Neutral endopeptidase (NEP) and its role in pathological pulmonary change with inhalation exposure to JP-8 jet fuel

John K. Pfaff, Brian J. Tollinger, R. Clark Lantz, Huizhong Chen, Allison M. Hays, Mark L. Witten

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)93-103
Number of pages11
JournalToxicology and Industrial Health
Volume12
Issue number1
DOIs
StatePublished - Jan 1996

Keywords

  • hydrocarbon inhalation
  • jet fuel
  • neutral endopeptidase
  • pulmonary epithelium
  • substance P

ASJC Scopus subject areas

  • Toxicology
  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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