Elevated Matrix Metalloproteinase‑9 Expression is Associated with COVID‑19 Severity: A Meta‑analysis

Overview

Journal Exp Ther Med

Specialty Pathology

Date 2023 Nov 6

PMID 37928509

Authors

Ling Ding

Haipeng Guo

Chao Zhang

Huixin Jin

Xuyang Guo

Tong Li

Affiliations

Soon will be listed here.

Abstract

The present meta-analysis investigated the clinical value of serum matrix metalloproteinase (MMP)-9 levels in Coronavirus Disease 2019 (COVID-19) patients. Studies assessing the outcomes of patients with COVID-19 in correlation with the MMP-9 levels were retrieved from PubMed, Web of Science, EMBASE, Cochrane, WANFANG, and CNKI. A meta-analysis was performed to compare the serum MMP-9 levels between different patient groups: Severe vs. non-severe; acute respiratory distress syndrome (ARDS) vs. non-ARDS; non-survivors vs. survivors; neurologic syndrome vs. non-neurologic syndrome; and obese diabetic vs. non-obese diabetic. A total of 2,062 COVID-19-confirmed patients from 12 studies were included in this meta-analysis. The serum MMP-9 levels were significantly higher in patients with severe COVID-19 than in those with non-severe COVID-19 [weighted mean difference (WMD) 246.61 (95% confidence interval (CI), 115.86-377.36), P<0.001]. Patients with ARDS exhibited significantly higher MMP-9 levels than those without ARDS [WMD 248.55 (95% CI, 63.84-433.25), P<0.001]. The MMP-9 levels in the non-survivors did not significantly differ from those in the survivors [WMD 37.79 (95% CI, -18.08-93.65), P=0.185]. Patients with comorbidities, including neurological syndromes, and obese diabetic patients had significantly higher MMP-9 levels than those without comorbidities [WMD 170.73 (95% CI, 95.61-245.85), P<0.001]. Serum MMP-9 levels were associated with COVID-19 severity and may serve as a therapeutic target for improving the prognosis of patients with COVID-19.

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References

Petito E, Falcinelli E, Paliani U, Cesari E, Vaudo G, Sebastiano M . Association of Neutrophil Activation, More Than Platelet Activation, With Thrombotic Complications in Coronavirus Disease 2019. J Infect Dis. 2020; 223(6):933-944. PMC: 7798977. DOI: 10.1093/infdis/jiaa756. View

Liberati A, Altman D, Tetzlaff J, Mulrow C, Gotzsche P, Ioannidis J . The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339:b2700. PMC: 2714672. DOI: 10.1136/bmj.b2700. View

Davey A, McAuley D, OKane C . Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair. Eur Respir J. 2011; 38(4):959-70. DOI: 10.1183/09031936.00032111. View

Bonetto V, Pasetto L, Lisi I, Carbonara M, Zangari R, Ferrari E . Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations. Front Immunol. 2023; 13:1070379. PMC: 9798841. DOI: 10.3389/fimmu.2022.1070379. View

Ramezani S, Ezzatifar F, Hojjatipour T, Hemmatzadeh M, Shabgah A, Gholizadeh Navashenaq J . Association of the matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of coronavirus disease 2019 (COVID-19); implications of contribution for development of neurological symptoms in the COVID-19 patients. Mol Biol Rep. 2022; 50(1):173-183. PMC: 9628292. DOI: 10.1007/s11033-022-07907-y. View

Huang H . Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances. Sensors (Basel). 2018; 18(10). PMC: 6211011. DOI: 10.3390/s18103249. View

Tsarouhas K, Tsitsimpikou C, Apostolakis S, Haliassos A, Tzardi M, Panagiotou M . Homocysteine and metalloprotease-3 and -9 in patients with ascending aorta aneurysms. Thromb Res. 2011; 128(5):e95-9. DOI: 10.1016/j.thromres.2011.07.008. View

Townsend M, Kyle T, Stanford F . commentary: COVID-19 and Obesity: Exploring Biologic Vulnerabilities, Structural Disparities, and Weight Stigma. Metabolism. 2020; 110:154316. PMC: 7358173. DOI: 10.1016/j.metabol.2020.154316. View

Barron E, Bakhai C, Kar P, Weaver A, Bradley D, Ismail H . Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020; 8(10):813-822. PMC: 7426088. DOI: 10.1016/S2213-8587(20)30272-2. View

10.

Marchesi C, Dentali F, Nicolini E, Maresca A, Tayebjee M, Franz M . Plasma levels of matrix metalloproteinases and their inhibitors in hypertension: a systematic review and meta-analysis. J Hypertens. 2011; 30(1):3-16. DOI: 10.1097/HJH.0b013e32834d249a. View

11.

Wang X, Khalil R . Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. Adv Pharmacol. 2018; 81:241-330. PMC: 5765875. DOI: 10.1016/bs.apha.2017.08.002. View

12.

Duda I, Krzych L, Jedrzejowska-Szypulka H, Lewin-Kowalik J . Plasma Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 as Prognostic Biomarkers in Critically Ill Patients. Open Med (Wars). 2020; 15:50-56. PMC: 7065420. DOI: 10.1515/med-2020-0008. View

13.

Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S . Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020; 581(7807):215-220. DOI: 10.1038/s41586-020-2180-5. View

14.

Lind L, Eriksson K, Grahn A . Chemokines and matrix metalloproteinases in cerebrospinal fluid of patients with central nervous system complications caused by varicella-zoster virus. J Neuroinflammation. 2019; 16(1):42. PMC: 6378740. DOI: 10.1186/s12974-019-1428-1. View

15.

Hsu A, Barrett C, DeBusk G, Ellson C, Gautam S, Talmor D . Kinetics and Role of Plasma Matrix Metalloproteinase-9 Expression in Acute Lung Injury and the Acute Respiratory Distress Syndrome. Shock. 2015; 44(2):128-36. PMC: 4830084. DOI: 10.1097/SHK.0000000000000386. View

16.

Nasr El-Din A, Ata K, Abdel-Gawad A, Fahmy N . Impact of High Serum Levels of MMP-7, MMP-9, TGF-β and PDGF Macrophage Activation Markers on Severity of COVID-19 in Obese-Diabetic Patients. Infect Drug Resist. 2021; 14:4015-4025. PMC: 8487291. DOI: 10.2147/IDR.S329004. View

17.

Kassianidis G, Siampanos A, Poulakou G, Adamis G, Rapti A, Milionis H . Calprotectin and Imbalances between Acute-Phase Mediators Are Associated with Critical Illness in COVID-19. Int J Mol Sci. 2022; 23(9). PMC: 9099708. DOI: 10.3390/ijms23094894. View

18.

Mondal S, Adhikari N, Banerjee S, Amin S, Jha T . Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur J Med Chem. 2020; 194:112260. DOI: 10.1016/j.ejmech.2020.112260. View

19.

Savic G, Stevanovic I, Mihajlovic D, Jurisevic M, Gajovic N, Jovanovic I . MMP-9/BDNF ratio predicts more severe COVID-19 outcomes. Int J Med Sci. 2022; 19(13):1903-1911. PMC: 9682503. DOI: 10.7150/ijms.75337. View

20.

Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K . Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020; 323(20):2052-2059. PMC: 7177629. DOI: 10.1001/jama.2020.6775. View