HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/L687    most recent 90509.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Dib, M. Articles by Gerard, N. P. PubMed PubMed Citation Articles by Dib, M. Articles by Gerard, N. P.

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

¹Ina Sue Perlmutter Laboratory, Pulmonary Division and ; ²Division of Newborn Medicine, Department of Pediatrics, Children's Hospital, and ; ³Department of Medicine, Harvard Medical School, Boston, Massachusetts

Submitted 30 September 2008 ; accepted in final form 20 July 2009

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 bronchoalveolar 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% O₂, 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.

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