title: Involvement of NADPH oxidase and iNOS in rodent pulmonary cytokine responses to urban air and mineral particles.
abstract: We have investigated the potential of two complex mineral particles (feldspar and mylonite), quartz (Min-U-Sil), and suspended particulate matter (SRM-1648) (SPM) from urban air to induce inflammatory cytokine responses in primary rat alveolar type 2 cells and alveolar macrophages, and the involvement of cellular formation of free radicals in these responses. All particle types induced an increased release of interleukin (IL)-6 and macrophage inflammatory protein (MIP)-2 from type 2 cells. Diphenyleneiodonium chloride (DPI), a selective inhibitor of NADPH-oxidase, reduced the IL-6 and MIP-2 responses to quartz, SPM and mylonite. N-(3-[Aminomethyl] benzyl) acetamidine (1400W), a selective inhibitor of inducible nitric oxide synthase (iNOS), significantly reduced the Il-6 response to SPM and feldspar in the type 2 cells. The macrophages displayed significantly increased TNF-alpha and MIP-2 release upon exposure to quartz or SPM. Here, DPI significantly reduced the tumor necrosis factor (TNF)-alpha and MIP-2 responses to quartz, and the MIP-2 response to SPM. No significant effect of 1400 W was detected in the alveolar macrophages. The role of particle-induced cellular generation of free radicals in lung cytokine responses was further elucidated in mice that lacked either NADPH-oxidase or iNOS as well as in wild-type (wt) mice. All particles were able to elicit increased cytokine levels in the bronchoalveolar lavage (BAL) fluid of the mice, although the levels depended on particle type. The NADPH-oxidase knockout (KO) mice demonstrated a significantly lower IL-6 and MIP-2 responses to SPM compared to their respective wt mice. The iNOS KO mice displayed significantly reduced IL-6, TNF-alpha, and MIP-2 responses to SPM. The overall results indicate the involvement of cellular free-radical formation in the pulmonary cytokine responses to particles of varying composition.
authors.affiliation: Division of Environmental Medicine, Section for Air Pollution Toxicology and Noise, Norwegian Institute of Public Health, Oslo, Norway. rune.becher@fhi.no
authors.forename: Rune
authors.initials: R
authors.lastname: Becher
authors.forename: Anders
authors.initials: A
authors.lastname: Bucht
authors.forename: Johan
authors.initials: J
authors.lastname: Øvrevik
authors.forename: Jan K
authors.initials: JK
authors.lastname: Hongslo
authors.forename: Hans Jørgen
authors.initials: HJ
authors.lastname: Dahlman
authors.forename: Jan Tore
authors.initials: JT
authors.lastname: Samuelsen
authors.forename: Per E
authors.initials: PE
authors.lastname: Schwarze
mesh_terms: D000393:Air Pollutants / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D005609:Free Radicals / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008903:Minerals / Q000008:administration & dosage* / Q000633:toxicity; D019255:NADPH Oxidases / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D052638:Particulate Matter / Q000008:administration & dosage* / Q000633:toxicity; D051381:Rats
chemical_list: D000393:Air Pollutants; D016207:Cytokines; D005609:Free Radicals; D008903:Minerals; D052638:Particulate Matter; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases