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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 , higher PAI-1 levels in nonsurviving than in surviving septic patients , and a positive correlation between TIMP-1 and PAI-1 in apparently healthy adult individuals . 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.
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.
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).
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.
Study supported, in part, by the grants FUNCISPI-42/07 and GTEI-SEMICYUC-2009.