Research

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

Leonardo Lorente¹ , María M Martín² , Lorenzo Labarta³ , César Díaz⁴ , Jordi Solé-Violán⁵ , José Blanquer⁶ , Josune Orbe⁷ , José A Rodríguez⁷ , Alejandro Jiménez⁸ , Juan M Borreguero-León⁹ , Felipe Belmonte² , Juan C Medina² , Maria C LLimiñana¹⁰ , José M Ferrer-Agüero⁵ , José Ferreres⁶ , María L Mora¹ , Santiago Lubillo² , Manuel Sánchez⁴ , Ysamar Barrios⁸ , Antonio Sierra¹¹ and José A Páramo⁷

¹  Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320, Santa Cruz de Tenerife, Spain

²  Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Crta del Rosario s/n. Santa Cruz de Tenerife, 38010, Spain

³  Intensive Care Unit, Hospital San Jorge de Huesca, Avenida Martínez de Velasco no. 36, Huesca, 22004, Spain

⁴  Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n. Las Palmas de Gran Canaria, 35016, Spain

⁵  Intensive Care Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n. Las Palmas de Gran Canaria, 35010, Spain

⁶  Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda. Blasco Ibáñez no. 17-19, Valencia, 46004, Spain

⁷  Atherosclerosis Research Laboratory, CIMA-University of Navarra, Avda Pío XII no. 55, Pamplona, 31008, Spain

⁸  Research Unit, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320, Santa Cruz de Tenerife, Spain

⁹  Laboratory Deparment, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320, Santa Cruz de Tenerife, Spain

¹⁰  Laboratory Department, Hospital San Jorge de Huesca, Avenida Martínez de Velasco no. 36, Huesca, 22004, Spain

¹¹  Microbiology Department, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320, Santa Cruz de Tenerife, Spain

author email corresponding author email

Critical Care 2009, 13:R158doi:10.1186/cc8115

Published:	2 October 2009

See related commentary by Hoffman et al., http://ccforum.com/content/13/6/1006

Abstract

Introduction

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. 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.

Methods

This 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.

Results

Sepsis 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).

Conclusions

The 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.