Asbestos Fibers and Silica Particles Stimulate Rat Alveolar Macrophages To Release Tumor Necrosis Factor: Autoregulatory Role of Leukotriene B4

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.