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

Abstract

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 tobaccoexposed 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-a (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.

MT1-MMP Cooperates with KrasG12D to Promote Pancreatic Fibrosis through Increased TGF-β Signaling

“…Two groups reported that loss of Smad4 in the Kras G12D background causes IPMNs in the majority of mice (32, 35). Even though it is not clear why MT1-MMP expression results in lesions with mucin production, it is interesting to note that MT1-MMP in the airways can induce a phenotypic shift to increase mucin production and can also proteolytically cleave the membrane bound mucins from the surface of epithelial cells (43, 44). …”

Role of aberrant metalloproteinase activity in the pro-inflammatory phenotype of bronchial epithelium in COPD

“…TAPI-2-insensitive MMP-14 has been identified as sheddase of syndecan-1, and this effect was inhibited by TIMP-2 expression [31,32]. Decreased expression of TIMP-2 mRNA has previously been reported in COPD versus control lung tissue [38] along with increased MMP-14 levels and/or activity in COPD patients [8]. We observed that TIMP-2 levels were significantly lower in PBECs from COPD than from healthy non-smokers and smokers.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…MMP-14 together with MMP-9 activity increases in COPD sputum; in particular, MMP-14 expression is induced in mucin production in COPD (Deshmukh et al, 2009). …”