title: Matrix Metalloproteinase-28 Is a Key Contributor to Emphysema Pathogenesis.
abstract: Chronic obstructive pulmonary disease (COPD) comprises chronic bronchitis and emphysema, and is a leading cause of morbidity and mortality. Because tissue destruction is the prominent characteristic of emphysema, extracellular proteinases, particularly those with elastolytic ability, are often considered to be key drivers in this disease. Several human and mouse studies have implicated roles for matrix metalloproteinases (MMPs), particularly macrophage-derived proteinases, in COPD pathogenesis. MMP-28 is expressed by the pulmonary epithelium and macrophage, and we have found that it regulates macrophage recruitment and polarization. We hypothesized that MMP-28 has contributory roles in emphysema via alteration of macrophage numbers and activation. Because of the established association of emphysema pathogenesis to macrophage influx, we evaluated the inflammatory changes and lung histology of Mmp28-/-mice exposed to 3 and 6 months of cigarette smoke. At earlier time points, we found altered macrophage polarization in the smoke-exposed Mmp28-/-lung consistent with other published findings that MMP-28 regulates macrophage activation. At both 3 and 6 months, Mmp28-/-mice had blunted inflammatory responses more closely resembling nonsmoked mice, with a reduction in neutrophil recruitment and CXCL1 chemokine expression. By 6 months, Mmp28-/-mice were protected from emphysema. These results highlight a previously unrecognized role for MMP-28 in promoting chronic lung inflammation and tissue remodeling induced by cigarette smoke and highlight another potential target to modulate COPD.
authors.affiliation: Department of Medicine, Center for Lung Biology, University of Washington, Seattle, Washington. Electronic address: manicone@uw.edu.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Manicone
authors.affiliation: Department of Medicine, Center for Lung Biology, University of Washington, Seattle, Washington.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: Department of Medicine, Center for Lung Biology, University of Washington, Seattle, Washington.
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Gong
authors.affiliation: Department of Medicine, Center for Lung Biology, University of Washington, Seattle, Washington.
authors.forename: William E
authors.initials: WE
authors.lastname: Eddy
authors.affiliation: Department of Medicine, Center for Lung Biology, University of Washington, Seattle, Washington.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Long
authors.affiliation: Department of Medicine, Center for Lung Biology, University of Washington, Seattle, Washington; Department of Comparative Medicine, Center for Lung Biology, University of Washington, Seattle, Washington.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Frevert
authors.affiliation: Department of Medicine, Center for Lung Biology, University of Washington, Seattle, Washington.
authors.forename: William A
authors.initials: WA
authors.lastname: Altemeier
authors.affiliation: Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
authors.affiliation: Department of Medicine, Center for Lung Biology, University of Washington, Seattle, Washington; Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: A McGarry
authors.initials: AM
authors.lastname: Houghton
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D008168:Lung / Q000201:enzymology; D016676:Macrophages, Alveolar / Q000201:enzymology; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000502:physiology; D011014:Pneumonia / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology; D011656:Pulmonary Emphysema / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: D018925:Chemokines; D014028:Tobacco Smoke Pollution; D053505:Matrix Metalloproteinases, Secreted; C477998:Mmp28 protein, mouse