Matrix Metalloproteinase-28 Is a Key Contributor to Emphysema Pathogenesis

Am J Pathol. 2017 Jun;187(6):1288-1300. doi: 10.1016/j.ajpath.2017.02.008. Epub 2017 Apr 8.


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.

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Chemokines / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Enzymologic / physiology
  • Lung / enzymology
  • Macrophages, Alveolar / enzymology
  • Male
  • Matrix Metalloproteinases, Secreted / deficiency
  • Matrix Metalloproteinases, Secreted / genetics
  • Matrix Metalloproteinases, Secreted / physiology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration / physiology
  • Pneumonia / enzymology
  • Pneumonia / etiology
  • Pneumonia / genetics
  • Pneumonia / pathology
  • Pulmonary Disease, Chronic Obstructive / enzymology
  • Pulmonary Emphysema / enzymology*
  • Pulmonary Emphysema / etiology
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / pathology
  • Tobacco Smoke Pollution / adverse effects


  • Chemokines
  • Tobacco Smoke Pollution
  • Matrix Metalloproteinases, Secreted
  • Mmp28 protein, mouse