Published ahead of print on November 15, 2007, doi:10.1165/rcmb.2006-0339OC Am. J. Respir. Cell Mol. Biol., Volume 38, Number 4, April 2008, 446-454 A more recent version of this article appeared on April 1, 2008
Submitted on September 7, 2006 Acrolein-activated Matrix Metalloproteinase 9 Contributes to Persistent Mucin ProductionHitesh S Deshmukh1,1 Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH, USA, 2 Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH, USA; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, 3 Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Parma, Italy, 4 CVRI, UCSF, San Francisco, CA, USA, 5 Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA * To whom correspondence should be addressed. E-mail: gleikauf{at}pitt.edu.
BACKGROUND Chronic obstructive pulmonary disease (COPD), a global public health problem, is characterized by progressive difficulty in breathing, with increased mucin production, especially in the small airways. Acrolein, a constituent of cigarette smoke and an endogenous mediator of oxidative stress, increases airway mucin 5, subtypes A and C (MUC5AC) production, however, the mechanism remains unclear. METHODS/RESULTS In this study, increased mMUC5AC transcripts and protein was associated with increased lung Matrix metalloproteinase 9 (mMMP9) transcripts, protein and activity in acrolein-exposed mice. Increased mMUC5AC transcripts and mucin protein were diminished in gene-targeted Mmp9 mice [Mmp9(-/-)] or in mice treated with an epidermal growth factor receptor (EGFR) inhibitor, erlotinib. Acrolein also decreased mTissue inhibitor of metalloproteinase protein 3 (a MMP9-inhibitor) transcript levels. In a cell-free system, acrolein increased pro-hMMP9 cleavage and activity in concentrations (100-300 nM) found in sputum from COPD subjects. Acrolein increased hMMP9 transcripts in human airway cells, which was inhibited by a MMP inhibitor, EGFR neutralizing antibody, or a mitogen-activated protein kinase (MAPK) 3/2 inhibitor. CONCLUSIONS Together these findings indicate that acrolein can initiate cleavage of pro-hMMP9 and EGFR/MAPK signaling that leads to additional MMP9 formation. Augmentation of hMMP9 activity, in turn, could contribute to persistent excessive mucin production.
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