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

Naval Medical Center Portsmouth, Virginia, Steele Memorial Children's Research Center Joan B. and Donald R. Diamond Lung Injury Laboratory University of Arizona Health Sciences Center Tucson, Arizona

Brian J. Tollinger

Department of Pediatrics, University of Arizona Health sciences Center, Steele Memorial Children's Research Center Joan B. and Donald R. Diamond Lung Injury Laboratory University of Arizona Health Sciences Center Tucson, Arizona

R. Clark Lantz

Department of Cell Biology and Anatomy, University of Arizona Health Sciences Center, Center for Toxicology, University of Arizona Health Sciences Center, Steele Memorial Children's Research Center Joan B. and Donald R. Diamond Lung Injury Laboratory University of Arizona Health Sciences Center Tucson, Arizona

Huizhong Chen

Department of Pediatrics, University of Arizona Health sciences Center, Steele Memorial Children's Research Center Joan B. and Donald R. Diamond Lung Injury Laboratory University of Arizona Health Sciences Center Tucson, Arizona

Allison M. Hays

Department of Pediatrics, University of Arizona Health sciences Center, Steele Memorial Children's Research Center Joan B. and Donald R. Diamond Lung Injury Laboratory University of Arizona Health Sciences Center Tucson, Arizona

Mark L. Witten

Department of Pediatrics, University of Arizona Health sciences Center, Department of Physiology, University of Arizona Health Sciences Center, Center for Toxicology, University of Arizona Health Sciences Center, Department of Pharmacology and Toxicology, University of Arizona Health Sciences Center, Steele Memorial Children's Research Center Joan B. and Donald R. Diamond Lung Injury Laboratory University of Arizona Health Sciences Center Tucson, Arizona

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.

Key Words: 3. Key Words: hydrocarbon inhalation • jet fuel • neutral endopeptidase • pulmonary epithelium • substance P.

Toxicology and Industrial Health, Vol. 12, No. 1, 93-103 (1996)
DOI: 10.1177/074823379601200106


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