ToxSci Advance Access published online on January 16, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp011
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Critical Role of Marco in Crystalline Silica-Induced Pulmonary Inflammation
The University of Montana, Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, Missoula MT 59812
Email addresses of authors: sheetal.thakur{at}umontana.edu, celine.beamer{at}umontana.edu, Christopher.Migliaccio{at}umontana.edu, andrij.holian{at}umontana.edu
Address correspondence to: Andrij Holian, Ph.D., The University of Montana, Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, 32 Campus Drive, Skaggs Building Room 280B, Missoula, MT-59812, E-mail: andrij.holian{at}umontana.edu, Tel: 406-243-4018, Fax: 406-243-2807
Received November 24, 2008; revision received January 12, 2009; accepted January 13, 2009
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Abstract |
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Chronic exposure to crystalline silica can lead to the development of silicosis, an irreversible, inflammatory and fibrotic pulmonary disease. Although, previous studies established the macrophage receptor with collagenous structure (MARCO) as an important receptor for binding and uptake of crystalline silica particles in vitro, the role of MARCO in regulating the inflammatory response following silica exposure in vivo remains unknown. Therefore, we determined the role of MARCO in crystalline silica-induced pulmonary pathology using C57Bl/6 wild-type (WT) and MARCO-/- mice. Increased numbers of MARCO+ pulmonary macrophages were observed following crystalline silica, but not PBS and titanium dioxide (TiO2), highlighting a specific role of MARCO in silica-induced pathology. We hypothesized that MARCO-/- mice will exhibit diminished clearance of crystalline silica leading to enhanced pulmonary inflammation and exacerbation of silicosis. Alveolar macrophages isolated from crystalline silica-exposed mice show diminished particle uptake in vivo as compared to WT mice, indicating abnormalities in clearance mechanisms. Furthermore, MARCO-/- mice exposed to crystalline silica showed enhanced acute inflammation and lung injury marked by increases in early response cytokines and inflammatory cells compared too WT mice. Similarly, histological examination of MARCO-/- lungs at three months post-crystalline silica exposure showed increased chronic inflammation compared to WT; however, only a small difference was observed with respect to development of fibrosis as measured by hydroxyproline content. Altogether, these results demonstrate that MARCO is important for clearance of crystalline silica in vivo and that the absence of MARCO results in exacerbations in innate pulmonary immune responses.
Key Words: fibrosis; silicosis; particle clearance; macrophages; scavenger receptors.
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