Neutral Endopeptidase (NEP) and Its Role in Pathological Pulmonary Change With Inhalation Exposure To JP-8 Jet Fuel

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Abstract
Through a simulated flightline exposure protocol, Fischer 344 rats (F344) were subjected to an aerosol/vapor mix of the military jet fuel, JP-8. Previous studies with this model of lung injury have revealed significant increases in pulmonary resistance, increased alveolar clearance of 99mTcDTPA, and a decrease in bronchoalveolar lavage fluid (BALF) concentration of the neuropeptide substance P (SP). Exposures to JP-8 were nose-only and for one hour daily. Six groups of Fischer 344 rats were exposed for 7, 28, or 56 days at two JP-8 concentrations (low dose = 469-520 mg/m3/hr, high dose = 814-1263 mg/m3/hr). Exposed groups were matched with longitudinal controls. In response to JP-8 inhalation, exposure animals demonstrated a dose-dependent as well as duration-determined reduction in BALF SP concentration. Both JP-8 concentrations caused significant pathological changes in lower pulmonary structures. We designed this study to elucidate the cause of SP deficits following JP-8 inhalation through correlation with neutral endopeptidase (NEP) concentration taken from paired samples. NEP activity is significantly increased after 28 days of high-dose exposure (HD28) when compared with longitudinal controls and low-dose exposures (7D, 28D, and 56D). A significant inverse relationship between SP and NEP activity is demonstrated through Spearman rank-order correlation (rs = -0.42, n = 52, p < 0.05), suggesting inactivation of SP as the cause of its deficit. Pulmonary airway changes strongly implicate airway epithelium as a primary site of injury. Tachykinin degradation from the peptidase, NEP, plays a role in the process of airway cell injury. This research demonstrates the possible use of NEP and SP lung concentrations as biomarkers of chronic hydrocarbon exposure.

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