Abstract
IntroductionMatrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis.MethodsThis was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls.ResultsSepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-α/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-α and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45).ConclusionsThe novel findings of our study on patients with severe sepsis (to our knowledge, the largest series reporting data about MMP levels in sepsis) are that reduced MMP-9/TIMP-1 ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that TIMP-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis.
Highlights
Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation
Critical Care Vol 13 No 5 Lorente et al Conclusions The novel findings of our study on patients with severe sepsis are that reduced MMP-9/ tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that tissue inhibitors of matrix metalloproteinases (TIMPs)-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis
Tion between MMP-9, MMP-10, TIMP-1, and several indicators of severity in sepsis, including biomarkers of coagulation, lactic acid, Acute Physiology and Chronic Health Evaluation (APACHE)-II, and SOFA scores; and (c) the nonsurviving sepsis patients had higher TIMP-1 levels, lower MMP-9/ TIMP-1 ratios, and nonsignificantly higher MMP-10 levels than did surviving patients. These results indicate that an alteration in the MMP-9/TIMP-1 ratio and MMP-10 levels may be of great pathophysiologic significance in sepsis patients
Summary
Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. Matrix metalloproteinases (MMPs) are a family of zinc-containing endoproteinases implicated in degradation and remodelling of the extracellular matrix (ECM). They can be classified broadly by substrate specificity into collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), stromelysins (MMP-3, 10, -11), elastases (MMP-7 and -12), and membrane-type (MT-MMPs, MMP-14, -15, -16, and -17). The action of MMPs and TIMPs has been reported in the coagulation/fibrinolytic system [4,5,6]; the MMP/TIMP system may play a role in the coagulation/ fibrinolytic response to sepsis
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