Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis

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.

Synergistic Effect of Thrombin and CD40 Ligand on Endothelial Matrix Metalloproteinase-10 Expression and Microparticle Generation In Vitro and In Vivo

“…21 We found a significant increase of MMP-10 and CD40L in septic patients, particularly in the nonsurviving group. Thrombin, protein C pathway, activators and inhibitors of fibrinolysis, and PARs play vital roles in the crosstalk between inflammation and coagulation in sepsis, 28 but the role of CD40L in sepsis still remains unclear.…”

“…This is associated with increased circulating levels of prothrombotic/inflammatory mediators, such as thrombin and CD40L, 4,7 and enhanced protease activity. 13,21 In this study, we describe for the first time that thrombin and CD40L act synergistically to induce MMP-10 both in vitro and in vivo, and to generate MPs carrying active MMP-10. The fact that thrombin mediates CD40 expression in ECs and that its inhibition significantly reduced MMP-10 expression strongly suggests that thrombin-induced CD40 upregulation could underlie this synergy.…”

Water-based, surfactant-free cytocompatible nanoparticle-microgel-composite biomaterials – rational design by laser synthesis, processing into fiber pads and impact on cell proliferation

“…The fact that embedded soluble ion-releasing nanoparticles can affect proliferation and migration is not surprising as h-KC migration was previously shown to be affected by the release of iron and zinc ions as specified in the introduction [11], [12], [13], [14], [15], [16]. While KC differentiation, ex vivo, was already described to be induced by topical applications of zinc [16], this parameter has to be studied further in order to supplement the potential effects of our system on the KC behavior.…”

“…Hereby zinc was shown to take a part in the KC differentiation mechanisms [16]. Finally the scar tissues are remodelled by a turn over between degradation of type III collagen by MMPs and type I neocollagenesis, where respectively zinc and iron are imperative [11], [12], [13], [15]. Based on this, it may be concluded that an optimized ion release system for zinc and iron based on nanocomposites would be highly beneficial to aide in wound healing, while the embedded nanoparticles could serve as excellent ion release source because of their high surface-to-volume ratio.…”

“…This process necessitates the synthesis of proteases by macrophages. The protease family mainly involved in wound healing is the matrix metallo-proteases (MMP), which is zinc dependent as its active site directly relies on a zinc ion [11], [12], [13]. Neutrophils, for their part, are known to show an enhanced oxidative metabolism under zinc ions influence [14].…”