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Elevated MMP-9 Is Associated With Accelerated Lung Function Decline and COPD Development: A Prospective Cohort Study
Xinru Ran1,2, Fan Wu2,3, Zihui Wang2
1Guangzhou Medical University-Guangzhou Institute of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China.
Background And Objective:
The imbalance in proteases/antiproteases caused by inflammation contributes to COPD, and matrix metalloproteinase-9 (MMP-9) may play an important role. Therefore, we aimed to investigate the associations of MMP-9 with respiratory health outcomes.
Methods:
This study was conducted in two parts. Firstly, we performed a prospective cohort study to investigate the association of circulating MMP-9 and respiratory health outcomes. Participants completed a questionnaire, spirometry, and chest CT, and provided blood samples at baseline. Follow-up visits were conducted annually. Study outcomes were the development of spirometry-defined COPD, lung function decline, and exacerbations. Secondly, we performed a two-sample Mendelian randomisation (MR) study to evaluate the causal effect between genetically predicted MMP-9 expression and lung function.
Results:
Overall, 1328 participants were included in the baseline analysis, and 1034 (78%) completed the 2-year follow-up. Higher plasma MMP-9 at baseline was associated with chronic respiratory symptoms, severe emphysema, and air trapping. During the 2-year follow-up, each SD increase in plasma MMP-9 was associated with accelerated decline in pre-bronchodilator FEV1 (adjusted difference = 6.4 [95% CI: 0.7-12.1] mL/year) and FVC (adjusted difference = 18.0 [95% CI: 7.6-28.5] mL/year), and a higher exacerbation incidence. In participants with normal spirometry at baseline, higher plasma MMP-9 was associated with progression to spirometry-defined COPD (adjusted OR = 1.93, 95% CI: 1.05-3.57). A MR study demonstrated similar results toward negative associations of genetically predicted MMP-9 expression with FEV1 and FVC.
Conclusion:
The longitudinal cohort and MR study provide evidence that MMP-9 might play a causative role in lung function decline and spirometry-defined COPD development.
Insights
Matrix metalloproteinase-9 (MMP-9) elevation is linked to chronic obstructive pulmonary disease (COPD) progression. Higher MMP-9 levels correlate with worsening lung function, increased symptoms, and COPD development.
Area of Science:
- Pulmonary Medicine
- Biochemistry
- Genetics
Background:
- Protease/antiprotease imbalance due to inflammation is implicated in COPD pathogenesis.
- Matrix metalloproteinase-9 (MMP-9) is a key enzyme potentially involved in COPD development.
Purpose of the Study:
- To investigate the association between MMP-9 levels and respiratory health outcomes.
- To evaluate the potential causal role of MMP-9 in COPD development and lung function decline.
Main Methods:
- A prospective cohort study assessed circulating MMP-9 in relation to respiratory symptoms, spirometry, CT scans, and exacerbations over 2 years.
- A two-sample Mendelian randomization (MR) study examined the causal effect of genetically predicted MMP-9 on lung function.
Main Results:
- Elevated plasma MMP-9 was associated with chronic respiratory symptoms, emphysema, and air trapping.
- Higher MMP-9 levels predicted accelerated decline in FEV1 and FVC, and increased exacerbation incidence.
- Mendelian randomization analysis supported a causal link between genetically predicted MMP-9 and reduced lung function (FEV1, FVC).
Conclusions:
- Longitudinal cohort and MR studies suggest MMP-9 plays a causative role in COPD development.
- MMP-9 is a potential therapeutic target for mitigating lung function decline and COPD progression.
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