Sustained sensitizing effects of tumor necrosis factor alpha on sensory nerves in lung and airways

Tumor necrosis factor alpha (TNF alpha) plays a significant role in the pathogenesis of airway inflammatory diseases. Inhalation of aerosolized TNF alpha induced airway hyperresponsiveness accompanied by airway inflammation in healthy human subjects, but the underlying mechanism is not fully understood. We recently reported a series of studies aimed to investigate if TNF alpha elevates the sensitivity of vagal bronchopulmonary sensory nerves in a mouse model; these studies are summarized in this mini-review. Our results showed that intratracheal instillation of TNF alpha induced pronounced airway inflammation 24 h later, as illustrated by infiltration of eosinophils and neutrophils and the release of inflammatory mediators and cytokines in the lung and airways. Accompanying these inflammatory reactions, the sensitivity of vagal pulmonary C-fibers and silent rapidly adapting receptors to capsaicin, a selective agonist of transient receptor potential vanilloid type 1 receptor, was markedly elevated after the TNF alpha treatment. A distinct increase in the sensitivity to capsaicin induced by TNF alpha was also observed in isolated pulmonary sensory neurons, suggesting that the sensitizing effect is mediated primarily through a direct action of TNF alpha on these neurons. Furthermore, the same TNF alpha treatment also induced a lingering (>7days) cough hyperresponsiveness to inhalation challenge of NH3 in awake mice. Both the airway inflammation and the sensitizing effect on pulmonary sensory neurons caused by the TNF alpha treatment were abolished in the TNF-receptor double homozygous mutant mice, indicating the involvement of TNF-receptor activation. These findings suggest that the TNF alpha-induced hypersensitivity of vagal bronchopulmonary afferents may be responsible for, at least in part, the airway hyperresponsiveness caused by inhaled TNF alpha in healthy individuals. (C) 2017 Elsevier Ltd. All rights reserved.