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

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 TRPVl-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 [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]). Our results showed the following. 1) A pretreatment with TNF[alpha] (50 ng/ml) for ~24 h increased significantly the peak [DELTA][[[Ca.sup.2+]].sub.i] evoked by capsaicin (Cap) in these neurons. A pretreatment with the same concentration of TNF[alpha] for a longer duration (~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 KC1 were not affected by TNF[alpha]. 4) The TNF[alpha]-induced hypersensitivity to Cap was not prevented by pretreatment with indomethacin (30 [micro]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. intracellular calcium; pulmonary afferent; transient receptor potential vanilloid type 1; airway inflammation; asthma doi: 10.1152/ajplung.00111.2010.