Autonomic Innervation of Human Airways: Structure, Function, and Pathophysiology in Asthma

Abstract

The human airways are innervated via efferent and afferent autonomic nerves, which regulate many aspects of airway function. It has been suggested that neural control of the airways may be abnormal in asthmatic patients, and that neurogenic mechanisms may contribute to the pathogenesis and pathophysiology of asthma. In this review, the autonomic innervation of the human airways and possible abnormalities in asthma are discussed. The parasympathetic nervous system is the dominant neuronal pathway in the control of airway smooth muscle tone. Stimulation of cholinergic nerves causes bronchoconstriction, mucus secretion, and bronchial vasodilation. Although abnormalities of the cholinergic innervation have been suggested in asthma, thus far the evidence for cholinergic dysfunction in asthmatic subjects is not convincing. Sympathetic nerves may control tracheobronchial blood vessels, but no innervation of human airway smooth muscle has been demonstrated. β-Adrenergic receptors, however, are abundantly expressed on human airway smooth muscle and activation of these receptors causes bronchodilation. The physiological role of β-adrenergic receptors is unclear and their function seems normal in asthmatic patients. Inhibitory nonadrenergic noncholinergic (NANC) nerves, containing vasoactive intestinal peptide and nitric oxide, may be the only neural bronchodilator pathways in human airways. Although a dysfunction of inhibitory NANC nerves has been proposed in asthma, thus far no differences in inhibitory NANC responses have been found between asthmatics and healthy subjects. Excitatory NANC nerves, extensively studied in animal airways, have also been detected in human airways. In animal studies, stimulation of excitatory NANC nerves causes bronchoconstriction, mucus secretion, vascular hyperpermeability, cough, and vasodilation, a process called ‘neurogenic inflammation’. Recent studies have demonstrated an interaction between the excitatory NANC nervous system and inflammatory cells. Neuropeptides may influence the recruitment, proliferation, and activation of leukocytes. On the other hand, inflammatory cells may modulate the neuronal phenotype and function. The functional relevance of the excitatory NANC nervous system and its interaction with the immune system in asthma still remains to be elucidated.

Pharmacotherapy of Asthma

“…Activation of vagal nerves in the airway constricts bronchial smooth muscle and increases secretions from mucous-producing cells. 4 Toward the end of the early phase of asthmatic response (3-8 hours), airway inflammation becomes more prominent. 5 Neutrophils, attracted by chemotaxis to the area of inflamed airway, leave the more permeable blood vessel and enter the respiratory tissues.…”

“…This substance was later identified as the leukotrienes. 19 It is now known that several leukotrienes, such as LTB 4 , LTC 4 and LTD 4 , mediate a number of the responses seen during an asthma attack including bronchoconstriction, edema, excess mucous secretion, and bronchial hyperreactivity. Studies have shown LTD4 to be nearly 100 times more potent than histamine in causing bronchoconstriction.…”

Two Guanylylcyclases Regulate the Muscarinic Activation of Airway Smooth Muscle

“…The parasympathetic nervous system is the dominant neuronal pathway in the control of airway smooth muscle tone. Stimulation of cholinergic nerves causes bronchoconstriction, and mucus secretion as in [2]. The human airways are innervated via efferent and afferent autonomic nerves, which regulate many aspects of airway function.…”

“…It has been suggested that neural control of the airways may be abnormal in asthmatic patients, and that neurogenic mechanisms may contribute to the pathogenesis and pathophysiology of asthma. Although abnormalities of the cholinergic innervation have been suggested in asthma, thus far the evidence for cholinergic dysfunction in asthmatic subjects is not convincing as mentioned in references [1,2]. Acetylcholine (Ach) is the predominant parasympathetic neurotransmitter, acting as an autocrine or paracrine hormone in the airways and its role in the regulation of bronchomotor tone and mucus secretion from airway submucosal glands in the respiratory tract is well established as described in [2].…”

“…Although abnormalities of the cholinergic innervation have been suggested in asthma, thus far the evidence for cholinergic dysfunction in asthmatic subjects is not convincing as mentioned in references [1,2]. Acetylcholine (Ach) is the predominant parasympathetic neurotransmitter, acting as an autocrine or paracrine hormone in the airways and its role in the regulation of bronchomotor tone and mucus secretion from airway submucosal glands in the respiratory tract is well established as described in [2]. More recent findings suggest that acetylcholine regulates additional functions in the respiratory tract, may promoting airway inflammation and remodelling, including airway smooth muscle thickening in inflammatory lung diseases as reported in references [3][4][5].…”