Neural regulation of airway smooth muscle tone

Abstract

Airway smooth muscle is innervated by sympathetic and parasympathetic nerves. When activated, airway nerves can markedly constrict bronchi either in vivo or in vitro, or can completely dilate a precontracted airway. The nervous system therefore plays a primary role in regulating airway caliber and its dysfunction is likely to contribute to the pathogenesis of airways diseases. The predominant contractile innervation of airway smooth muscle is parasympathetic and cholinergic in nature, while the primary relaxant innervation of the airways is comprised of noncholinergic (nitric oxide synthase- and vasoactive intestinal peptide-containing) parasympathetic nerves. These parasympathetic nerves are anatomically and physiologically distinct from one another and differentially regulated by reflexes. Sympathetic-adrenergic nerves play little if any role in directly regulating smooth muscle tone in the human airways. Activation of airway afferent nerves (rapidly adapting receptors, C-fibers) can evoke increases in airway smooth muscle parasympathetic nerve activity, or decreases in parasympathetic nerve activity (through activation of slowly adapting receptors). Extrapulmonary afferents can also modulate nerve mediated regulation of airway smooth muscle tone. In guinea pigs and rats, peripheral activation of tachykinin-containing airway afferent nerves evokes bronchospasm via release of substance P and neurokinin A. This effect of airway afferent nerve activation appears to be unique to guinea pigs and rats. The actions and interactions between the components of airway innervation are discussed.

Introduction

Pioneering studies carried out prior to and just after the beginning of the 20th century established a powerful hypothetical model of autonomic control of airway smooth muscle: Parasympathetic, cholinergic pathways with preganglionic fibers carried by the vagus nerves mediate bronchospasm via activation of cholinergic ganglion neurons intrinsic to the airways, while adrenergic nerve fibers emanating from thoracic and superior cervical sympathetic ganglia mediate bronchodilatation (see Dixon and Brodie, 1903, Dixon and Ransom, 1912). Based on this model it was further hypothesized that airway caliber was determined by the balance of these opposing influences, and that pathological conditions such as asthma produced an imbalance in autonomic control, leading to bronchospasm and airways hyperresponsiveness (reviewed in Macklin, 1929, Widdicombe, 1963, Barnes, 1986).

The utility of the model of airway smooth muscle innervation described above should not be underestimated. In some species, this hypothetical arrangement of the nervous system has withstood nearly a century of research without refutation (Widdicombe, 1963, Cabezas et al., 1971). Likewise, in virtually all other species, this scheme has had reasonably accurate predictive value, an assertion that is supported by the fact that it produced two major classes of therapeutics for pulmonary disease (Goldie et al., 1990, Gross, 1997). Nevertheless, with the discovery of nonadrenergic, noncholinergic (NANC) nerves innervating airway smooth muscle, it became necessary to reassess the validity of some aspects of this model of airway neural control (Barnes, 1986, Diamond and Altiere, 1988, Canning and Undem, 1994). This review summarizes our current understanding of airway smooth muscle innervation.