Cytokine and Growth Factor Release by Alveolar Macrophages: Potential Biomarkers of Pulmonary Toxicity

Abstract

Studies comparing pulmonary responses to crystalline silica (SiO₂) and titanium dioxide (0.3 μm diameter, TiO₂-F) demonstrated a positive correlation between alveolar macrophage (AM) release of interleukin-1 (IL-1), tumor necrosis factor (TNF) and fibronectin and, pulmonary granuloma formation, inflammation and fibrosis, respectively. AM IL-1 release was associated with the development of pulmonary granulomas after SiO₂ exposure. AM release of TNF positively correlated with the degree of neutrophil recruitment after SiO₂ or TiO₂-F exposure. A persistent increase in AM fibronectin release consistently correlated with the development of pulmonary fibrosis after SiO₂ or TiO₂-F exposure. Studies comparing pulmonary responses to ultrafine TiO₂ (TiO₂-D; particle diameter, 0.02 μm) with TiO₂-F demonstrate that ultrafine particles have a relatively greater toxicity on a mass/lung basis. Exposure to TiO₂-D resulted in a persistent increase in AM TNF and fibronectin release which was associated with neutrophil recruitment and fibrosis, respectively. TiO₂-D did not stimulate AM IL-1 release and this was consistent with the absence of a granulomatous response to TiO₂-D. In light of the known bioactivities of IL-1, TNF and fibronectin, these correlative findings suggest that these mediators play significant roles in pulmonary responses to mineral dust exposure and may serve as potential early biomarkers of pulmonary toxicity.