Cooperation of the Inducible Nitric Oxide Synthase and Cytochrome P450 1A1 in Mediating Lung Inflammation and Mutagenicity Induced by Diesel Exhaust Particles

Details

• Personal Author:
  Barger MW ; Castranova, Vincent ; Ma JKH ; Ma JYC ; Zhao HW
• Description:
  Diesel exhaust particles (DEPs) have been shown to activate oxidant generation by alveolar macrophages (AMs), alter xenobiotic metabolic pathways, and modify the balance of pro-antiinflammatory cytokines. In this study we investigated the role of nitric oxide (NO) in DEP-mediated and DEP organic extract (DEPE) -mediated inflammatory responses and evaluated the interaction of inducible NO synthase (iNOS) and cytochrome P450 1A1 (CYP1A1). Male Sprague-Dawley rats were intratracheally (IT) instilled with saline, DEPs (35 mg/kg), or DEPEs (equivalent to 35 mg DEP/kg), with or without further treatment with an iNOS inhibitor, aminoguanidine (AG; 100 mg/kg), by intraperitoneal injection 30 min before and 3, 6, and 9 hr after IT exposure. At 1 day postexposure, both DEPs and DEPEs induced iNOS expression and NO production by AMs. AG significantly lowered DEP- and DEPE-induced iNOS activity but not the protein level while attenuating DEPE- but not DEP-mediated pulmonary inflammation, airway damage, and oxidant generation by AMs. DEP or DEPE exposure resulted in elevated secretion of both interleukin (IL) -12 and IL-10 by AMs. AG significantly reduced DEP- and DEPE-activated AMs in IL-12 production. In comparison, AG inhibited IL-10 production by DEPE-exposed AMs but markedly increased its production by DEP-exposed AMs, suggesting that NO differentially regulates the pro- and antiinflammatory cytokine balance in the lung. Both DEPs and DEPEs induced CYP1A1 expression. AG strongly inhibited CYP1A1 activity and lung S9 activity-dependent 2-aminoanthracene mutagenicity. These studies show that NO plays a major role in DEPE-induced lung inflammation and CYP-dependent mutagen activation but a lesser role in particulate-induced inflammatory damage. [Description provided by NIOSH]
• Subjects:
  Animals Environmental Monitoring Laboratories Lung Diseases Mutagens Occupational Health Safety Vehicle Emissions
• Keywords:
  Animal-studies Diesel-exhausts Exposure-assessment Exposure-levels Laboratory-animals Lung-disorders Mutagenesis Mutagenicity
• ISSN:
  0091-6765
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  114
• Issue:
  8
• NIOSHTIC Number:
  nn:20030794
• Citation:
  Environ Health Perspect 2006 Aug; 114(8):1253-1258
• Contact Point Address:
  J.Y.C. Ma, Pathology and Physiology Research Branch, HELD, NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505-2888 USA
• Email:
  jym1@cdc.gov
• CAS Registry Number:
  Nitric oxide (CAS RN 10102-43-9)
• Federal Fiscal Year:
  2006
• Peer Reviewed:
  True
• Source Full Name:
  Environmental Health Perspectives
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d405982d06de3c43786c12d0d1c66b79714401791dec4574896d9a48fe4b40d448f14a9f183aea47f98b11b3410cb887533deb0487f3137a4b93721f84cc4c0e
• Download URL:
  https://stacks.cdc.gov/view/cdc/191289/cdc_191289_DS1.pdf
• File Type:
  [PDF - 108.98 KB ]