A mechanistic review of silica-induced inhalation toxicity.

Crystalline forms of silica have been proposed as positive control material for the toxicity test of inhaled particulate/fibrous matter, although mechanism of silica-induced inhalation toxicity has not yet been established. Inhalation exposure of α-quartz to rodents induces severe lung inflammation and fibrosis only after a certain period of latency, despite strong surface reactivity. The delayed occurrence of inhalation toxicity by α-quartz may be largely attributed to the sequestration of α-quartz particles by alternatively activated (M2) macrophages that express abundant levels of scavenger receptors but are relatively insensitive to inflammatory stimuli. When exposure to α-quartz continues, lung dust burden reaches a particle overload level, at which M2 macrophages cannot accommodate further quartz particles. Free quartz particles distributed in the interstitium interact with another subtype of macrophages, classically activated/inflammatory (M1) macrophages, which secrete various inflammatory cytokines, but silica-laden M1 macrophages initiate granuloma formation, which sequesters silica particles, too. Furthermore, the ability of M2 macrophages to clear foreign matter, particularly bacterial endotoxins [lipopolysaccharides (LPS)], may decrease due to α-quartz cytotoxicity. When LPS concentration in the lung reaches a certain level, LPS primes M1 macrophages to prepare for interleukin-1β production in response to α-quartz and also stimulates M1 macrophages and plasmacytoid dendritic cells (pDCs) to produce tumor necrosis factor (TNF)-α and interferon (IFN)-β, respectively. Besides, IFN-β may enhance TNF-α production in LPS-stimulated M1 macrophages. The elevated levels of inflammatory cytokines produce progressive lung inflammation and fibrosis.