NK1-receptor activation prevents hydrocarbon-induced lung injury in mice

1 Department of Pathology, University of Vermont, Burlington, Vermont 05405-0068; and 2 Department of Pediatrics, University of Arizona, Tucson, Arizona 85724-5073 Recent evidence suggests that neurokinin (NK)-receptor activation may have a protective role in maintaining lung integrity when challenged by airborne toxicants such as sulfur dioxide, ozone, acrolein, or hydrocarbons. To investigate the effect of NK 1 -receptor activation on hydrocarbon-induced lung injury, B6.A.D. ( Ahr d / Nat s ) mice received subchronic exposures to JP-8 jet fuel (JP-8). Lung injury was assessed by the analysis of pulmonary physiology, bronchoalveolar lavage fluid, and morphology. Hydrocarbon exposure to target JP-8 concentrations of 50 mg/m 3 , with saline treatment, was characterized by enhanced respiratory permeability to 99m Tc-labeled diethylenetriaminepentaacetic acid, alveolar macrophage toxicity, and bronchiolar epithelial damage. Mice administered [Sar 9 ,Met(O 2 ) 11 ]substance P, an NK 1 -receptor agonist, after each JP-8 exposure had the appearance of normal pulmonary values and tissue morphology. In contrast, endogenous NK 1 -receptor antagonism by CP-96345 administration exacerbated JP-8-enhanced permeability, alveolar macrophage toxicity, and bronchiolar epithelial injury. These data indicate that NK 1 -receptor activation may have a protective role in preventing the development of hydrocarbon-induced lung injury, possibly through the modulation of bronchiolar epithelial function. tachykinin; JP-8 jet fuel; inhalation; pulmonary toxicology