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

• DOI: 10.1164/rccm.200903-0328oc
• Publication Date: 2009-08-07T01:43:17Z
• Authors: Hitesh S. Deshmukh; Anne McLachlan; Jeffrey J. Atkinson; William D. Hardie; Thomas R. Korfhagen; Maggie Dietsch; Yang Liu; Peter Y. P. Di; Scott C. Wesselka...; Michael T. Borchers; George D. Leikauf
• Keywords: Matrix Metalloproteinase 3; Matrix (chemical analysis); Matrix metalloproteinase 9

Induced mainly by cigarette smoking, chronic obstructive pulmonary disease (COPD) is a global public health problem characterized progressive difficulty in breathing and increased mucin production. Previously, we reported that acrolein levels found COPD sputum could activate matrix metalloproteinase-9 (MMP9).To determine whether increases expression activity of MMP14, critical membrane-bound endopeptidase can initial MMP-activation cascade.MMP14 adduct formation were measured following direct treatment. MMP14 was human airway epithelial cells. immunohistochemistry performed with tissue, acrolein- or tobacco-exposed mice.In cell-free system, acrolein, concentrations equal to those sputum, directly adducted cysteine 319 the hemopexin-like domain activated MMP14. In cells, activity, which inhibited proprotein convertase inhibitor, hexa-d-arginine. epithelium subjects, immunoreactive protein increased. mouse lung, tobacco smoke lung protein. acrolein-induced transcripts an epidermal growth factor receptor (EGFR) neutralizing antibody, EGFR kinase metalloproteinase mitogen-activated (MAPK) 3/2 MAPK8 inhibitors, but not MAPK14 inhibitor. Decreasing vitro small interfering (si)RNA diminished MUC5AC transcripts. acrolein-exposed mice transgenic lung-specific transforming factor-alpha (an ligand) expression, these effects erlotinib.Taken together, findings implicate production COPD.