DISTINCTIVE PROFILE OF ALVEOLAR MACROPHAGE-DERIVED CYTOKINE RELEASE INDUCED BY FIBROGENIC AND NONFIBROGENIC MINERAL DUSTS

Groups of 7 Wistar rats each received a single intratracheal instillat ion of either saline (control), UICC chrysotile B asbestos (5 mg), or very short 4T30 chrysotile asbestos fibers (5 mg). Five animals in eac h group were killed at 1, 3, and 6 wk posttreatment and analyzed by br onchoalveolar lavage (BAL) for BAL cell populations and cytokine produ ction in conjunction with histopathological assessment Of lung tissue. Chrysotile B and short 4T30 chrysotile fibers induced chronic inflamm atory reactions characterized by alveolar macrophage (AM) accumulation that resulted, respectively, in lung fibrosis and resolving granuloma . Alveolar macrophages (AM) obtained from rats treated with UICC chrys otile B and short 4T30 chrysotile produced enhanced levels of interleu kin-1 (IL-1) and interleukin-6 (IL-6), both spontaneously and in respo nse to lipopolysaccharide (LPS). A different pattern of response was o bserved for tumor necrosis factor-alpha (TNF-alpha). Fibrogenic chryso tile B caused biphasic changes characterized by a significant inhibiti on of LPS-induced TNF-alpha release by AM 1 and 3 wk after treatment f ollowed by stimulation of spontaneous and LPS-induced TNF-alpha at 6 w k. In contrast, no significant change in spontaneous and LPS-induced T NF-alpha release was seen with AM from animals with resolving granulom a (4T30 group). Thus, modulation of AM-derived TNF-alpha was correlate d under these conditions with the fibrogenic potential of asbestos dus ts. These data support a role for TNF-alpha in fibrosis and suggest th at TNF-alpha may represent a useful marker of lung damage induced by f ibrogenic dusts.