Skip to main content
Top
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Body Plethysmography | Research

The usefulness of MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for diagnosis and assessment of COPD severity

Authors: Sanja Dimic-Janjic, Mir Alireza Hoda, Branislava Milenkovic, Jelena Kotur-Stevuljevic, Mihailo Stjepanovic, Daniela Gompelmann, Jelena Jankovic, Milica Miljkovic, Jelena Milin-Lazovic, Natasa Djurdjevic, Dragana Maric, Ivan Milivojevic, Spasoje Popevic

Published in: European Journal of Medical Research | Issue 1/2023

Login to get access

Abstract

Background

Inflammation, oxidative stress and an imbalance between proteases and protease inhibitors are recognized pathophysiological features of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with COPD and to assess their relationship with lung function, symptom severity scores and recent acute exacerbations.

Methods

In this observational cohort study, serum levels of MMP-9 and TIMP-1 and the MMP-9/TIMP-1 ratio in the peripheral blood of COPD patients with stable disease and healthy controls were determined, and their association with lung function (postbronchodilator spirometry, body plethysmography, single breath diffusion capacity for carbon monoxide), symptom severity scores (mMRC and CAT) and exacerbation history were assessed.

Results

COPD patients (n = 98) had significantly higher levels of serum MMP-9 and TIMP-1 and a higher MMP-9/TIMP-1 ratio than healthy controls (n = 47) (p ≤ 0.001). The areas under the receiver operating characteristic curve for MMP-9, TIMP-1 and the MMP-9/TIMP-1 ratio for COPD diagnosis were 0.974, 0.961 and 0.910, respectively (all p < 0.05). MMP-9 and the MMP-9/TIMP-1 ratio were both negatively correlated with FVC, FEV1, FEV1/FVC, VC, and IC (all p < 0.05). For MMP-9, a positive correlation was found with RV/TLC% (p = 0.005), and a positive correlation was found for the MMP-9/TIMP-1 ratio with RV% and RV/TLC% (p = 0.013 and 0.002, respectively). Patients with COPD GOLD 3 and 4 presented greater MMP-9 levels and a greater MMP-9/TIMP-1 ratio compared to GOLD 1 and 2 patients (p ≤ 0.001). No correlation between diffusion capacity for carbon monoxide and number of acute exacerbations in the previous year was found.

Conclusions

COPD patients have elevated serum levels of MMP-9 and TIMP-1 and MMP-9/TIMP-1 ratio. COPD patients have an imbalance between MMP-9 and TIMP-1 in favor of a pro-proteolytic environment, which overall indicates the importance of the MMP-9/TIMP-1 ratio as a potential biomarker for COPD diagnosis and severity.
Literature
1.
go back to reference Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Eur Respir J. 2017;49:3.CrossRef Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Eur Respir J. 2017;49:3.CrossRef
2.
go back to reference Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med. 2014;35(1):71–86.PubMedCrossRef Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med. 2014;35(1):71–86.PubMedCrossRef
3.
go back to reference Löffek S, Schilling O, Franzke CW. Biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38(1):191–208.PubMedCrossRef Löffek S, Schilling O, Franzke CW. Biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38(1):191–208.PubMedCrossRef
4.
go back to reference Starr AE, Dufour A, Maier J, Overall CM. Biochemical analysis of matrix metalloproteinase activation of chemokines CCL15 and CCL23 and increased glycosaminoglycan binding of CCL16. J Biol Chem. 2012;287(8):5848–60.PubMedCrossRef Starr AE, Dufour A, Maier J, Overall CM. Biochemical analysis of matrix metalloproteinase activation of chemokines CCL15 and CCL23 and increased glycosaminoglycan binding of CCL16. J Biol Chem. 2012;287(8):5848–60.PubMedCrossRef
5.
go back to reference Young D, Das N, Anowai A, Dufour A. Matrix metalloproteases as influencers of the cells’ social media. Int J Mol Sci. 2019;20:16.CrossRef Young D, Das N, Anowai A, Dufour A. Matrix metalloproteases as influencers of the cells’ social media. Int J Mol Sci. 2019;20:16.CrossRef
6.
go back to reference Jasper AE, McIver WJ, Sapey E, Walton GM. Understanding the role of neutrophils in chronic inflammatory airway disease. F1000Res. 2019;8:557.CrossRef Jasper AE, McIver WJ, Sapey E, Walton GM. Understanding the role of neutrophils in chronic inflammatory airway disease. F1000Res. 2019;8:557.CrossRef
7.
go back to reference Xu X, Jackson PL, Tanner S, Hardison MT, Roda MA, Blalock JE, et al. A self-propagating matrix metalloprotease-9 (MMP-9) dependent cycle of chronic neutrophilic inflammation. PLoS ONE. 2011;6(1):e15781.PubMedPubMedCentralCrossRef Xu X, Jackson PL, Tanner S, Hardison MT, Roda MA, Blalock JE, et al. A self-propagating matrix metalloprotease-9 (MMP-9) dependent cycle of chronic neutrophilic inflammation. PLoS ONE. 2011;6(1):e15781.PubMedPubMedCentralCrossRef
8.
go back to reference D W, T S, J D. Collagenolytic matrix metalloproteinases in chronic obstructive lung disease and cancer. Cancers. 2015;7(1):329–41.CrossRef D W, T S, J D. Collagenolytic matrix metalloproteinases in chronic obstructive lung disease and cancer. Cancers. 2015;7(1):329–41.CrossRef
9.
go back to reference Murthy S, Ryan A, He C, Mallampalli RK, Carter AB. Rac1-mediated mitochondrial H2O2 generation regulates MMP-9 gene expression in macrophages via inhibition of SP-1 and AP-1. J Biol Chem. 2010;285(32):25062–73.PubMedPubMedCentralCrossRef Murthy S, Ryan A, He C, Mallampalli RK, Carter AB. Rac1-mediated mitochondrial H2O2 generation regulates MMP-9 gene expression in macrophages via inhibition of SP-1 and AP-1. J Biol Chem. 2010;285(32):25062–73.PubMedPubMedCentralCrossRef
10.
go back to reference Murthy S, Ryan AJ, Carter AB. SP-1 regulation of MMP-9 expression requires serine-586 in the PEST domain. Biochem J. 2012;445(2):229–36.PubMedCrossRef Murthy S, Ryan AJ, Carter AB. SP-1 regulation of MMP-9 expression requires serine-586 in the PEST domain. Biochem J. 2012;445(2):229–36.PubMedCrossRef
11.
go back to reference Vandooren J, den Steen PEV, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol. 2013;48(3):222–72.PubMedCrossRef Vandooren J, den Steen PEV, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol. 2013;48(3):222–72.PubMedCrossRef
12.
14.
go back to reference O’Donnell DE, Webb KA, Neder JA. Lung hyperinflation in COPD: applying physiology to clinical practice. COPD Res Pract. 2015;1(1):4.CrossRef O’Donnell DE, Webb KA, Neder JA. Lung hyperinflation in COPD: applying physiology to clinical practice. COPD Res Pract. 2015;1(1):4.CrossRef
15.
go back to reference Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.PubMedCrossRef Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.PubMedCrossRef
16.
go back to reference Gagnon P, Guenette JA, Langer D, Laviolette L, Mainguy V, Maltais F, et al. Pathogenesis of hyperinflation in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;15(9):187–201. Gagnon P, Guenette JA, Langer D, Laviolette L, Mainguy V, Maltais F, et al. Pathogenesis of hyperinflation in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;15(9):187–201.
17.
go back to reference Barjaktarevic I, Springmeyer S, Gonzalez X, Sirokman W, Coxson HO, Cooper CB. Diffusing capacity for carbon monoxide correlates best with tissue volume from quantitative CT scanning analysis. Chest. 2015;147(6):1485–93.PubMedCrossRef Barjaktarevic I, Springmeyer S, Gonzalez X, Sirokman W, Coxson HO, Cooper CB. Diffusing capacity for carbon monoxide correlates best with tissue volume from quantitative CT scanning analysis. Chest. 2015;147(6):1485–93.PubMedCrossRef
18.
go back to reference Milenkovic B, Dimic-Janjic S, Kotur-Stevuljevic J, Kopitovic I, Jankovic J, Stjepanovic M, et al. Validation of serbian version of chronic obstructive pulmonary disease assessment test. VSP. 2020;77(3):294–9.CrossRef Milenkovic B, Dimic-Janjic S, Kotur-Stevuljevic J, Kopitovic I, Jankovic J, Stjepanovic M, et al. Validation of serbian version of chronic obstructive pulmonary disease assessment test. VSP. 2020;77(3):294–9.CrossRef
19.
go back to reference Miravitlles M, Calle M, Soler-Cataluña JJ. Clinical phenotypes of COPD: identification, definition and implications for guidelines. Arch Bronconeumol. 2012;48(3):86–98.PubMedCrossRef Miravitlles M, Calle M, Soler-Cataluña JJ. Clinical phenotypes of COPD: identification, definition and implications for guidelines. Arch Bronconeumol. 2012;48(3):86–98.PubMedCrossRef
21.
go back to reference Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948–68.PubMedCrossRef Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948–68.PubMedCrossRef
22.
go back to reference Celli BR, MacNee W, Agusti A, Anzueto A, Berg B, Buist AS, et al. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932–46.PubMedCrossRef Celli BR, MacNee W, Agusti A, Anzueto A, Berg B, Buist AS, et al. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932–46.PubMedCrossRef
23.
go back to reference Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017;49(1):1600016.PubMedCrossRef Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017;49(1):1600016.PubMedCrossRef
24.
go back to reference MacIntyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720–35.PubMedCrossRef MacIntyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720–35.PubMedCrossRef
26.
go back to reference Fischer BM, Pavlisko E, Voynow JA. Pathogenic triad in COPD: oxidative stress, protease–antiprotease imbalance, and inflammation. Int J Chron Obstruct Pulmon Dis. 2011;6:413–21.PubMedPubMedCentralCrossRef Fischer BM, Pavlisko E, Voynow JA. Pathogenic triad in COPD: oxidative stress, protease–antiprotease imbalance, and inflammation. Int J Chron Obstruct Pulmon Dis. 2011;6:413–21.PubMedPubMedCentralCrossRef
29.
go back to reference Linder R, Rönmark E, Pourazar J, Behndig A, Blomberg A, Lindberg A. Serum metalloproteinase-9 is related to COPD severity and symptoms—cross-sectional data from a population based cohort-study. Respir Res. 2015;16(1):28.PubMedPubMedCentralCrossRef Linder R, Rönmark E, Pourazar J, Behndig A, Blomberg A, Lindberg A. Serum metalloproteinase-9 is related to COPD severity and symptoms—cross-sectional data from a population based cohort-study. Respir Res. 2015;16(1):28.PubMedPubMedCentralCrossRef
30.
go back to reference Ilumets H, Mazur W, Toljamo T, Louhelainen N, Nieminen P, Kobayashi H, et al. Ageing and smoking contribute to plasma surfactant proteins and protease imbalance with correlations to airway obstruction. BMC Pulm Med. 2011;11(1):19.PubMedPubMedCentralCrossRef Ilumets H, Mazur W, Toljamo T, Louhelainen N, Nieminen P, Kobayashi H, et al. Ageing and smoking contribute to plasma surfactant proteins and protease imbalance with correlations to airway obstruction. BMC Pulm Med. 2011;11(1):19.PubMedPubMedCentralCrossRef
31.
go back to reference Piesiak P, Brzecka A, Kosacka M, Passowicz-Muszyńska E, Dyła T, Jankowska R. Concentrations of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in serum of patients with chronic obstructive pulmonary disease. Pol Merkur Lekarski. 2011;31(185):270–3.PubMed Piesiak P, Brzecka A, Kosacka M, Passowicz-Muszyńska E, Dyła T, Jankowska R. Concentrations of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in serum of patients with chronic obstructive pulmonary disease. Pol Merkur Lekarski. 2011;31(185):270–3.PubMed
32.
go back to reference Mercer P, Shute J, Bhowmik A, Donaldson G, Wedzicha J, Warner J. MMP-9, TIMP-1 and inflammatory cells in sputum from COPD patients during exacerbation. Respir Res. 2005;6(1):151.PubMedPubMedCentralCrossRef Mercer P, Shute J, Bhowmik A, Donaldson G, Wedzicha J, Warner J. MMP-9, TIMP-1 and inflammatory cells in sputum from COPD patients during exacerbation. Respir Res. 2005;6(1):151.PubMedPubMedCentralCrossRef
33.
go back to reference Esa SA, Rawy AM, El-Behissy MM, Kamel MH, El-Hwaitty HMMM. Study of the level of sputum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor metalloproteinase-1 (TIMP-1) in COPD patients. Egypt J Chest Dis Tubercul. 2014;63(4):861–7.CrossRef Esa SA, Rawy AM, El-Behissy MM, Kamel MH, El-Hwaitty HMMM. Study of the level of sputum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor metalloproteinase-1 (TIMP-1) in COPD patients. Egypt J Chest Dis Tubercul. 2014;63(4):861–7.CrossRef
34.
go back to reference Ostridge K, Williams N, Kim V, Bennett M, Harden S, Welch L, et al. Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD. Thorax. 2016;71(2):126–32.PubMedCrossRef Ostridge K, Williams N, Kim V, Bennett M, Harden S, Welch L, et al. Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD. Thorax. 2016;71(2):126–32.PubMedCrossRef
35.
go back to reference Sng JJ, Prazakova S, Thomas PS, Herbert C. MMP-8, MMP-9 and neutrophil elastase in peripheral blood and exhaled breath condensate in COPD. COPD J Chronic Obstr Pulm Dis. 2017;14(2):238–44.CrossRef Sng JJ, Prazakova S, Thomas PS, Herbert C. MMP-8, MMP-9 and neutrophil elastase in peripheral blood and exhaled breath condensate in COPD. COPD J Chronic Obstr Pulm Dis. 2017;14(2):238–44.CrossRef
36.
go back to reference Hk K, Y H, Mn L, Jj Y, Wj K. Relationship between plasma matrix metalloproteinase levels, pulmonary function, bronchodilator response, and emphysema severity. Int J Chron Obstruct Pulmon Dis. 2016;11:1129–37. Hk K, Y H, Mn L, Jj Y, Wj K. Relationship between plasma matrix metalloproteinase levels, pulmonary function, bronchodilator response, and emphysema severity. Int J Chron Obstruct Pulmon Dis. 2016;11:1129–37.
37.
go back to reference Wells JM, Parker MM, Oster RA, Bowler RP, Dransfield MT, Bhatt SP, et al. Elevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene. JCI Insight. 2018;3:22.CrossRef Wells JM, Parker MM, Oster RA, Bowler RP, Dransfield MT, Bhatt SP, et al. Elevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene. JCI Insight. 2018;3:22.CrossRef
38.
go back to reference Stanojkovic I, Kotur-Stevuljevic J, Milenkovic B, Spasic S, Vujic T, Stefanovic A, et al. Pulmonary function, oxidative stress and inflammatory markers in severe COPD exacerbation. Respir Med. 2011;105(Suppl 1):S31-37.PubMedCrossRef Stanojkovic I, Kotur-Stevuljevic J, Milenkovic B, Spasic S, Vujic T, Stefanovic A, et al. Pulmonary function, oxidative stress and inflammatory markers in severe COPD exacerbation. Respir Med. 2011;105(Suppl 1):S31-37.PubMedCrossRef
39.
go back to reference Ólafsdóttir IS, Janson C, Lind L, Hulthe J, Gunnbjörnsdóttir M, Sundström J. Serum levels of matrix metalloproteinase-9, tissue inhibitors of metalloproteinase-1 and their ratio are associated with impaired lung function in the elderly: a population-based study. Respirology. 2010;15(3):530–5.PubMedCrossRef Ólafsdóttir IS, Janson C, Lind L, Hulthe J, Gunnbjörnsdóttir M, Sundström J. Serum levels of matrix metalloproteinase-9, tissue inhibitors of metalloproteinase-1 and their ratio are associated with impaired lung function in the elderly: a population-based study. Respirology. 2010;15(3):530–5.PubMedCrossRef
40.
go back to reference Kang MJ, Oh YM, Lee JC, Kim DG, Park MJ, Lee MG, et al. Lung matrix metalloproteinase-9 correlates with cigarette smoking and obstruction of airflow. J Korean Med Sci. 2003;18(6):821–7.PubMedPubMedCentralCrossRef Kang MJ, Oh YM, Lee JC, Kim DG, Park MJ, Lee MG, et al. Lung matrix metalloproteinase-9 correlates with cigarette smoking and obstruction of airflow. J Korean Med Sci. 2003;18(6):821–7.PubMedPubMedCentralCrossRef
41.
go back to reference Beeh KM, Beier J, Kornmann O, Buhl R. Sputum matrix metalloproteinase-9, tissue inhibitor of metalloprotinease-1, and their molar ratio in patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and healthy subjects. Respir Med. 2003;97(6):634–9.PubMedCrossRef Beeh KM, Beier J, Kornmann O, Buhl R. Sputum matrix metalloproteinase-9, tissue inhibitor of metalloprotinease-1, and their molar ratio in patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and healthy subjects. Respir Med. 2003;97(6):634–9.PubMedCrossRef
42.
go back to reference Papakonstantinou E, Klagas I, Karakiulakis G, Prince SS, Roth M, Tamm M, et al. Activation of MMP-9 in BAL is increased in COPD exacerbation independently of smoking, lung function, microbiology and treatment. Eur Respir J. 2014;44:58. Papakonstantinou E, Klagas I, Karakiulakis G, Prince SS, Roth M, Tamm M, et al. Activation of MMP-9 in BAL is increased in COPD exacerbation independently of smoking, lung function, microbiology and treatment. Eur Respir J. 2014;44:58.
43.
go back to reference D’Armiento JM, Goldklang MP, Hardigan AA, Geraghty P, Roth MD, Connett JE, et al. Increased matrix metalloproteinase (MMPs) levels do not predict disease severity or progression in emphysema. PLoS ONE. 2013;8:2.CrossRef D’Armiento JM, Goldklang MP, Hardigan AA, Geraghty P, Roth MD, Connett JE, et al. Increased matrix metalloproteinase (MMPs) levels do not predict disease severity or progression in emphysema. PLoS ONE. 2013;8:2.CrossRef
44.
go back to reference Tsay JCJ, Hu Y, Goldberg JD, Wang B, Vijayalekshmy S, Yie TA, et al. Value of metalloproteinases in predicting COPD in heavy urban smokers. Respir Res. 2020;21(1):228.PubMedPubMedCentralCrossRef Tsay JCJ, Hu Y, Goldberg JD, Wang B, Vijayalekshmy S, Yie TA, et al. Value of metalloproteinases in predicting COPD in heavy urban smokers. Respir Res. 2020;21(1):228.PubMedPubMedCentralCrossRef
45.
go back to reference Snitker S, Xie K, Ryan KA, Yu D, Shuldiner AR, Mitchell BD, et al. Correlation of circulating MMP-9 with white blood cell count in humans: effect of smoking. PLoS ONE. 2013;8(6):e66277.PubMedPubMedCentralCrossRef Snitker S, Xie K, Ryan KA, Yu D, Shuldiner AR, Mitchell BD, et al. Correlation of circulating MMP-9 with white blood cell count in humans: effect of smoking. PLoS ONE. 2013;8(6):e66277.PubMedPubMedCentralCrossRef
46.
go back to reference Vlahos R, Wark PAB, Anderson GP, Bozinovski S. Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD. PLoS ONE. 2012;7(3):e33277.PubMedPubMedCentralCrossRef Vlahos R, Wark PAB, Anderson GP, Bozinovski S. Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD. PLoS ONE. 2012;7(3):e33277.PubMedPubMedCentralCrossRef
Metadata
Title
The usefulness of MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for diagnosis and assessment of COPD severity
Authors
Sanja Dimic-Janjic
Mir Alireza Hoda
Branislava Milenkovic
Jelena Kotur-Stevuljevic
Mihailo Stjepanovic
Daniela Gompelmann
Jelena Jankovic
Milica Miljkovic
Jelena Milin-Lazovic
Natasa Djurdjevic
Dragana Maric
Ivan Milivojevic
Spasoje Popevic
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01094-7

Other articles of this Issue 1/2023

European Journal of Medical Research 1/2023 Go to the issue