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.

Increased local and systemic CRP-related MMP activation might provide a link between inflammation and plaque vulnerability.

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Objectives-Assessment of vascular risk in asymptomatic patients and the response to medical therapy is a major challenge for prevention of cardiovascular events. Our aim was to identify proteins differentially released by healthy versus atherosclerotic arterial walls, which could be found in plasma and serve as markers of atherosclerosis. Methods and Results-We have analyzed supernatants obtained from cultured human carotid plaques and healthy arteries by surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry ProteinChip System. Surfaceenhanced laser-desorption/ionization analysis unveiled an 18.4-kDa peak released in lower amount by carotid plaques than normal endarteries. This protein was identified as soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). To confirm that sTWEAK was the protein of interest, Western blot and enzyme-linked immunosorbent assay were performed. Both techniques confirmed that sTWEAK levels were decreased in carotid plaque supernatants. Subsequent measurement of sTWEAK in plasma showed a reduced concentration in subjects with carotid stenosis (Nϭ30) compared with healthy subjects matched by sex and age (Nϭ28) 1 Atherogenesis is a complex process characterized by lipid deposition and a chronic inflammatory response. The resulting pathological vascular remodeling involves inflammatory cell recruitment, fibrosis, smooth muscle cell proliferation, and neovascularization. 2 Our hypothesis is that atherosclerotic plaque prone to rupture could display a particular profile of released proteins, reflecting directly the late events preceding rupture such as proteolysis or cell death. The levels of several inflammatory molecules in circulating blood have been shown to be elevated in subjects at risk for an acute coronary event. [3][4] Most of existing markers were proposed based on the assessment of proteins in plasma related to inflammation process associated with atherosclerosis (eg, C-reactive protein, CD40 ligand). 5 We have recently reported a new strategy to identify potential biological markers directly released by the arterial wall, using a proteomic approach. 6 -7 Incubation of endarterectomy samples versus control endarteries in a serum-free culture medium allowed us to harvest separately the proteins released from pathological and healthy areas and the supernatants (conditioned media) were subsequently analyzed by 2-dimensional electrophoresis. After identification of the differentially released proteins, their levels are measured in plasma to assess their potential as biomarkers of atherosclerosis. In this article, using a similar approach, we have analyzed the conditioned media from normal mammary endarteries versus carotid atherosclerotic endarterectomy samples by surface-enhanced laser desorption ionization (SELDI) time-of-flight (TOF) mass spectrometry (MS). This method is based on the chromatographic fractionation of the proteome on ProteinChips before MS analysis; it allows an easy and quantitative comparison of profiles of proteins relea...