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.

Tumour necrosis factor enhances the asbestos-induced production of reactive oxygen metabolites by human polymorphonuclear leucocytes (PMN)

“…Because asbestos fibres also stimulate macrophages to release TN F [22). a simultaneous effect of TNF and asbestos fibres on inflammatory cells is most likely.…”

Altered functions of alveolar macrophages and NK cells involved in asbestos-related diseases

“…It is well known that AM play a crucial role in inflammation caused by exposure to asbestos. AM produce reactive oxygen species (ROS) [1], reactive nitrogen species (RNS) [2,3], as well as chemoattractant and inflammatory cytokines including tumor necrosis factor-alpha (TNF-a), interleukin (IL)-1b, and IL-6 [4,5]. Since inhaled asbestos accumulates in the lungs, inflammation caused by asbestos continues chronically.…”

An analytical review of silicone immunology

“…Crystalline silica particles activate macrophages, stimulate the production of cytokines by macrophages and T lymphocytes (14)(15)(16), and enhance the antibody response to foreign proteins (17). Inhalation of fine silica particles causes pulmonary fibrosis (18) and is generally believed to cause scleroderma (19,20).…”

“…Crystalline silica is abundant in the environment, occurring in sand and glass among other materials, and a true cellular sensitivity to it could cause severe cutaneous hypersensitivity reactions. This material is also a nonspecific activator of macrophages (14)(15)(16). Second, the assay was unusual in 2 respects.…”