Stromelysin-2 (MMP-10) facilitates clearance and moderates inflammation and cell death following lung exposure to long multiwalled carbon nanotubes

Abstract

Tyler C Vandivort,1,2 Timothy P Birkland,1 Talita P Domiciano,3 Somenath Mitra,4 Terrance J Kavanagh,2 William C Parks1 1Cedars-Sinai Medical Center, Women’s Guild Lung Institute, Los Angeles, CA, 2Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, 3Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, 4Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, NJ, USA Abstract: Multiwalled carbon nanotubes (MWCNTs) are nanomaterials composed of multiple layers of graphene cylinders with unique properties that make them valuable for a number of industries. However, rising global production has led to concerns regarding potential occupational exposures to them as raw materials during handling. This is especially true for long MWCNT fibers, whose aspect ratio has been posited to initiate pathology similar to that of asbestos. Matrix metalloproteinases (MMPs) are a class of extracellular endopeptidases that control various processes related to tissue repair, inflammation, and more. Stromelysin-2 (MMP-10) has roles in modulating macrophage activation and function, and hence, we used an MMP-10 null (Mmp10-/-) mouse model to assess its role in controlling lung responses to inhaled long MWCNTs. Oropharyngeal aspiration of long MWCNTs (80 µg/mouse) by wild-type mice induced expression of Mmp10 mRNA, which was accompanied by a robust inflammatory response characterized by elevated expression of Tnfa, Il6, and Il1b. In Mmp10-/- mice, we found that absence of MMP-10 led to impaired pulmonary clearance of MWCNTs and reduced macrophage cell survival. Exposure of wild-type bone marrow-derived macrophages (BMDMs) and alveolar macrophages to MWCNTs caused a rapid, dose-dependent upregulation of Mmp10 mRNA expression, which was accompanied by expression of pro-inflammatory products (Il6 and Il1b). These products were further enhanced in Mmp10-/- macrophages, resulting in increased caspase-3-dependent cell death compared with wild-type cells. These findings indicate that MMP-10 facilitates the clearance of MWCNTs and moderates the pro-inflammatory response of exposed alveolar and infiltrated macrophages. Keywords: MMP-10, multiwalled carbon nanotubes, lung injury, macrophages, apoptosis

Keywords

• MMP-10
• Multi-walled carbon nanotubes
• lung injury
• macrophages
• apoptosis