Neuronal modulation of airway and vascular tone and their influence on nonspecific airways responsiveness in asthma

Abstract

The autonomic nervous system provides both cholinergic and noncholinergic neural inputs to end organs within the airways, which includes the airway and vascular smooth muscle. Heightened responsiveness of the airways to bronchoconstrictive agents is a hallmark feature of reactive airways diseases. The mechanisms underpinning airways hyperreactivity still largely remain unresolved. In this paper we summarize the substantial body of evidence that implicates dysfunction of the autonomic nerves that innervate smooth muscle in the airways and associated vasculature as a prominent cause of airways hyperresponsiveness in asthma.

Figure 1

Two distinct vagal parasympathetic pathways regulate airway tone. Cholinergic preganglionic neurons originate in the brainstem and provide cholinergic drive to airway autonomic ganglia. Cholinergic postganglionic neurons are the major contractile input to the airways, whereas noncholinergic neurons expressing nitric oxide and vasoactive intestinal peptide provide the relaxant innervation to the airways. Airway sensory nerves contribute differential reflex regulation over cholinergic and non-cholinergic vagal pathways at the level of the brainstem and/or the airway ganglia. Dysfunction in ganglionic neurotransmission, neuromuscular transmission, or sensory reflexive control will precipitate changes in airway smooth muscle reactivity.

Figure 2

Airway vascular tone and blood flow regulate airway smooth muscle reactivity. The airway vasculature is densely innervated by sympathetic (tyrosine hydroxylase expressing) neurons which provide a basal level of adrenergic vascular tone. Soluble and insoluble particles in the airway wall are actively cleared by the submucosal vasculature. Increased blood flow is associated with increased clearance, and this can significantly modify airway smooth muscle reactivity to bronchoactive agents which are deposited onto, or generated within, the airway wall. See text for additional details.