Calcium transient evoked by TRPV1 activators is enhanced by tumor necrosis factor-α in rat pulmonary sensory neurons

Hu Y, Gu Q, Lin RL, Kryscio R, Lee LY. Calcium transient evoked by TRPV1 activators is enhanced by tumor necrosis factor-alpha in rat pulmonary sensory neurons. Am J Physiol Lung Cell Mol Physiol 299: L483-L492, 2010. First published July 16, 2010; doi:10.1152/ajplung.00111.2010.-TNF alpha, a proinflammatory cytokine known to be involved in the pathogenesis of allergic asthma, has been shown to induce hyperalgesia in somatic tissue via a sensitizing effect on dorsal root ganglion neurons expressing transient receptor potential vanilloid type 1 receptor (TRPV1). Because TRPV1-expressing pulmonary sensory neurons play an important role in regulating airway function, this study was carried out to determine whether TNF alpha alters the sensitivity of these neurons to chemical activators. Responses of isolated nodose and jugular ganglion neurons innervating the rat lungs were determined by measuring the transient increase in intracellular Ca2+ concentration ([Ca2+](i)). Our results showed the following. 1) A pretreatment with TNF alpha (50 ng/ml) for similar to 24 h increased significantly the peak Delta[Ca2+](i) evoked by capsaicin (Cap) in these neurons. A pretreatment with the same concentration of TNF alpha for a longer duration (similar to 48 h) did not further increase the response, but pretreatment for a shorter duration (1 h) or with a lower concentration (25 ng/ml, 24 h) failed to enhance the Cap sensitivity. 2) The same TNF alpha pretreatment also induced similar but less pronounced and less uniform increases in the responses to acid (pH 6.5-5.5), 2-aminoethoxydiphenyl borate (2-APB), a common activator of TRPV1, V2, and V3 channels, and allyl isothiocyanate (AITC), a selective activator of TRPA1 channel. 3) In sharp contrast, the responses to ATP, ACh, and KCl were not affected by TNF alpha. 4) The TNF alpha-induced hypersensitivity to Cap was not prevented by pretreatment with indomethacin (30 mu M). 5) The immunoreactivity to both TNF receptor types 1 and 2 were detected in rat vagal pulmonary sensory neurons. In conclusion, prolonged treatment with TNF alpha induces a pronounced potentiating effect on the responses of isolated pulmonary sensory neurons to TRPV1 activators. This action of TNF alpha may contribute in part to the airway hyperresponsiveness induced by this cytokine.