Abstract
Prior studies have demonstrated that the ion channel TRPV4 is functionally expressed in airway smooth muscle cells and that TRPV4 SNPs are associated with airflow obstruction in COPD patients. We sought to employ isometric tension measurements in ex vivo airways to determine whether acute pharmacological activation of TRPV4 with the potent agonist GSK1016790 would constrict human bronchial tissue. As predicted, TRPV4 activation in the human airway produces contractions that are blocked by the non-selective TRP channel blocker ruthenium red. Moreover, the novel TRPV4-selective blocker GSK2334775 inhibited these contractions over a concentration range consistent with its in vitro potency against recombinant and native TRPV4-containing channels. Surprisingly, TRPV4-dependent contractions were also blocked by a 5-lipoxygenase inhibitor and two structurally-distinct cysteinyl leukotriene 1 receptor antagonists. In aggregate, our results fail to support the hypothesis that TRPV4 in airway smooth muscle cells acutely regulates airway contractility. Rather, we provide pharmacological evidence that TRPV4 activation causes human airway constriction that is entirely dependent upon the production of cysteinyl leukotrienes. Together, these data identify a novel mechanism by which TRPV4 activation may contribute to pathological remodeling and inflammation, in addition to airflow obstruction, in the diseased human respiratory tract.
- eicosanoids
- leukotrienes
- pulmonary toxicology
- respiratory toxicants
- transient receptor potential channels
- The American Society for Pharmacology and Experimental Therapeutics