In chronic asthma, structural remodeling ensues, causing thickening of airway walls, bronchial hyper-responsiveness, and mucous hypersecretion.

There are two primary mechanisms the body employs to maintain airway caliber and control airway smooth muscle tone, namely the neural networks and inflammatory mediators.

The parasympathetic innervation dominates the regulation of lower respiratory airway smooth muscles and secretion. The postganglionic cholinergic nerves of the parasympathetic nervous system mediate muscle contraction through the acetylcholine-associated pathways.

The sympathetic nervous system indirectly regulates airway smooth muscle tone through the activation of adrenal medullary cortex (epinephrine release) and surface b2 receptors (b2AR) on airway muscles. 

Cross-talk between muscarinic AChR and b2AR in airway smooth muscles determines the lung function.

In addition, non-adrenergic non-cholinergic nerves mediate muscle relaxation through nitric oxide  or the neuropeptide vasoactive intestinal peptide. The muscarinic (M3) receptors on smooth muscle are pro-inflammatory and play a profound role in airway constriction and glandular secretion.

Low-voltage VNS induced a modest rise in the plasma epinephrine and norepinephrine Levels. Cervical VNS has demonstrated an acute bronchodilatory effect possibly through the adrenergic system or other central mechanism.  (Yuan and Silberstein, 2016c)