title: Stromelysin-2 (MMP-10) facilitates clearance and moderates inflammation and cell death following lung exposure to long multiwalled carbon nanotubes.
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 ofMmp10mRNA, which was accompanied by a robust inflammatory response characterized by elevated expression ofTnfa,Il6, andIl1b. InMmp10-/-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 ofMmp10mRNA expression, which was accompanied by expression of pro-inflammatory products (Il6andIl1b). These products were further enhanced inMmp10-/-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.
authors.affiliation: Cedars-Sinai Medical Center, Women's Guild Lung Institute, Los Angeles, CA; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA.
authors.forename: Tyler C
authors.initials: TC
authors.lastname: Vandivort
authors.affiliation: Cedars-Sinai Medical Center, Women's Guild Lung Institute, Los Angeles, CA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Birkland
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Talita P
authors.initials: TP
authors.lastname: Domiciano
authors.affiliation: Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, NJ, USA.
authors.forename: Somenath
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.affiliation: Cedars-Sinai Medical Center, Women's Guild Lung Institute, Los Angeles, CA.
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D007249:Inflammation / Q000201:enzymology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D037742:Nanotubes, Carbon / Q000633:toxicity*; D011014:Pneumonia / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D037742:Nanotubes, Carbon; D053148:Caspase 3; D053506:Matrix Metalloproteinase 10
keywords: MMP-10; apoptosis; lung injury; macrophages; multiwalled carbon nanotubes