Influence of TIMP-1/MMP-9 ratio on the severity and mortality in sepsis

Introduction

The role of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in sepsis remains unclear. Previously reported have been higher circulating levels of TIMP-1 in septic patients than in controls [1], higher PAI-1 levels in nonsurviving than in surviving septic patients [2], and a positive correlation between TIMP-1 and PAI-1 in apparently healthy adult individuals [3]. The objective of this study was to determine the association between TIMP-1/MMP-9 ratio and PAI-1, and its influence on the severity and mortality of patients with sepsis.

Methods

This was a multicenter, observational and prospective study carried out in six Spanish ICUs. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis. Serum levels of MMP-9, TIMP-1 and plasma levels of PAI-1 were measured at the time of diagnosis.

Results

Nonsurviving septic patients presented higher levels of TIMP-1 (P < 0.001), higher TIMP-1/MMP-9 ratio (P < 0.001), higher levels of PAI-1 (P < 0.001), higher SOFA score (P < 0.001), higher lactic acid levels (P < 0.001) and lower platelet count (P < 0.001) than surviving ones. TIMP-1/MMP-9 ratio positively correlated with PAI-1(P < 0.001), lactic acid levels (P < 0.001), SOFA score (P < 0.001), INR ratio (P < 0.001), aPTT (P < 0.001), and negatively with platelet count (P < 0.001). The mortality prediction by TIMP-1/MMP-9 ratio (AUC = 0.66; 95% CI = 0.58 to 0.74; P < 0.001) was similar to that provided by other markers of severity such as lactic acid (AUC = 0.67; 95% CI = 0.58 to 0.75; P < 0.001) and SOFA score (AUC = 0.71; 95% CI = 0.64 to 0.79; P < 0.001).

Conclusions

The TIMP-1/MMP-9 ratio may be of great pathophysiological significance in terms of severity and mortality in sepsis, and may represent a biomarker to predict the clinical outcome of septic patients. The novel finding of our study is the association between TIMP-1/MMP-9 ratio and PAI-1 levels in sepsis, which can contribute in the organ dysfunction and mortality of sepsis.