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

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.

SUBMITTER: Deshmukh HS

PROVIDER: S-EPMC2274947 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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

Deshmukh Hitesh S HS Shaver Colleen C Case Lisa M LM Dietsch Maggie M Wesselkamper Scott C SC Hardie William D WD Korfhagen Thomas R TR Corradi Massimo M Nadel Jay A JA Borchers Michael T MT Leikauf George D GD

American journal of respiratory cell and molecular biology 20071115 4

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 meta ...[more]

PMID: 18006877

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Project description:RationaleInduced 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).ObjectivesTo determine whether acrolein increases expression and activity of MMP14, a critical membrane-bound endopeptidase that can initial a MMP-activation cascade.MethodsMMP14 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.Measurements and main resultsIn 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.ConclusionsTaken together, these findings implicate acrolein-induced MMP14 expression and activity in mucin production in COPD.

Project description:IntroductionPeriodontitis affects a significant portion of the global population and is associated with systemic health issues. Salivary biomarkers such as salivary matrix metalloproteinase-8 (MMP-8) and its activated form (aMMP-8) have been studied for their roles in tissue degradation and inflammation in periodontitis. This meta-analysis investigates the association between salivary MMP-8 and aMMP-8 levels and periodontitis.MethodsA systematic literature search was conducted utilizing PubMed, Embase, Web of Science, and Cochrane Library databases up to October 2023, yielding 35 studies that quantified MMP-8 or aMMP-8 in saliva from patients with periodontitis and healthy controls. Data were extracted, and standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated. Heterogeneity was assessed, and subgroup analyses were performed based on saliva collection techniques. Meta-regression analysis evaluated the impact of publication year on heterogeneity.ResultsThe meta-analysis included 35 studies. Pooled results indicated significantly higher levels of MMP-8 and aMMP-8 in periodontitis cases compared to healthy controls (SMD: 2.71, 95% CI: 1.04-4.38, p = 0.002) with substantial heterogeneity (I2 = 94.5%). No significant difference was found between MMP-8 and aMMP-8 (p = 0.445). Subgroup analyses by saliva collection technique did not reduce heterogeneity significantly. Meta-regression showed that publication year did not impact heterogeneity. Small-study effects and publication bias were present, suggesting caution in interpreting the results.DiscussionThe findings support the potential of MMP-8 and aMMP-8 as biomarkers for periodontitis, although substantial heterogeneity and methodological differences among studies pose challenges. Standardized protocols and larger sample sizes are necessary to enhance the reliability of these biomarkers in clinical practice. Despite limitations, salivary diagnostics hold promise for non-invasive, early detection and monitoring of periodontitis.ConclusionSalivary MMP-8 and aMMP-8 levels are significantly associated with periodontitis, highlighting their potential as diagnostic biomarkers. However, methodological improvements and standardization are essential for their clinical application. Collaborative efforts and advancements in salivary diagnostics are crucial for improving periodontitis management and patient outcomes.

Dataset Information

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

Publications

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

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