title: Thiol antioxidants inhibit the adjuvant effects of aerosolized diesel exhaust particles in a murine model for ovalbumin sensitization.
abstract: Although several epidemiological studies indicate a correlation between exposure to ambient particulate matter and adverse health effects in humans, there is still a fundamental lack of understanding of the mechanisms involved. We set out to test the hypothesis that reactive oxygen species are involved in the adjuvant effects of diesel exhaust particles (DEP) in a murine OVA sensitization model. First, we tested six different antioxidants, N-acetylcysteine (NAC), bucillamine (BUC), silibinin, luteolin, trolox (vitamin E), and ascorbic acid, for their ability to interfere in DEP-mediated oxidative stress in vitro. Of the six agents tested, only the thiol antioxidants, BUC and NAC, were effective at preventing a decrease in intracellular reduced glutathione:glutathione disulfide ratios, protecting cells from protein and lipid oxidation, and preventing heme oxygenase 1 expression. Therefore, we selected the thiol antioxidants for testing in the murine OVA inhalation sensitization model. Our data demonstrate that NAC and BUC effectively inhibited the adjuvant effects of DEP in the induction of OVA-specific IgE and IgG1 production. Furthermore, NAC and BUC prevented the generation of lipid peroxidation and protein oxidation in the lungs of OVA- plus DEP-exposed animals. These findings indicate that NAC and BUC are capable of preventing the adjuvant effects of inhaled DEP and suggest that oxidative stress is a key mechanistic component in the adjuvant effect of DEP. Antioxidant treatment strategies may therefore serve to alleviate allergic inflammation and may provide a rational basis for treating the contribution of particulate matter to asthmatic disease.
authors.affiliation: Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, University of California School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Whitekus
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Meiying
authors.initials: M
authors.lastname: Wang
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Horwitz
authors.forename: Sally K
authors.initials: SK
authors.lastname: Nelson
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Horwitz
authors.forename: Nicholas
authors.initials: N
authors.lastname: Brechun
authors.forename: David
authors.initials: D
authors.lastname: Diaz-Sanchez
authors.forename: Andre E
authors.initials: AE
authors.lastname: Nel
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors*; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006969:Hypersensitivity, Immediate / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D001335:Vehicle Emissions
chemical_list: D000276:Adjuvants, Immunologic; D000336:Aerosols; D000975:Antioxidants; D007074:Immunoglobulin G; D013438:Sulfhydryl Compounds; D001335:Vehicle Emissions; D007073:Immunoglobulin E; D010047:Ovalbumin; D003545:Cysteine; C026535:bucillamine; D000111:Acetylcysteine