The Function and Regulation of Macrophage Matrix Metalloproteinase 10 (MMP-10) in Lung Injury and Fibrosis

Thesis (Ph.D.)--University of Washington, 2015-12Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases long assumed to primarily function in the breakdown of extracellular matrix (ECM). However, a growing body of work indicates that distinct MMPs are important for the innate response to injury. Mmp10 (also stromelysin-2) has also been linked with this response in various models (e.g. partial hepatectomy and bile duct ligation, colitis, P. aeruginosa infection in the lungs), and its expression is sustained in a number of diseases including atherosclerosis, cystic fibrosis, and idiopathic pulmonary fibrosis. Here I used mice deficient in Mmp10 to ascertain the role of MMP-10 in two pulmonary models of sterile damage: the pro-fibrotic drug bleomycin, and long multi-walled carbon nanotubes (L-MWCNT), a type of engineered nanomaterial with properties similar to asbestosis. I found that macrophage Mmp10 was protective in both models through somewhat dissimilar mechanisms. Whereas Mmp10 ablation resulted in increased inflammation and fibrogenesis with bleomycin, likely resulting from enhanced CCL2-mediated macrophage recruitment, no difference in CCL2 was seen post-L-MWCNT. Instead, Mmp10 promoted pulmonary clearance of these particles, and protected macrophages from inflammation and death at 24 hours post-exposure. As MMPs are largely regulated transcriptionally, I examined macrophage Mmp10 signaling in vitro with four disparate stimuli: LPS, bronchoalveolar lavage post-bleomycin, PMA, and L-MWCNT. I found these agents differ in their potency, temporal pattern of induction, and utilization of signaling components (i.e. TLR4, protein kinase C, and mitogen activated protein kinases), but that each was ultimately NFκB-dependent. I conclude that Mmp10 is a well-conserved, protective component of the macrophage response to sterile lung damage