A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury.
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% 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.
Dib
Marwan
M
Ina Sue Perlmutter Laboratory, Children's Hospital, 320 Longwood Ave., Boston, MA 02115, USA.
Zsengeller
Zsuzsanna
Z
Mitsialis
Alex
A
Lu
Bao
B
Craig
Stewart
S
Gerard
Craig
C
Gerard
Norma P
NP
D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D004487:Edema / Q000209:etiology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D018496:Hyperoxia; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D015996:Survival Rate; D050916:TRPV Cation Channels / Q000502:physiology
D016207:Cytokines; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D009195:Peroxidase; D010100:Oxygen