Association of sepsis-related mortality with early increase of TIMP-1/MMP-9 ratio.

Leonardo Lorente,Jordi Solé-Violán,María M Martín,Josune Orbe,Juan M Borreguero-León,José A Páramo,Alejandro Jiménez,César Díaz,José Blanquer,José A Rodríguez,Lorenzo Labarta,Jose Carlos Alves-Filho

doi:10.1371/journal.pone.0094318

Abstract

ObjectiveHigher 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.MethodsMulticenter, 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.ResultsWe 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.ConclusionsThe 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.

Highlights

Sepsis represents a systemic response of the immune system to infection leading to high mortality and costs [1,2]
The regulation of Matrix metalloproteinases (MMPs) activity is complex and occurs at several levels [7], such as transcriptional (MMP gene expression in cells) which is modified by tumour necrosis factor (TNF)-a, interleukin-1b and transforming growth factor (TGF)-b; post- transcriptional which is influenced by glucocorticoids and TGF-b; translational which is regulated by plasmin and thrombin; and posttranslational which is affected by oxidative stress, nitrosative stress, phosphorylation [8], proteolysis and tissue inhibitors of matrix metalloproteinases (TIMPs)
We focus on the determination of the TIMP-1/MMP-9 ratio because in previous studies we assessed serum TIMP-1 and MMP-9 levels [19,23], and because MMP-9 is inhibited by TIMP-1

Summary

Introduction

Sepsis represents a systemic response of the immune system to infection leading to high mortality and costs [1,2]. Previous clinical studies including our own have shown higher circulating levels of MMP-9 and TIMP-1 in septic patients than in controls [12,13,14,15,16,17,18,19,20,21,22], and higher levels of TIMP-1 [15,19,20,23] at the time of severe sepsis diagnosis in non-surviving than in surviving patients. An association between circulating TIMP-1 and plasminogen activator inhibitor (PAI)-1 levels in septic patients at severe sepsis diagnosis has been reported [23].

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Results

Conclusion