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Matrix Metalloproteinase-14 Mediates a Phenotypic Shift in the Airways to Increase Mucin Production

¹ Department of Environmental Health and ² Department of Chemistry, University of Cincinnati, Cincinnati, Ohio; ³ Division of Pulmonary and Critical Care Medicine, Washington University, St. Louis, Missouri; ⁴ Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center and ⁵ Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and ⁶ Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to George Leikauf, Ph.D., Department of Environmental and Occupational Health, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 328, Pittsburgh, PA 15219-3130. E-mail: gleikauf{at}pitt.edu

Rationale: Induced mainly by cigarette smoking, chronic obstructive pulmonary disease (COPD) is a global public health problem characterized by progressive difficulty in breathing and increased mucin production. Previously, we reported that acrolein levels found in COPD sputum could activate matrix metalloproteinase-9 (MMP9).

Objectives: To determine whether acrolein increases expression and activity of MMP14, a critical membrane-bound endopeptidase that can initial a MMP-activation cascade.

Methods: MMP14 activity and adduct formation were measured following direct acrolein treatment. MMP14 expression and activity was measured in human airway epithelial cells. MMP14 immunohistochemistry was performed with COPD tissue, and in acrolein- or tobacco-exposed mice.

Measurements and Main Results: In a cell-free system, acrolein, in concentrations equal to those found in COPD sputum, directly adducted cysteine 319 in the MMP14 hemopexin-like domain and activated MMP14. In cells, acrolein increased MMP14 activity, which was inhibited by a proprotein convertase inhibitor, hexa-D-arginine. In the airway epithelium of COPD subjects, immunoreactive MMP14 protein increased. In mouse lung, acrolein or tobacco smoke increased lung MMP14 activity and protein. In cells, acrolein-induced MMP14 transcripts were inhibited by an epidermal growth factor receptor (EGFR) neutralizing antibody, EGFR kinase inhibitor, metalloproteinase inhibitor, or mitogen-activated protein kinase (MAPK) 3/2 or MAPK8 inhibitors, but not a MAPK14 inhibitor. Decreasing the MMP14 protein and activity in vitro by small interfering (si)RNA to MMP14 diminished the acrolein-induced MUC5AC transcripts. In acrolein-exposed mice or transgenic mice with lung-specific transforming growth factor- (an EGFR ligand) expression, lung MMP14 and MUC5AC levels increased and these effects were inhibited by a EGFR inhibitor, erlotinib.

Conclusions: Taken together, these findings implicate acrolein-induced MMP14 expression and activity in mucin production in COPD.

Key Words: cigarette smoke • acrolein • erlotinib • mucous cell metaplasia • chronic obstructive pulmonary disease

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Acrolein is a component of cigarette smoke and also can be endogenously generated in the airways of persons with chronic obstructive pulmonary disease (COPD). What This Study Adds to the Field Low-level acrolein concentrations (equivalent to those present in COPD sputum) activated and increased matrix metalloproteinase-14 (MMP14) transcripts, protein, and activity. MMP14 immunostaining increased in the airway epithelium of subjects with COPD. Inhibition of MMP14 induction, by epidermal growth factor receptor kinase inhibitors, reduced acrolein-induced mucin levels in mouse lung. Thus, local pharmacological inhibition of MMP14 in the airway epithelium could be useful in the treatment of COPD-related mucin overproduction.