Heavy metals zinc, cadmium and copper stimulate pulmonary C‐fibers via direct activation of TRPA1

Abstract

Airway exposure to zinc dust and zinc‐containing ambient particulates can cause symptoms of airway irritation and inflammation. However, the underlying molecular and cellular mechanisms are largely unknown. Transient receptor potential A1 (TRPA1) is selectively expressed in a subpopulation of pulmonary C‐fiber afferents, and has been considered as a major irritant sensor in the lung and airways. Using whole‐cell patch‐clamp recording and Ca2+ imaging, we have demonstrated that application of ZnCl2 concentration‐dependently evoked inward current and Ca2+ transient in isolated vagal pulmonary sensory neurons; both responses were almost completely prevented after pretreatment with AP18, a selective TRPA1 antagonist. In anesthetized spontaneously breathing animals, intratracheal instillation of ZnCl2 (2 mM, 25 μl) evoked pronounced respiratory sensory irritation in wild‐type mice, and the effect was essentially absent in TRPA1‐deficient mice. In addition, our study showed that two other heavy metals cadmium and copper also stimulated pulmonary sensory neurons via direct activation of TRPA1. In summary, our results suggest that activation of TRPA1 in pulmonary C‐fiber sensory nerves may contribute to the respiratory toxicity induced by airway exposure to these three heavy metals. Funded in part by grants from NIH AI076714 and AHA 0835320N.