We have earlier shown that H₂S acts as a mediator of inflammation. In this study, we have investigated the involvement of substance P and neurogenic inflammation in H₂S-induced lung inflammation. Intraperitoneal administration of NaHS (1-10 mg/kg), an H₂S donor, to mice caused a significant increase in circulating levels of substance P in a dose-dependant manner. H₂S alone could also cause lung inflammation, as evidenced by a significant increase in lung myeloperoxidase activity and histological evidence of lung injury. Maximum effect of H₂S on substance P levels and on lung inflammation was observed 1 h after NaHS administration. At this time, a significant increase in lung levels of TNF- and IL-1 was also observed. In substance P deficient mice, the preprotachykinin-A (PPT-A) knockout mice, H₂S did not cause any lung inflammation. Furthermore, pretreatment of mice with CP-96,345 (2.5 mg/kg, i.p.), an antagonist of the neurokinin-1 (NK-1) receptor, protected mice against lung inflammation caused by H₂S. However, treatment with antagonists of NK2, NK3 and calcitonin-gene related peptide (CGRP) receptors did not have any effect on H₂S-induced lung inflammation. Depleting neuropeptide from sensory neurons by capsaicin (50mg/kg, s.c.) significantly reduced the lung inflammation caused by H₂S. In addition, pretreatment of mice with capsazepine (15 mg/kg, s.c.), an antagonist of the transient receptor potential vanilloid (TRPV)-1, protected mice against H₂S-induced lung inflammation. These results demonstrate a key role of substance P and neurogenic inflammation in H₂S-induced lung injury in mice.