Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in ICU patients

Matrix-metalloproteases (MMPs) and their tissue-inhibitors (TIMPs), modulated by different single nucleotide polymorphisms (SNPs), are critical in sepsis development. Ninety ICU severely septic and 91 ICU uninfected patients were prospectively studied. MMP-1 (−1607 1G/2G), MMP-3 (−1612 5A/6A), MMP-8 (−799 C/T), MMP-9 (−1562 C/T), and MMP-13 (−77A/G) SNPs were genotyped. Plasma MMPs (-1, -2, -3, -8, -9, -10, -13) and TIMPs (-1,-2,-4) were measured. AA homozygotes and A allele carriers of MMP-13 (−77 A/G) and 1G2G carriers of the MMP-1 (−1607 1G/2G) SNPs frequencies were different between septic and uninfected patients (p < 0.05), as well as plasma MMP-3, -8, -9 -10 and TIMP-2 levels (p < 0.04). No differences in MMPs levels among MMP-13 or MMP-1 SNPs genotypes carriers were observed. The area under the ROC curve for MMP-8 in the diagnosis of sepsis was 0.87 (95% CI 0.82–0.92), and that of CRP was 0.98 (0.94–0.998), whereas the area of MMP-9 in the detection of non-septic state was 0.73 (0.65–0.80), p < 0.0001 for all curves. Sepsis associated with increased MMP-8 and decreased MMP-9 levels in multivariate analysis (p < 0.0002). We report for the first time an association between MMP-13 and MMP-1 SNPs and sepsis. An independent association of MMP-8 and MMP-9 levels with sepsis was also observed.

[1]  N. Webster,et al.  Matrix metalloproteinase‐9 concentrations in critically ill patients , 2001, Anaesthesia.

[2]  Xue-qing Xu,et al.  Association between Polymorphisms in the Promoter Regions of Matrix Metalloproteinases (MMPs) and Risk of Cancer Metastasis: A Meta-Analysis , 2012, PloS one.

[3]  S. Baudouin,et al.  A systematic review of the quality of genetic association studies in human sepsis , 2006, Intensive Care Medicine.

[4]  E. Ruokonen,et al.  Serum MMP-8, -9 and TIMP-1 in sepsis: high serum levels of MMP-8 and TIMP-1 are associated with fatal outcome in a multicentre, prospective cohort study. Hypothetical impact of tetracyclines. , 2011, Pharmacological research.

[5]  J. Gu,et al.  Matrix metalloproteinase polymorphisms and bladder cancer risk. , 2006, Cancer research.

[6]  K. Walley,et al.  Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. , 2003, Chest.

[7]  T. Salo,et al.  Matrix-metalloproteinase-2, -8 and -9 in serum and skin blister fluid in patients with severe sepsis , 2010, Critical care.

[8]  G. Rice,et al.  Matrix metalloproteinase-3 and coronary remodelling: implications for unstable coronary disease. , 2007, Cardiovascular research.

[9]  Alejandro Jiménez,et al.  Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis , 2009, Critical care.

[10]  F. Cambien,et al.  Plasma Concentrations and Genetic Variation of Matrix Metalloproteinase 9 and Prognosis of Patients With Cardiovascular Disease , 2003, Circulation.

[11]  Gillian Murphy,et al.  Structure and function of matrix metalloproteinases and TIMPs. , 2006, Cardiovascular research.

[12]  C. Sprung,et al.  The ACCP-SCCM consensus conference on sepsis and organ failure. , 1992, Chest.

[13]  C. Sprung,et al.  Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. , 1995, Critical care medicine.

[14]  J. Chiche,et al.  Genetic polymorphisms of matrix metalloproteinase 12 and 13 genes are implicated in endometriosis progression. , 2008, Human reproduction.

[15]  S. Opal,et al.  A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis , 2011, EMBO molecular medicine.

[16]  P. Liaw,et al.  Elevated plasma matrix metalloproteinases and their tissue inhibitors in patients with severe sepsis. , 2011, Journal of critical care.

[17]  C. Cooper,et al.  Variation in the matrix metalloproteinase‐3, ‐7, ‐12 and ‐13 genes is associated with functional status in rheumatoid arthritis , 2007, International journal of immunogenetics.

[18]  J. Rello,et al.  Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. , 2003, Chest.

[19]  William C. Parks,et al.  Matrix metalloproteinases as modulators of inflammation and innate immunity , 2004, Nature Reviews Immunology.

[20]  F. Schmidt.  Meta-Analysis , 2008 .

[21]  W. Ollier,et al.  Association of matrix metalloproteinase 3 promoter genotype with disease outcome in rheumatoid arthritis , 2004, Genes and Immunity.

[22]  J. Odeberg,et al.  Serum matrix metalloproteinase‐3 concentration is influenced by MMP‐3 −1612 5A/6A promoter genotype and associated with myocardial infarction , 2005, Journal of internal medicine.

[23]  J. Paramo,et al.  The 372 T/C genetic polymorphism of TIMP-1 is associated with serum levels of TIMP-1 and survival in patients with severe sepsis , 2013, Critical Care.

[24]  S. Ye.  Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome. , 2006, Cardiovascular research.

[25]  A. Henney,et al.  Progression of Coronary Atherosclerosis Is Associated with a Common Genetic Variant of the Human Stromelysin-1 Promoter Which Results in Reduced Gene Expression* , 1996, The Journal of Biological Chemistry.

[26]  R. Vandenbroucke,et al.  The first MMP in sepsis , 2011, EMBO molecular medicine.

[27]  S. Curran,et al.  The Structure, Regulation, and Function of Human Matrix Metalloproteinase-13 , 2002, Critical reviews in biochemistry and molecular biology.

[28]  M. Borggrefe,et al.  Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: Prognostic value of TIMP-1 in severe sepsis , 2006, Scandinavian journal of infectious diseases.

[29]  V. Álvarez,et al.  A functional polymorphism in MMP1 could influence osteomyelitis development , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[30]  Bronwyn A. Kingwell,et al.  Matrix Metalloproteinase-9 Genotype Influences Large Artery Stiffness Through Effects on Aortic Gene and Protein Expression , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[31]  J. Lantos,et al.  Dynamic changes of matrix metalloproteinases and their tissue inhibitors in severe sepsis. , 2011, Journal of critical care.

[32]  Wu-chang Yang,et al.  Functional polymorphisms in matrix metalloproteinases-1, -3, -9 are associated with arteriovenous fistula patency in hemodialysis patients. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[33]  Meilin Wang,et al.  MMP-9 -1562C>T contributes to periodontitis susceptibility. , 2013, Journal of clinical periodontology.

[34]  Mitchell M. Levy,et al.  2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference , 2003, Intensive Care Medicine.

[35]  R. Dellinger,et al.  Cardiovascular management of septic shock. , 2003, Critical care medicine.

[36]  D. Remick,et al.  Pathophysiology of sepsis. , 2007, The American journal of pathology.