Abstract
ObjectiveMatrix 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.MethodsThis 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.ResultsNon-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.ConclusionsThe 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.
Highlights
Traumatic brain injury (TBI) is an important cause of disability, mortality and cost [1]
The regulation of its activity is complex and occurs at several levels [6], such as transcriptional (MMP gene expression in cells) that is influenced by numerous stimulatory and suppressive factors that influence multiple signalling pathways, as tumor necrosis factor (TNF)-a, interleukin-1b, transforming growth factor (TGF)-b, TGF-a; posttranscriptional that is influenced by glucocorticoids and TGF-b; translational that is influenced by plasmin and thrombin; and post-translational that is influenced by oxidative stress, nitrosidative stress, phosphorylation, proteolysis and tissue inhibitors of matrix metalloproteinases (TIMPs)
Multiple binomial logistic regression analysis showed that serum TIMP-1 could predict 30-day mortality (OR = 1.01; 95% CI = 1.001–1.013; P = 0.03) controlling for APACHE-II and computer tomography (CT) classification (Table 2)
Summary
Traumatic brain injury (TBI) is an important cause of disability, mortality and cost [1]. During the secondary injury there is an increase in the permeability of bloodbrain-barrier (BBB) and appears brain edema [2,3,4,5]. Matrix metalloproteinases (MMPs) are a family of zinccontaining endoproteinases implicated in degradation and remodelling 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), elastases (MMP-7 and -12) and membranetype (MT-MMPs, MMP-14, -15, -16 and -17). The findings of several animal studies suggested that MMP are involved in the disruption of the BBB, edema formation and inflammation after central nervous system trauma [15,16,17]
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