Matrix metalloproteinase-14 mediates a phenotypic shift in the airways to increase mucin production.
BACKGROUND
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).


OBJECTIVE
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.


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-alpha (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.
Deshmukh
Hitesh S
HS
Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.
McLachlan
Anne
A
Atkinson
Jeffrey J
JJ
Hardie
William D
WD
Korfhagen
Thomas R
TR
Dietsch
Maggie
M
Liu
Yang
Y
Di
Peter Y P
PY
Wesselkamper
Scott C
SC
Borchers
Michael T
MT
Leikauf
George D
GD
D000171:Acrolein / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D000069347:Erlotinib Hydrochloride; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D009077:Mucins / Q000096:biosynthesis* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000648:ultrastructure
D009077:Mucins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000171:Acrolein; D000069347:Erlotinib Hydrochloride; D053511:Matrix Metalloproteinase 14