Sputum matrix metalloproteinase-8 and -9 and tissue inhibitor of metalloproteinase-1 in bronchiectasis: Clinical correlates and prognostic implications
Wei-jie Guan
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorYong-hua Gao
Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Search for more papers by this authorGang Xu
Department of Geriatrics Medicine, Guangzhou First People's Hospital, Guangzhou, Guangdong, China
Search for more papers by this authorZhi-ya Lin
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorYan Tang
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorYing-ying Gu
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorGui-hong Liu
Department of Pathology, Panyu Central Hospital, Guangzhou, Guangdong, China
Search for more papers by this authorHui-min Li
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorCorresponding Author
Rong-chang Chen
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Correspondence: Rong-chang Chen, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong, China. Email: [email protected]Search for more papers by this authorNan-shan Zhong
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorWei-jie Guan
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorYong-hua Gao
Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Search for more papers by this authorGang Xu
Department of Geriatrics Medicine, Guangzhou First People's Hospital, Guangzhou, Guangdong, China
Search for more papers by this authorZhi-ya Lin
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorYan Tang
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorYing-ying Gu
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorGui-hong Liu
Department of Pathology, Panyu Central Hospital, Guangzhou, Guangdong, China
Search for more papers by this authorHui-min Li
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorCorresponding Author
Rong-chang Chen
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Correspondence: Rong-chang Chen, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong, China. Email: [email protected]Search for more papers by this authorNan-shan Zhong
Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Search for more papers by this authorAbstract
Background and objective
The triplet of airway infection, inflammation and bronchial wall destruction associated with excessive matrix metalloproteinases (MMP) release and imbalance of tissue inhibitor metalloproteinase-1 (TIMP-1) is implicated in bronchiectasis. We sought to determine the associations between sputum MMP (MMP-8, MMP-9) and TIMP-1 and the severity of bronchiectasis; the utility of MMP in predicting risks of future bronchiectasis exacerbations (BE); and the changes in MMP levels during BE.
Methods
We recruited 102 patients with stable bronchiectasis and 22 healthy subjects. For bronchiectasis patients, baseline measurements consisted of sputum inflammation and MMP measurements, bacterial culture, spirometry and chest high-resolution computed tomography (HRCT). Bronchiectasis patients were followed up for 1 year to determine the frequency of BE. Changes in MMP levels during BE were assessed in 36 bronchiectasis patients.
Results
Sputum MMP-8, MMP-9 and MMP-9/TIMP-1 ratio in bronchiectasis patients were significantly increased compared with healthy subjects. MMP-8 and MMP-9 levels, but not TIMP-1, were positively correlated with clinical measures, including HRCT scores, spirometry and Bronchiectasis Severity Index. Seventy-nine bronchiectasis patients were included in survival analyses of BE. Lower levels of baseline MMP-9 were associated with reduced risks of and a longer time to the first BE during follow-up. MMP-8 and MMP-9, but not TIMP-1 or MMP-9/TIMP-1 ratio, were significantly heightened during BE.
Conclusions
Sputum MMP might be useful biomarkers for the assessment of bronchiectasis severity and the prediction of future risks of BE. Our results provide the rationales for the future clinical application of MMP inhibitors.
Supporting Information
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Appendix S1 Methods & results. Figure S1 Comparison of MMP levels based on bronchiectasis aetiologies. (A) Comparison of MMP-8 levels based on bronchiectasis aetiologies. (B) Comparison of MMP-9 levels based on bronchiectasis aetiologies. (C) Comparison of MMP-9/TIMP-1 ratio based on bronchiectasis aetiologies; 124 subjects (102 bronchiectasis patients plus 22 healthy subjects) were recruited in study 1. Figure S2 Distribution of baseline MMP levels according to Bronchiectasis Severity Index. (A) Distribution of baseline MMP-8 according to Bronchiectasis Severity Index. (B) Distribution of baseline MMP-9 according to Bronchiectasis Severity Index. (C) Distribution of baseline MMP-9/TIMP-1 ratio according to Bronchiectasis Severity Index. **P < 0.01. BSI: Bronchiectasis Severity Index. 124 subjects (102 bronchiectasis patients plus 22 healthy subjects) were recruited in study 1. Figure S3 Distribution of baseline MMP levels in patients with and without BE reported during follow-up. (A) Distribution of baseline MMP-8 in patients with and without BE reported during follow-up. (B) Distribution of baseline MMP-9 in patients with and without BE reported during follow-up. (C) Distribution of baseline MMP-9/TIMP-1 ratio in patients with and without BE reported during follow-up. *P < 0.05. BE+: Patients with BE during follow-up; BE−: Patients without BE during follow-up. 124 subjects (102 bronchiectasis patients plus 22 healthy subjects) were recruited in study 1. Figure S4 Correlation between baseline MMP-9 levels and the frequency of and time to BE during follow-up. (A) Correlation between baseline MMP-9 levels and the frequency of all BE reported during follow-up. (B) Correlation between baseline MMP-9 levels and the time to the first BE during follow-up. 102 bronchiectasis patients were included in study 3, with 79 patients finally included in the survival analyses. Table S1 Principles regarding antibiotics prescription for bronchiectasis exacerbations. Table S2 MMP for discriminating bronchiectasis patients from healthy subjects. Table S3 Geometric means of sputum MMP when stratified by different parameters in clinically stable bronchiectasis. Table S4 Correlation between sputum inflammatory biomarker levels and clinical parameters in clinically stable bronchiectasis. Table S5 Correlation between MMP and sputum inflammation in clinically stable bronchiectasis. Table S6 Incidence of and time to the first BE during 1-year follow-up. Table S7 Baseline characteristics when stratified by the magnitude of changes in MMP levels during bronchiectasis exacerbations. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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