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Meta-Analysis
. 2014 Apr 11;9(4):e94318.
doi: 10.1371/journal.pone.0094318. eCollection 2014.

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

Leonardo Lorente  1 , María M Martín  2 , Jordi Solé-Violán  3 , José Blanquer  4 , Lorenzo Labarta  5 , César Díaz  6 , Juan M Borreguero-León  7 , Josune Orbe  8 , José A Rodríguez  8 , Alejandro Jiménez  9 , José A Páramo  8
Affiliations
Meta-Analysis

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

Leonardo Lorente et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Serum MMP-9, TIMP-1 and TIMP-1/MMP-9 ratio in survivor and non-survivor septic patient showed as median (percentiles 25–75).
MMP  =  Matrix metalloproteinase; TIMP  =  Tissue inhibitor of matrix metalloproteinase.
Figure 2
Figure 2. Serum TNF-alpha and IL-10 levels and plasma PAI-1 levels in survivor and non-survivor septic patients showed as median (percentile 25–75).
TNF  =  tumour necrosis factor; IL  =  Interleukin; PAI  =  Plasminogen activator inhibitor.
Figure 3
Figure 3. Receiver operation characteristic analyses using TIMP-1/MMP-9 ratio at day 1, 4 and 8 after admission as predictor of mortality at 30 days in severe septic patients.
See this image and copyright information in PMC

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