Abstract
Silicosis is a common occupational disease and represents a significant contributor to respiratory morbidity and mortality worldwide. Lipid-laden macrophages, or foam cells, are observed in the lungs of patients with silicosis but the mechanisms mediating their formation remain poorly understood. In this study, we sought to elucidate the mechanisms by which silica promotes foam cell formation in the lung, and to determine whether uptake of lipids alone is sufficient to drive TGF-β production by alveolar macrophages. Consistent with previous reports, we found that foam cells were markedly increased in the lungs of patients with silicosis and that these findings associated with both higher levels of intracellular lipid levels (oxidized LDL, ox-LDL) and elevated transcript levels for the lipid scavenger receptor CD36 and the nuclear receptor PPARγ. Employing a rat alveolar macrophage cell line, we found that exposure to silica dust or ox-LDL alone had a modest effect on the induction of foam cell formation and only silica was capable of inducing the production of TGF-β. In contrast, foam cell formation and TGF-β production were both dramatically increased when cells were exposed to a combination of silica dust and ox-LDL. Moreover, we found that these endpoints were markedly attenuated by either blocking CD36 or inhibiting the activity of PPARγ. Altogether, our findings suggest that foam cell formation and TGF-β production are driven by the simultaneous uptake of silica and lipids in alveolar macrophages and that strategies aimed at blocking lipid uptake by alveolar macrophages might be effective in ameliorating fibrotic responses to silica in the lung.
Highlights
Alveolar macrophages (AM) are the first line of defense against foreign substances entering the lower airways, and are essential for clearing silica dust from the lung[1]
Consistent with cells that had accumulated intracellular lipids, we found that transcript levels for the lipid scavenger receptor CD36 and the intracellular lipid receptor PPAR-γ were significantly increased in BAL cells from silicosis patients (Fig. 3A,B) (P < 0.05), supporting the notion that lipid homeostasis is altered in pulmonary silicosis
Foam cells are a hallmark feature of diseased tissues in a wide range of organs, including the lung, in the setting of pulmonary fibrosis
Summary
Alveolar macrophages (AM) are the first line of defense against foreign substances entering the lower airways, and are essential for clearing silica dust from the lung[1]. Uptake of silica dust by AMs has been shown to play an important role in the pathobiology of silicosis, by driving the production of factors that contribute to lung inflammation and by promoting the production of pro-fibrotic substances. The mechanisms mediating macrophage lipid clearance in the lung are less well-understood it has been shown that AMs express most, if not all, of the machinery involved in the uptake and clearance of lipids in atherosclerotic plaques With this in mind, our primary objectives in this study were to determine whether silicosis alters the expression of the machinery involved in regulating lipid homeostasis in AMs, and to determine whether exposure to SiO2 or lipids alone can drive AMs to adopt a foam cell appearance and produce TGF-β
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