Wong, Simon S., Nina N. Sun, R. Clark Lantz, and Mark L. Witten. Substance P and neutral endopeptidase in development of acute respiratory distress syndrome (ARDS) following fire smoke inhalation. Am. J. Physiol.--- (Lung Cell. Mol. Physiol.---): -To characterize the tachykininergic effects in fire smoke (FS)-induced Acute Respiratory Distress Syndrome (ARDS), we designed a series of studies in Fischer 344/NH rats, including the time-course, the doseeffect, and the intervention designs. It was found that the high (20-min) level of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4%, 55.6%, 46.3%, and 43.0% of neutral endopeptidase (NEP) activity in lung tissue at all time points of 1, 6, 12, and 24 h after FS inhalation, respectively. Immunolabeling directed against NEP showed that density loss in the airway epithelium, but not in smooth muscle cells, occurred as early as 1 h after FS inhalation due to cell damage and shedding. These changes were also accompanied, in the same temporal pattern, with extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, the levels of BALF SP and tissue NEP activity dose-dependently increased and decreased, respectively, following 0, low (10-min), and high (20-min) levels of FS inhalation. However, neither the time-course nor the dose-response study had an observed difference of either NK-1R density or distribution in the lungs with immunohistochemical analysis. Treatment (10 mg/kg, i.m., immediately following the high level of FS inhalation) of rats with SR 140333B, a NK-1R antagonist, significantly prevented FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR 140333B (either 1.0 or 10.0 mg/kg, i.m.) fully abolished early (1 h) plasma extravasation following FS inhalation. Taken together, these findings suggest that a combination of a high persistent level of SP and substantial disruption of NEP activity induced an exaggerated neurogenic inflammation mediated by NK-1R, which may be leading to an uncontrolled influx of protein-rich edema fluid and cells into the alveolar spaces as a consequence of increased vascular permeability.