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. In this study, increased mMUC5AC transcripts and protein were 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 (an 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 subjects with COPD. Acrolein increased hMMP9 transcripts in human airway cells, which was inhibited by an MMP inhibitor, EGFR-neutralizing antibody, or a mitogen-activated protein kinase (MAPK) 3/2 inhibitor. 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.

Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production / Deshmukh HS; Shaver C; Case LM; Dietsch M; Wesselkamper SC; Hardie WD; Korfhagen TR; Corradi M; Nadel JA; Borchers MT; Leikauf GD.. - In: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY. - ISSN 1044-1549. - 38(2008), pp. 446-454. [10.1165/rcmb.2006-0339OC]

Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production.

CORRADI, Massimo;
2008

Abstract

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. In this study, increased mMUC5AC transcripts and protein were 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 (an 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 subjects with COPD. Acrolein increased hMMP9 transcripts in human airway cells, which was inhibited by an MMP inhibitor, EGFR-neutralizing antibody, or a mitogen-activated protein kinase (MAPK) 3/2 inhibitor. 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.
Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production / Deshmukh HS; Shaver C; Case LM; Dietsch M; Wesselkamper SC; Hardie WD; Korfhagen TR; Corradi M; Nadel JA; Borchers MT; Leikauf GD.. - In: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY. - ISSN 1044-1549. - 38(2008), pp. 446-454. [10.1165/rcmb.2006-0339OC]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2376514
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