A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury

作者：Dib Marwan; Zsengeller Zsuzsanna; Mitsialis Alex; Lu Bao; Craig Stewart; Gerard Craig; Gerard Norma P^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2009, 297(4): L687-L697.

DOI：10.1152/ajplung.90509.2008

• tachykinins
• neurogenic inflammation
• oxidative lung injury
• transient receptor potential vanilloid type 1
• TRPV1

Dib M, Zsengeller Z, Mitsialis A, Lu B, Craig S, Gerard C, Gerard NP. A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury. Am J Physiol Lung Cell Mol Physiol 297: L687-L697, 2009. First published July 24, 2009; doi:10.1152/ajplung.90509.2008.-The neuropeptide substance P manifests its biological functions through ligation of a G protein-coupled receptor, the NK1R. Mice with targeted deletion of this receptor reveal a preponderance of proinflammatory properties resulting from ligand activation, demonstrating a neurogenic component to multiple forms of inflammation and injury. We hypothesized that NK1R deficiency would afford a similar protection from inflammation associated with hyperoxia. Counter to our expectations, however, NK1R-/- animals suffered significantly worse lung injury compared with wild-type mice following exposure to 90% oxygen. Median survival was shortened to 84 h for NK1R-/- mice from 120 h for wild-type animals. Infiltration of inflammatory cells into the lungs was significantly increased; NK1R-/- animals also exhibited increased pulmonary edema, hemorrhage, and bron-choalveolar lavage fluid protein levels. TdT-mediated dUTP nick end labeling ( TUNEL) staining was significantly elevated in NK1R-/- animals following hyperoxia. Furthermore, induction of metallothionein and Na+-K+-ATPase was accelerated in NK1R-/- compared with wild-type mice, consistent with increased oxidative injury and edema. In cultured mouse lung epithelial cells in 95% O-2, however, addition of substance P promoted cell death, suggesting the neurogenic component of hyperoxic lung injury is mediated by additional mechanisms in vivo. Release of bioactive constituents including substance P from sensory neurons results from activation of the vanilloid receptor, TRPV1. In mice with targeted deletion of the TRPV1 gene, acute hyperoxic injury is attenuated relative to NK1R-/- animals. Our findings thus reveal a major neurogenic mechanism in acute hyperoxic lung injury and demonstrate concerted actions of sensory neurotransmitters revealing significant protection for NK1R-mediated functions.

• 出版日期2009-10