LAUSR

Lung ischemia-reperfusion injury (LIRI) is a common and severe clinical complication. As the injury occurs, the pulmonary afferent nerves play an important role in regulating respiratory functions under pathophysiological conditions. The purpose of this study was to examine expression of proteinaseactivated receptor-2 (PAR2) and transient receptor potential A1 (TRPA1) in pulmonary vagal afferent nerves of LIRI and further to determine molecular mediators linking activation of PAR2 and TRPA1. A rat model of LIRI was used. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were employed to examine pro-inflammatory cytokines (PICs, i.e., IL-1β, IL-6 and TNF-α), and the protein levels of PIC receptors, PAR2, TRPA1, and intracellular signals. In the results, IL-1β, IL-6 and TNF-α along with their receptors were amplified in afferent nerves of LIRI rats as compared with control rats. Sensory PAR2 and TRPA1 were also upregulated by LIRI. Blocking PAR2 by infusion of FSLLRY-NH2 attenuated upregulation of TRPA1 via intracellular signals, namely p38-MAPK and JNK. Moreover, blocking individual PIC receptor attenuated PAR2 and TRPA1 in pulmonary vagal afferent nerves. Our data showed specific signaling pathways leading LIRI to activation of PIC signal and activation of PAR2 and TRPA1 in pulmonary vagal afferent nerves via intracellular mediators. Targeting one or more of these signaling molecules may present opportunities to improve the abnormalities in vagal afferent nerve-mediated respiratory functions observed as LIRI occurs.