthetized and ventilated guinea pigs received [Sar(9),Met(O(2))(11)]-substance P intravenously.
• M(2) receptor function and airway reactivity to vagal stimulation were assessed.
• Interventions included inflammatory cell depletion (cyclophosphamide), MBP antibody administration, NK(1) receptor antagonist (SR-140333), and intravenous heparin.

Main Results:

• Substance P administration induced M(2) receptor dysfunction and airway hyperreactivity.
• Pre-treatment with cyclophosphamide, MBP antibody, or SR-140333 prevented these effects.
• Intravenous heparin rapidly reversed M(2) dysfunction and hyperreactivity.
• These findings suggest substance P stimulates NK(1) receptors, leading to MBP release from lung eosinophils.

Conclusions:

• Substance P-induced airway hyperreactivity is mediated by MBP released from eosinophils.
• MBP blocks inhibitory neuronal M(2) receptors, increasing acetylcholine release and causing hyperreactivity.
• This pathway involves NK(1) receptor activation and highlights a neuro-immune mechanism in airway hyperresponsiveness.