Association between Serum Tissue Inhibitor of Matrix Metalloproteinase-1 Levels and Mortality in Patients with Severe Brain Trauma Injury Leonardo Lorente 1 *, Marı ´a M. Martı´n 2 , Patricia Lo ´ pez 2 , Luis Ramos 3 , Jose ´ Blanquer 4 , Juan J. Ca ´ ceres 5 , Jordi Sole ´ -Viola ´n 6 , Jorge Solera 7 , Judith Cabrera 1 , Mo ´ nica Argueso 4 , Raquel Ortiz 3 , Marı´a L. Mora 1 , Santiago Lubillo 2 , Alejandro Jime ´ nez 8 , Juan M. Borreguero-Leo ´n 9 , Agustı´n Gonza ´ lez 9 , Josune Orbe 10 , Jose ´ A. Rodrı ´guez 10 , Jose ´ A. Pa ´ ramo 10 1 Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain, 2 Intensive Care Unit, Hospital Universitario Nuestra Sen ˜ ora de Candelaria, Santa Cruz de Tenerife, Spain, 3 Intensive Care Unit, Hospital General La Palma, La Palma, Spain, 4 Intensive Care Unit, Hospital Clı ´nico Universitario de Valencia, Fundacio ´n INCLIVA, Valencia, Spain, 5 Intensive Care Unit, Hospital Insular, Las Palmas de Gran Canaria, Spain, 6 Intensive Care Unit, Hospital Universitario Dr. Negrı ´n, Las Palmas de Gran Canaria, Spain, 7 Deparment of Anesthesiology and Reanimation, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain, 8 Research Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain, 9 Laboratory Department, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain, 10 Atherosclerosis Research Laboratory, CIMA-University of Navarra, Pamplona, Spain Abstract Objective: Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a role in neuroinflammation after brain trauma injury (TBI). Previous studies with small sample size have reported higher circulating MMP-2 and MMP-9 levels in patients with TBI, but no association between those levels and mortality. Thus, the aim of this study was to determine whether serum TIMP-1 and MMP-9 levels are associated with mortality in patients with severe TBI. Methods: This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of TIMP-1, MMP-9 and tumor necrosis factor (TNF)-alpha, and plasma levels of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 plasma were measured in 100 patients with severe TBI at admission. Endpoint was 30-day mortality. Results: Non-surviving TBI patients (n = 27) showed higher serum TIMP-1 levels than survivor ones (n = 73). We did not find differences in MMP-9 serum levels. Logistic regression analysis showed that serum TIMP-1 levels were associated 30-day mortality (OR = 1.01; 95% CI = 1.001–1.013; P = 0.03). Survival analysis showed that patients with serum TIMP-1 higher than 220 ng/mL presented increased 30-day mortality than patients with lower levels (Chi-square = 5.50; P = 0.02). The area under the curve (AUC) for TIMP-1 as predictor of 30-day mortality was 0.73 (95% CI = 0.624–0.844; P,0.001). An association between TIMP-1 levels and APACHE-II score, TNF- alpha and TF was found. Conclusions: The most relevant and new findings of our study, the largest series reporting data on TIMP-1 and MMP-9 levels in patients with severe TBI, were that serum TIMP-1 levels were associated with TBI mortality and could be used as a prognostic biomarker of mortality in TBI patients. Citation: Lorente L, Martı ´n MM, Lo ´ pez P, Ramos L, Blanquer J, et al. (2014) Association between Serum Tissue Inhibitor of Matrix Metalloproteinase-1 Levels and Mortality in Patients with Severe Brain Trauma Injury. PLoS ONE 9(4): e94370. doi:10.1371/journal.pone.0094370 Editor: Nikos K. Karamanos, University of Patras, Greece Received November 27, 2013; Accepted March 15, 2014; Published April 11, 2014 Copyright: ß 2014 Lorente et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported, in part, by grants from Instituto de Salud Carlos III (I3SNSINT-11-063 and I3SNS-INT-12-087) (Madrid, Spain) and co-financed with Fondo Europeo de Desarrollo Regional (FEDER), CIMA (University of Navarra, Pamplona, Spain), and the ERANET-NEURON program from Ministerio de Economia y Competitividad (grant agreement No. 2011-1334). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: lorentemartin@msn.com Introduction Traumatic brain injury (TBI) is an important cause of disability, mortality and cost [1]. Primary injury refers to the initial physical forces applied to brain during the impact. Secondary injury occurs over a period of hours or days following the initial traumatic injury, and is developed by different mediators. During the secondary injury there is an increase in the permeability of blood- brain-barrier (BBB) and consequently appears brain edema [2–5]. Matrix metalloproteinases (MMPs) are a family of zinc- containing endoproteinases implicated in degradation and remod- elling 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), PLOS ONE | www.plosone.org 1 April 2014 | Volume 9 | Issue 4 | e94370