Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis.
BACKGROUND
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-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha 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.
Intensive Care Unit, Hospital Universitario de Canarias, Ofra, 38320 Santa Cruz de Tenerife, Spain. lorentemartin@msn.com
Leonardo
L
Lorente
María M
MM
Martín
Lorenzo
L
Labarta
César
C
Díaz
Jordi
J
Solé-Violán
José
J
Blanquer
Josune
J
Orbe
José A
JA
Rodríguez
Alejandro
A
Jiménez
Juan M
JM
Borreguero-León
Felipe
F
Belmonte
Juan C
JC
Medina
Maria C
MC
Llimiñana
José M
JM
Ferrer-Agüero
José
J
Ferreres
María L
ML
Mora
Santiago
S
Lubillo
Manuel
M
Sánchez
Ysamar
Y
Barrios
Antonio
A
Sierra
José A
JA
Páramo
D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000097:blood*; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D019370:Observation; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018805:Sepsis / Q000097:blood / Q000401:mortality* / Q000503:physiopathology*; D012720:Severity of Illness Index; D013030:Spain / Q000453:epidemiology; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
D015415:Biomarkers; D019715:Tissue Inhibitor of Metalloproteinase-1; D053506:Matrix Metalloproteinase 10; D020780:Matrix Metalloproteinase 9