title: Asbestos fibers and silica particles stimulate rat alveolar macrophages to release tumor necrosis factor. Autoregulatory role of leukotriene B4.
abstract: Alveolar macrophages (AM) can play a crucial role in the pathogenesis of pulmonary disease via their ability to produce potent inflammatory and fibrogenic mediators. We found that rat AM cultured with 1 to 100 micrograms/ml of silica particles or asbestos fibers produced tumor necrosis factor (TNF) and leukotriene B4 (LTB4) in a concentration-dependent fashion, whereas latex beads, an inert phagocytic stimulus, failed to induce significant augmentation of either TNF or LTB4. In a time course study, AM stimulated for 2 h with silica or asbestos produced an increased amount of LTB4, which preceded the rise in TNF activity detected 7 and 24 h after culture initiation. The induction appears to involve the synthesis of new protein since actinomycin D and cycloheximide abrogate the majority of the stimulatory effect. We next examined the role of LTB4 in mineral-dust-induced TNF production. The lipoxygenase inhibitors nordihydroguaiaretic acid (NDGA) and AA861 used at 1 to 50 micrograms/ml reduced in a concentration-dependent fashion asbestos- or silica-stimulated TNF release. On the other hand, "reconstitutive" experiments in which we added exogenous LTB4 (10(-14) to 10(-8) M) to AM treated with lipoxygenase inhibitors showed partial restoration of TNF production induced by chrysotile or silica, with peak effect at 10(-10)M LTB4. The present study demonstrated that AM incubated in the presence of chrysotile A or silica can produce both LTB4 and TNF and that endogenous lipoxygenase metabolites as well as exogenous LTB4 can act to amplify TNF production. These observations suggest a common mechanism by which asbestos and silica may modulate the production of inflammatory and fibrogenic cytokines.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Québec, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Dubois
authors.forename: E
authors.initials: E
authors.lastname: Bissonnette
authors.forename: M
authors.initials: M
authors.lastname: Rola-Pleszczynski
mesh_terms: D000818:Animals; D001194:Asbestos / Q000633:toxicity*; D001195:Asbestosis / Q000209:etiology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects*; D007975:Leukotriene B4 / Q000032:analysis / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012822:Silicon Dioxide / Q000633:toxicity*; D012829:Silicosis / Q000209:etiology; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D001194:Asbestos; D007975:Leukotriene B4; D012822:Silicon Dioxide