title: Association of sepsis-related mortality with early increase of TIMP-1/MMP-9 ratio.
abstract: OBJECTIVE
  Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 at the time of severe sepsis diagnosis have been reported in nonsurviving than in surviving patients. However, the following questions remain unanswered: 1) Does TIMP-1/MMP-9 ratio differ throughout the first week of intensive care between surviving and non-surviving patients? 2) Is there an association between TIMP-1/MMP-9 ratio and sepsis severity and mortality during such period? 3) Could TIMP-1/MMP-9 ratio during the first week be used as an early biomarker of sepsis outcome? 4) Is there an association between TIMP-1/MMP-9 ratio and coagulation state and circulating cytokine levels during the first week of intensive care in these patients? The present study sought to answer these questions.
  
  
  METHODS
  Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units (ICUs) of 295 patients with severe sepsis. Were measured circulating levels of TIMP-1, MMP-9, tumour necrosis factor (TNF)-alpha, interleukin (IL)-10 and plasminogen activator inhibitor (PAI)-1 at day 1, 4 and 8. End-point was 30-day mortality.
  
  
  RESULTS
  We found higher TIMP-1/MMP-9 ratio during the first week in non-surviving (n = 98) than in surviving patients (n = 197) (p<0.01). Logistic regression analyses showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 was associated with mortality. Receiver operating characteristic (ROC) curves showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 could predict mortality. There was an association between TIMP-1/MMP-9 ratio and TNF-alpha, IL-10, PAI-1 and lactic acid levels, SOFA score and platelet count at days 1, 4 and 8.
  
  
  CONCLUSIONS
  The novel findings of our study were that non-surviving septic patients showed persistently higher TIMP-1/MMP-9 ratio than survivors ones during the first week, which was associated with severity, coagulation state, circulating cytokine levels and mortality; thus representing a new biomarker of sepsis outcome.
authors.affiliation: Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lorente
authors.affiliation: Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Martín
authors.affiliation: Intensive Care Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Solé-Violán
authors.affiliation: Intensive Care Unit, Hospital Clínico Universitario de Valencia, Valencia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Blanquer
authors.affiliation: Intensive Care Unit, Hospital San Jorge de Huesca, Huesca, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Labarta
authors.affiliation: Intensive Care Unit, Hospital Insular, Las Palmas de Gran Canaria, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Díaz
authors.affiliation: Laboratory Department, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Borreguero-León
authors.affiliation: Atherosclerosis Research Laboratory, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Josune
authors.initials: J
authors.lastname: Orbe
authors.affiliation: Atherosclerosis Research Laboratory, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Rodríguez
authors.affiliation: Research Unit, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Jiménez
authors.affiliation: Atherosclerosis Research Laboratory, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Páramo
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D019934:International Normalized Ratio; D019344:Lactic Acid / Q000097:blood; D016015:Logistic Models; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D012372:ROC Curve; D018805:Sepsis / Q000097:blood* / Q000201:enzymology / Q000401:mortality*; D013030:Spain / Q000453:epidemiology; D017741:Survivors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019344:Lactic Acid; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
references.citation: Crit Care. 2010;14(2):R49
references.pmid: 20356362
references.citation: Annu Rev Cell Dev Biol. 2001;17:463-516
references.pmid: 11687497
references.citation: Nat Rev Mol Cell Biol. 2002 Mar;3(3):207-14
references.pmid: 11994741
references.citation: Crit Care Med. 2006 Feb;34(2):344-53
references.pmid: 16424713
references.citation: Crit Care. 2009;13(5):R158
references.pmid: 19799791
references.citation: Int J Hematol. 2006 Dec;84(5):398-405
references.pmid: 17189219
references.citation: Circulation. 2002 Sep 17;106(12):1543-9
references.pmid: 12234962
references.citation: Am J Respir Cell Mol Biol. 1999 Mar;20(3):458-64
references.pmid: 10030844
references.citation: Scand J Infect Dis. 2006;38(10):867-72
references.pmid: 17008230
references.citation: Intensive Care Med. 1996 Jul;22(7):707-10
references.pmid: 8844239
references.citation: Am J Respir Crit Care Med. 1996 Aug;154(2 Pt 1):346-52
references.pmid: 8756805
references.citation: Crit Care Med. 2001 Jul;29(7):1303-10
references.pmid: 11445675
references.citation: FASEB J. 2007 Aug;21(10):2486-95
references.pmid: 17435175
references.citation: Anaesthesia. 2001 Aug;56(8):729-32
references.pmid: 11493234
references.citation: Shock. 2009 Aug;32(2):228-35
references.pmid: 19060786
references.citation: Am J Respir Crit Care Med. 2003 Feb 15;167(4):593-8
references.pmid: 12588713
references.citation: Pharmacol Res. 2011 Dec;64(6):590-4
references.pmid: 21742038
references.citation: Lancet. 1999 Aug 14;354(9178):556-60
references.pmid: 10470700
references.citation: Intensive Care Med. 2003 Apr;29(4):530-8
references.pmid: 12664219
references.citation: Crit Care Med. 1985 Oct;13(10):818-29
references.pmid: 3928249
references.citation: Thromb Haemost. 1989 Jun 30;61(3):459-62
references.pmid: 2678584
references.citation: Am Heart J. 2006 May;151(5):1101.e1-8
references.pmid: 16644343
references.citation: Biochemistry (Mosc). 2002 Jan;67(1):92-8
references.pmid: 11841344
references.citation: Eur J Pharmacol. 2006 May 10;537(1-3):52-8
references.pmid: 16624282
references.citation: Nature. 1997 Apr 10;386(6625):616-9
references.pmid: 9121586
references.citation: Clin Chim Acta. 2001 Dec;314(1-2):241-4
references.pmid: 11718702
references.citation: Am J Med Sci. 1998 Dec;316(6):355-60
references.pmid: 9856688
references.citation: Crit Rev Biochem Mol Biol. 2010 Oct;45(5):351-423
references.pmid: 20812779
references.citation: Crit Care. 2013 May 25;17(3):R94
references.pmid: 23706069
references.citation: J Crit Care. 2011 Dec;26(6):556-65
references.pmid: 21439766
references.citation: Thromb Res. 2008;121(4):535-42
references.pmid: 17681591
references.citation: Clin Exp Immunol. 2005 Oct;142(1):12-20
references.pmid: 16178851
references.citation: Atherosclerosis. 2007 Nov;195(1):212-5
references.pmid: 17222415
references.citation: Mol Med. 2009 Jul-Aug;15(7-8):275-82
references.pmid: 19593412
references.citation: Clin Cancer Res. 2007 Apr 1;13(7):2054-60
references.pmid: 17404086
references.citation: Br J Pharmacol. 2004 Sep;143(1):193-201
references.pmid: 15289295
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:211-42
references.pmid: 17129183
references.citation: Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1477-87
references.pmid: 22492089
references.citation: Br J Pharmacol. 2002 Dec;137(8):1330-8
references.pmid: 12466243