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Prognostic utility of early plasma matrix metalloproteinases -2 and -9 concentrations after severe traumatic brain injury

Abstract

Objective:

To determine whether the matrix metalloproteinases-2 and -9 plasma levels were associated with intensive care unit mortality in patients who suffered severe traumatic brain injury, despite the presence of extracerebral injuries.

Methods:

This prospective cohort enrolled 39 male patients who suffered severe traumatic brain injury (Glasgow coma scale: 3 - 8 at hospital admission). The plasma matrix metalloproteinase -2 and matix metalloproteinase -9 levels were determined by ELISA at the time of intensive care unit admission.

Results:

Severe traumatic brain injury was associated with a 46% intensive care unit mortality rate. Higher plasma matrix metalloproteinase -9 concentrations were associated with mortality: 147.94 ± 18.00ng/mL for survivors and 224.23 ± 23.86ng/mL for nonsurvivors (mean ± standard error of the mean, p = 0.022). In contrast, there was no significant association between matrix metalloproteinase -2 levels and intensive care unit mortality: 315.68 ± 22.90ng/mL for survivors and 336.55 ± 24.29ng/mL for nonsurvivors (p = 0.499). Additionally, there were no significant associations between matrix metalloproteinase -2 (p = 0.711) and matrix metalloproteinase -9 (p = 0.092) levels and the presence of associated lesions.

Conclusion:

Increased plasma matrix metalloproteinase -9 levels were associated with intensive care unit mortality following severe traumatic brain injury, regardless of the presence of extracerebral injuries. Conversely, in this same context, plasma matrix metalloproteinase -2 levels were not associated with short-term fatal outcome prediction.

Keywords:
Traumatic brain injury; Biomarkers; Matrix metalloproteinase-2; Matrix metalloproteinase-9; Fatal outcome; Mortality

RESUMO

Objetivo:

Determinar se os níveis plasmáticos das metaloproteinases de matriz -2 e -9 tem associação com a mortalidade na unidade de terapia intensiva em pacientes com trauma craniencefálico grave, independentemente de lesões não cerebrais associadas.

Métodos:

Esta coorte prospectiva incluiu 39 pacientes do sexo masculino com trauma craniencefálico grave (escore na escala de coma Glasgow na admissão hospitalar: 3 - 8). Os níveis plasmáticos das metaloproteinases -2 e -9 foram determinados por ELISA no momento da admissão na unidade de terapia intensiva.

Resultados:

O trauma craniencefálico grave apresentou mortalidade de 46% na unidade de terapia intensiva. Concentrações mais elevadas de metaloproteinase -9 apresentaram associação com a mortalidade: 147,94 ± 18,00ng/mL para pacientes que sobreviveram e 224,23 ± 23,86ng/mL para os que não sobreviveram (média ± erro padrão, respectivamente; p = 0,022). Todavia, não houve associação significativa entre os níveis de metaloproteinase -2 e a mortalidade na unidade de terapia intensiva: 315,68 ± 22,90ng/mL para o grupo de sobreviventes e 336,55 ± 24,29ng/mL entre os pacientes que não sobreviveram (p = 0,499). Além disso, não se observaram associações significativas entre os níveis de metaloproteinase -2 (p = 0,711) ou metaloproteinase -9 (p = 0,092) e a presença de lesões não cerebrais associadas.

Conclusão:

Em vítimas de traumatismo craniencefálico grave, níveis elevados de metaloproteinase -9 tiveram valor preditivo para o desfecho fatal na unidade de terapia intensiva independentemente da presença de lesões não cerebrais associadas. Por outro lado, no mesmo cenário, os níveis plasmáticos de metaloproteinase -2 não apresentaram associação com a mortalidade na unidade de terapia intensiva

Descritores:
Traumatismo craniencefálico; Biomarcadores; Desfecho fatal; Mortalidade; Metaloproteinase de matriz-2; Metaloproteinase de matriz-9

INTRODUCTION

Traumatic brain injury (TBI) is the major cause of death and disabilities in young people worldwide.(11 Ghajar J. Traumatic brain injury. Lancet. 2000;356(9233):923-9.) Severe TBI has been associated with a mortality rate of 30 to 50% (with approximately 90% of deaths occurring within 48 hours of insult) and often causes permanent sequelae.(22 Coronado VG, Xu L, Basavaraju SV, McGuire LC, Wald MM, Faul MD, Guzman BR, Hemphill JD; Centers for Disease Control and Prevention (CDC). Centers for Disease Control and Prevention (CDC). Surveillance for traumatic brain injury-related deaths--United States, 1997-2007. MMWR Surveill Summ. 2011;60(5):1-32.) Though the prompt identification of salvageable brain tissue is crucial for the management of patients sustaining severe TBI, the early assessment of injury severity in these patients represents a challenge in intensive care unit (ICU) settings.(11 Ghajar J. Traumatic brain injury. Lancet. 2000;356(9233):923-9.,33 Regner A, Kaufman M, Friedman G, Chemale I. Increased serum S100beta protein concentrations following severe head injury in humans: a biochemical marker of brain death? Neuroreport. 2001;12(4):691-4.,44 Morganti-Kossmann MC, Satgunaseelan L, Bye N, Kossmann T. Modulation of immune response by head injury. Injury. 2007;38(12):1392-400.) Neurotrauma causes damage to the blood-brain barrier (BBB) and, consequently, biomolecules are released into the circulation; this has incited the search for predictive biomarkers that employ minimally invasive sampling techniques and may translate to clinical practice (e.g., S100B, neuron-specific enolase, glial fibrillary acidic protein, and plasma DNA).(33 Regner A, Kaufman M, Friedman G, Chemale I. Increased serum S100beta protein concentrations following severe head injury in humans: a biochemical marker of brain death? Neuroreport. 2001;12(4):691-4.,55 Regner A, Meirelles LD, Ikuta N, Cecchini A, Simon D. Prognostic utility of circulating nucleic acids in acute brain injuries. Expert Rev Mol Diagn. 2018;18(11):925-38.,66 Rodrigues Filho EM, Simon D, Ikuta N, Klovan C, Dannebrock FA, Oliveira de Oliveira C, et al. Elevated cell-free plasma DNA level as an independent predictor of mortality in patients with severe traumatic brain injury. J Neurotrauma. 2014:31(19):1639-46.) Primary injury after severe TBI is caused by mechanical forces that engender deformation of brain tissue. This primary injury triggers a secondary wave of events (i.e., excitoxicity, oxidative stress, metabolic crisis, changes in BBB permeability, inflammatory response, ischemia, and edema), occurring within seconds to minutes after the brain lesion and lasting for days, months, or years.(11 Ghajar J. Traumatic brain injury. Lancet. 2000;356(9233):923-9.,44 Morganti-Kossmann MC, Satgunaseelan L, Bye N, Kossmann T. Modulation of immune response by head injury. Injury. 2007;38(12):1392-400.,77 Regner A, Meirelles LS, Simon D. Traumatic penumbra: opportunities for neuroprotective and neurorestorative processes. In: Gorbunov N, editor. Traumatic brain injury: pathobiology, advanced diagnostics and acute management. London, UK: IntechOpen; 2018. pp. 49-83.) The ongoing brain damage, which is characteristic of secondary injury, evolves to increased intracranial pressure that can culminate in brain death, particularly in the first 72 hours post-trauma.(77 Regner A, Meirelles LS, Simon D. Traumatic penumbra: opportunities for neuroprotective and neurorestorative processes. In: Gorbunov N, editor. Traumatic brain injury: pathobiology, advanced diagnostics and acute management. London, UK: IntechOpen; 2018. pp. 49-83.)

Matrix metalloproteinases (MMPs) have been implicated in neural injury progression (i.e., BBB breakdown, contusion expansion, and vasogenic edema) following TBI.(88 Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384-92.,99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.) Matrix metalloproteinases form a large family of zinc-dependent endopeptidases related to the dynamic remodulation of the extracellular matrix (ECM). The remodeling of the ECM after neurotrauma has been shown to affect neuronal guidance, synaptic plasticity and regenerative responses.(88 Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384-92.,99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.) Matrix metalloproteinases are finely tuned enzymes that are strategically regulated at the level of transcription, maturation from precursor pro-MMPs, interaction with various ECM components, and inhibition by endogenous inhibitors.(99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.) Neurons, astrocytes, oligodendrocytes, microglia and endothelial cells have all been shown to express specific MMPs differently after injury, according to brain region, cellular source, and the type of injury.(99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.,1010 Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia. 2005;50(4):329-39.) Matrix metalloproteinases are also produced by circulating leukocytes that invade the brain during inflammation.(99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.)

Under normal quiescent conditions, MMP expression is very limited, and MMPs are detected either in small amounts or not at all in tissues or the circulation. However, the inflammatory pathway signaling molecules involved in brain injury affect the gene transcription of MMPs.(77 Regner A, Meirelles LS, Simon D. Traumatic penumbra: opportunities for neuroprotective and neurorestorative processes. In: Gorbunov N, editor. Traumatic brain injury: pathobiology, advanced diagnostics and acute management. London, UK: IntechOpen; 2018. pp. 49-83.

8 Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384-92.
-99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.) Matrix metalloproteinases are upregulated in TBI and can degrade crucial components of the cerebrovascular matrix, leading to disruption of the BBB and exacerbation of edema post-TBI.(99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.) Several studies in animal models have suggested that MMP-2 and -9, which are inducible MMPs found in the ECM, cerebrospinal fluid, and blood,(99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.) play important roles in neuroinflammation and secondary injury progression after TBI.(88 Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384-92.,1111 Grossetete M, Phelps J, Arko L, Yonas H, Rosenberg GA. Elevation of matrix metalloproteinases 3 and 9 in cerebrospinal fluid and blood in patients with severe traumatic brain injury. Neurosurgery. 2009;65(4):702-8.

12 Copin JC, Rebetez MM, Turck N, Robin X, Sanchez JC, Schaller K, et al. Matrix metalloproteinase 9 and cellular fibronectin plasma concentrations are predictors of the composite endpoint of length of stay and death in the intensive care unit after severe traumatic brain injury. Scand J Trauma Resusc Emerg Med. 2012;20:83.

13 Lorente L, Martín MM, López P, Ramos L, Blanquer J, Cáceres JJ, et al. Association between serum tissue inhibitor of matrix metalloproteinase-1 levels and mortality in patients with severe brain trauma injury. PLoS One. 2014;9(4):e94370.

14 del Zoppo GJ, Frankowski H, Gu Y, Osada T, Kanazawa M, Milner R, et al. Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab. 2012;32(5):919-32.
-1515 Suofu Y, Clark JF, Broderick JP, Kurosawa Y, Wagner KR, Lu A. Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience. 2012;212:180-9.) In acute brain injury models, MMP-9 has been shown to have a dual role - a pathological role in BBB disruption, neuronal cell death and hemorrhage early after injury, and a healing role in mediating brain regeneration and neurovascular remodeling during the later repair phase.(1616 Zhao HD, Zhang YD. The effects of previous statin treatment on plasma matrix metalloproteinase-9 level in Chinese stroke patients undergoing trombolysis. J Stroke Cerebrovasc Dis. 2014;23(10):2788-93.,1717 Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001;21(19):7724-32.)

In a cortical contusion model in rats, it was shown that MMP-9 contributes to BBB disruption and brain edema, both of which were attenuated by treatment with the broad-spectrum MMP inhibitor GM6001.(1818 Shigemori Y, Katayama Y, Mori T, Maeda T, Kawamata T. Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats. Acta Neurochir Suppl. 2006;96:130-3.) Furthermore, MMP-9 knockout mice also exhibited a significant decrease in motor deficits after trauma.(1919 Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci. 2000;20(18):7037-42.) In human TBI, several studies investigating a small number of patients have reported higher cerebrospinal fluid (CSF) or circulating MMP-2 and/or MMP-9 levels in patients with TBI.(88 Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384-92.,1111 Grossetete M, Phelps J, Arko L, Yonas H, Rosenberg GA. Elevation of matrix metalloproteinases 3 and 9 in cerebrospinal fluid and blood in patients with severe traumatic brain injury. Neurosurgery. 2009;65(4):702-8.,2020 Vajtr D, Benada O, Kukacka J, Prusa R, Houstava L, Toupalík P, et al. Correlation of ultrastructural changes of endothelial cells and astrocytes occurring during blood brain barrier damage after traumatic brain injury with biochemical markers of BBB leakage and inflammatory response. Physiol Res. 2009;58(2):263-8.) Recently, studies with larger sample sizes presented controversies regarding the association of plasma MMP-9 levels and mortality in patients with severe TBI. Lorente et al.(1313 Lorente L, Martín MM, López P, Ramos L, Blanquer J, Cáceres JJ, et al. Association between serum tissue inhibitor of matrix metalloproteinase-1 levels and mortality in patients with severe brain trauma injury. PLoS One. 2014;9(4):e94370.) showed no association of MMP-9 plasma levels and mortality in a cohort of 100 patients. On the other hand, in accordance with the study conducted by Copin et al.,(1212 Copin JC, Rebetez MM, Turck N, Robin X, Sanchez JC, Schaller K, et al. Matrix metalloproteinase 9 and cellular fibronectin plasma concentrations are predictors of the composite endpoint of length of stay and death in the intensive care unit after severe traumatic brain injury. Scand J Trauma Resusc Emerg Med. 2012;20:83.) we recently showed an association between plasma MMP-9 levels and ICU mortality.(2121 Simon D, Evaldt J, Nabinger DD, Fontana MF, Klein MG, do Amaral Gomes J, et al. A. Plasma matrix metalloproteinase-9 levels predict intensive care unit mortality early after severe traumatic brain injury. Brain Inj. 2017;31(3):390-5.) Therefore, there are still controversies regarding the prognostic utility of MMP-2 and MMP-9 levels shortly after severe TBI.

Thus, the aim of this study was to test whether plasma MMP-2 and MMP-9 levels after severe TBI were associated with the primary short-term outcome (ICU mortality) in a series of male patients (isolated or with associated multitrauma). We demonstrated that while MMP-2 did not correlate with ICU mortality, MMP-9 plasma levels may represent a promising predictive biomarker for early prognosis prediction after severe TBI.

METHODS

Ethical approval of the study protocol (CEP-ULBRA 2008-239H) was granted by the Research Ethics Board of Universidade Luterana do Brasil. This study prospectively evaluated a cohort of 39 male patients admitted to the ICUs of three regional trauma centers (Hospital Cristo Redentor, Hospital de Pronto Socorro de Porto Alegre and Hospital de Pronto Socorro Nelson Marchezan de Canoas) due to severe TBI (Glasgow Coma Scale - GCS 3 - 8 at hospital admission). The patients enrolled had no previous history of neurological or psychiatric disease. On admission to the trauma emergency room, patients were initially evaluated, resuscitated (with crystalloids) and then underwent emergency surgery when necessary. Only patients transferred to the trauma ICU within 12 hours of the head injury were included in the study. The clinical outcome variables for severe TBI included survival (ICU discharge), length of stay in the ICU and neurological assessment using the GCS at admission and Glasgow Outcome Scale (GOS) at ICU discharge. At admission to the trauma ICU, circulatory function and GCS scores were monitored. All patients were sedated and mechanically ventilated, and corticosteroids were not administered. Previous studies established sex differences in the pathophysiology and outcome after acute neurological injury.(2222 Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000;17(5):367-88.) Less susceptibility to postischemic and posttraumatic brain injury in females has been observed.(2222 Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000;17(5):367-88.) Thus, to avoid interference from possible sex-dependent differences in outcome following brain trauma, only males were enrolled in the study.

Blood sampling and plasma MMP-2 and -9 determinations

Peripheral venous blood was collected into heparin-containing tubes at ICU admission. Blood samples were centrifuged at 1000g for 10 minutes, and then the plasma was removed (with great care taken not to disturb the pellet) and frozen in aliquots at -20°C until batch evaluation. Plasma MMP-2 and MMP-9 concentrations were determined by ELISA (Human MMP-2 and MMP-9 kits, Invitrogen, California, USA).

Statistical analysis

Continuous variables were compared between groups using Student’s t-test or the nonparametric Mann-Whitney U test. Categorical variables were tested using the chi-square test. Correlations were analyzed using Spearman´s nonparametric correlation method or linear regression method. The extent to which the plasma MMP-9 concentrations differed between individuals surviving or dying in the ICU after severe TBI was assessed using receiver operator characteristics (ROC) plots. The ROC plot was obtained by calculating the sensitivity and specificity for every distinct observed data value and plotting sensitivity against 1-(specificity). The ROC curve was used to evaluate the optimal cut-off values measured at study entry for predicting an unfavorable outcome. A cut-off point on the curves was chosen to attain the best compromise between sensitivity and specificity for death in the ICU. Logistic regression analysis was performed to eliminate the effect of confounding factors, and the dependent variable was the primary outcome (dead/alive). The independent variables tested were age, prehospital care, associated injury, craniotomy, GCS score at hospital admission, infection during ICU stay and plasma MMP-9 levels. All p values presented are two-tailed, and p < 0.05 was considered statistically significant.

RESULTS

Characteristics of the traumatic brain injury population

This study included 39 male patients who suffered severe TBI. Table 1 shows the characteristics of the TBI patients stratified according to primary outcome measure (ICU mortality). Severe TBI was associated with a 46% mortality rate, and the median time between traumatic events and death was 4 days; most occurred within 72 hours after ICU admission. The median age of the patients was 30 years, and there was no significant difference in age between the patients who survived (median 27 years) and the patients who did not (median 33 years). Most patients (84%) received prehospital care. Surviving patients were admitted to the hospital with GCS scores of 6.35 ± 1.69 (mean ± S.D.), while those who had fatal outcomes had significantly lower GCS scores (4.66 ± 1.97; p = 0.013). A total of 15 (38.5%) patients underwent craniotomy. The length of stay in the ICU ranged from 1 to 40 days, with a significant difference when comparing survivors (median 17, range 4 - 40) and nonsurvivors (median 4.0, range 1 - 22 days; p < 0.001). The mean GCS and GOS scores at ICU discharge were 10.47 ± 4.18 and 2.95 ± 1.01, respectively. The main mechanism of injury was related to motor vehicle accidents (46%), followed by interpersonal violence (26%). Twenty-three patients (59%) presented associated injuries; however, there was no significant difference between the presence of multisystem trauma and ICU mortality (p = 0.088) (Table 1).

Table 1
Traumatic brain injury study population stratified by the primary outcome measure (intensive care unit mortality)

Characteristics of the TBI population stratified by the type of severe TBI (isolated TBI or TBI associated with multitrauma) are depicted in table 2. There were no significant differences in age, GCS scores at either emergency room or ICU admission, blood pressure at hospital admission, time between trauma and outcome, or GCS scores at ICU discharge between the groups (Table 2). However, we observed a trend (p = 0.058) of lower GCS at ICU discharge in patients who suffered multisystem trauma associated with TBI (Table 2).

Table 2
Characteristics of the traumatic brain injury study population stratified by the type of traumatic brain injury (isolated/associated with multitrauma)

Plasma MMP-2 and MMP-9 levels

Plasma MMP-2 and MMP-9 levels were determined early after TBI at ICU admission (mean 6.4 ± 5.5 hours after hospital admission). The mean plasma MMP-2 concentration in patients with severe TBI was 325.31 ± 16.53ng/mL (mean ± S.E. M) (Table 1). There was no significant difference between MMP-2 levels in the survivor (315.68 ± 22.90ng/mL) and nonsurvivor (336.55 ± 24.29ng/mL) groups (p = 0.499) (Table 1). Besides, there was no correlation between MMP-2 levels and GOS scores at ICU discharge (Spearman´s rho = -0.172, p = 0.309). Additionally, regarding the type of lesion, there was no significant difference (p = 0.711) in plasma levels of MMP-2: 316.59 ± 25.57ng/mL in the isolated TBI and 331.38 ± 22.06ng/mL in the TBI associated with multitrauma groups (mean ± standard error of the mean - SEM) (Table 2).

The mean plasma MMP-9 concentration in patients with severe TBI was 183.15 ± 15.73ng/mL (mean ± SEM) (Table 1). Notably, there was a significant difference between MMP-9 levels in the survivor (147.94 ± 18.00ng/mL) and nonsurvivor (224.23 ± 23.86ng/mL) groups (p = 0.002, Mann-Whitney U test) (Table 1). Indeed, there was a correlation between higher levels of MMP-9 and ICU mortality (Spearman´s rho = 0.498, p = 0.001). Additionally, there was also a correlation between MMP-9 levels and the length of stay in the ICU (linear regression, p = 0.020) and GOS scores at ICU discharge (Spearman´s rho = -0.491, p = 0.002). In contrast, there was no significant difference between MMP-9 levels and the type of lesion: 197.89 ± 24.53ng/mL for patients with isolated TBI and 172.90 ± 20.68ng/mL for patients with associated extracerebral injuries (mean ± standard error of the mean - SEM, p = 0.092) (Table 2). Furthermore, there were no correlations between MMP-9 levels and craniotomy (Spearman´s rho = -0.160, p = 0.339) or infection during the ICU stay (Spearman´s rho = -0.101, p = 0.539). ROC curves were plotted, and a cut-off point that would ensure the detection of the highest proportion of individuals with fatal outcomes with the least compromise in specificity was chosen. Therefore, a cut-off point of 150.1ng/mL of MMP-9 within 12 hours after hospital admission was chosen. The diagnostic characteristic of this cut-off point was a specificity of plasma MMP-9 concentration for predicting mortality of 86% and a sensitivity of 72%. The area under the curve for MMP-9 plasma concentration was 0.788 (95% confidence interval - 95%CI: 0.640 - 0.936; p = 0.002).

Logistic regression analysis was performed to assess the independent influence of MMP-9 plasma levels on the TBI primary outcome (ICU mortality). After adjusting for confounding variables, we found that lower GCS at hospital admission (p = 0.049), infection during the ICU stay (p = 0.031) and plasma MMP-9 levels (p = 0.011) were variables independently associated with poor outcome (death).

DISCUSSION

Considering that the correct and timely diagnosis of deterioration in severe TBI remains a major challenge in clinical practice, we studied plasma MMP-2 and MMP-9 levels in 39 male patients at ICU admission; levels were assessed in the early phase after severe TBI (mean 6.4 hours after hospital admission). The study showed an association between higher plasma MMP-9 levels and ICU mortality, despite the presence of associated multitrauma. In contrast, there was no significant association between MMP-2 levels and the short-term fatal outcome. In accordance with the literature, patients enrolled in our study were mostly young men involved in traffic accidents and interpersonal violence.(11 Ghajar J. Traumatic brain injury. Lancet. 2000;356(9233):923-9.) The intensive care unit mortality rate was 46%, and lower GCS scores at hospital admission, infection during the ICU stay and plasma MMP-9 levels were independently associated with poor outcome (death).

In the context of TBI, MMPs are involved in rapidly progressing brain injury, typically leading to BBB disruption, cell death and brain edema.(1515 Suofu Y, Clark JF, Broderick JP, Kurosawa Y, Wagner KR, Lu A. Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience. 2012;212:180-9.) Matrix metalloproteinases are also thought to play important roles in cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, synaptogenesis, apoptosis, and host defense.(99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.) In addition to these functions, MMPs act on proinflammatory cytokines to regulate various aspects of neuroinflammation following TBI.(2323 da Silva Meirelles L, Simon D, Regner A. Neurotrauma: the crosstalk between neurotrophins and inflammation in the acutely injured brain. Int J Mol Sci. 2017;18(5):1082.) Brain injury activates microglia that, in turn, may release MMP-2, -9 and IL-6.(2424 Gottschall PE, Yu X, Bing B. Increased production of gelatinase B (matrix metalloproteinase-9) and interleukin-6 by activated rat microglia in culture. J Neurosci Res. 1995;42(3):335-42.) In fact, Suehiro et al.(2525 Suehiro E, Fujisawa H, Akimura T, Ishihara H, Kajiwara K, Kato S, et al. Increased matrix metalloproteinase-9 in blood in association with activation of interleukin-6 after traumatic brain injury: influence of hypothermic therapy. J Neurotrauma. 2004;21(12):1706-11.) reported that hypothermia can be neuroprotective by reducing postinjury increases in MMP-9 and IL-6. Furthermore, Harkness et al.(2626 Harkness KA, Adamson P, Sussman JD, Davies-Jones GA, Greenwood J, Woodroofe MN. Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium. Brain. 2000;123(Pt 4):698-709.) showed that in vitro activation of brain microvascular endothelium with proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), results in a selective upregulation of the expression of MMP-9. Notably, our group has reported increased levels of circulating Fas, TNF-alpha and IL-6 early after severe TBI.(2727 Crespo AR, Da Rocha AB, Jotz GP, Schneider RF, Grivicich I, Pinheiro K, et al. Increased serum sFas and TNFalpha following isolated severe head injury in males. Brain Inj. 2007;21(4):441-7.,2828 Ferreira LC, Regner A, Miotto KD, Moura SD, Ikuta N, Vargas AE, et al. Increased levels of interleukin-6, -8 and -10 are associated with fatal outcome following severe traumatic brain injury. Brain Inj. 2014;28(10):1311-6.) Additionally, Kim et al.(2929 Kim JY, Kim N, Zheng Z, Lee JE, Yenari MA. The 70 kDa heat shock protein protects against experimental traumatic brain injury. Neurobiol Dis. 2013;58:289-95.) showed that Hsp70 knockout mice subjected to TBI present increased lesion size, worsened brain hemorrhage and increased expression and activation of MMPs. Notably, in a previous study, we demonstrated a correlation between serum Hsp70 concentrations and outcome after severe TBI.(3030 da Rocha AB, Zanoni C, de Freitas GR, André C, Himelfarb S, Schneider RF, et al. Serum Hsp70 as an early predictor of fatal outcome after severe traumatic brain injury in males. J Neurotrauma. 2005;22(9):966-77.)

In animal studies, evidence shows that MMP-2 and MMP-9 contribute to secondary injury progression following neurotrauma.(1414 del Zoppo GJ, Frankowski H, Gu Y, Osada T, Kanazawa M, Milner R, et al. Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab. 2012;32(5):919-32.,1515 Suofu Y, Clark JF, Broderick JP, Kurosawa Y, Wagner KR, Lu A. Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience. 2012;212:180-9.,3131 Alvarez-Sabín J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribó M, et al. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke. 2004;35(6):1316-22.,3232 Rosell A, Ortega-Aznar A, Varez-Sabín J, Fernández-Cadenas I, Ribó M, Molina CA, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke. 2006;37(6):1399-406.) Wang et al.(1919 Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci. 2000;20(18):7037-42.) demonstrated that in knockout mice deficient in MMP-9, gene expression indicated reduced morphological damage in a model of TBI. Furthermore, downregulation of MMP-9 attenuated brain edema after TBI,(3333 Mori T, Wang X, Aoki T, Lo HE. Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury. J Neurotrauma. 2002;19(11):1411-9.) whereas SB-3CT, a potent and selective inhibitor of MMP-2 and MMP-9, reduced secondary injury progression and improved long-term neurobehavioral outcomes post-TBI.(3434 Hadass O, Tomlinson BN, Gooyit M, Chen S, Purdy JJ, Walker JM, et al. Selective inhibition of matrix metalloproteinase-9 attenuates secondary damage resulting from severe traumatic brain injury. PLoS One. 2013;8(10):e76904.) Recently, Pijet et al.(3535 Pijet B, Stefaniuk M, Kostrzewska-Ksiezyk A, Tsilibary PE, Tzinia A, Kaczmarek L. Elevation of MMP-9 levels promotes epileptogenesis after traumatic brain injury. Mol Neurobiol. 2018;55(12):9294-306.) showed the contribution of MMP-9 to long-term structural and physiological alterations in brain circuitry post-TBI. Nonetheless, the time course and peak of MMP-2 and MMP-9 expression and activation following acute brain injury are still uncertain; elevation in the brain may begin as early as 10 minutes after trauma and persist for over 7 days.(1515 Suofu Y, Clark JF, Broderick JP, Kurosawa Y, Wagner KR, Lu A. Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience. 2012;212:180-9.,1919 Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci. 2000;20(18):7037-42.)

Concerning human TBI, Vilalta et al.(88 Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384-92.) observed elevated levels of pro-MMP-2 and pro-MMP-9 in the plasma and CSF of 20 patients 12 hours after TBI. Grossetete et al.(1111 Grossetete M, Phelps J, Arko L, Yonas H, Rosenberg GA. Elevation of matrix metalloproteinases 3 and 9 in cerebrospinal fluid and blood in patients with severe traumatic brain injury. Neurosurgery. 2009;65(4):702-8.) reported high levels of MMP-9 in the CSF of 7 patients early after severe TBI. Additionally, Liu et al.(3636 Liu CL, Chen CC, Lee HC, Cho DY. Matrix metalloproteinase-9 in the ventricular cerebrospinal fluid correlated with the prognosis of traumatic brain injury. Turk Neurosurg. 2014;24(3):363-8.) reported that early determination of MMP-9 concentrations in the CSF of 6 TBI patients correlated with prognosis. Suehiro et al.(2525 Suehiro E, Fujisawa H, Akimura T, Ishihara H, Kajiwara K, Kato S, et al. Increased matrix metalloproteinase-9 in blood in association with activation of interleukin-6 after traumatic brain injury: influence of hypothermic therapy. J Neurotrauma. 2004;21(12):1706-11.) found elevated levels of circulating MMP-9 at hospital admission in patients with TBI, while Vajtr et al.(2020 Vajtr D, Benada O, Kukacka J, Prusa R, Houstava L, Toupalík P, et al. Correlation of ultrastructural changes of endothelial cells and astrocytes occurring during blood brain barrier damage after traumatic brain injury with biochemical markers of BBB leakage and inflammatory response. Physiol Res. 2009;58(2):263-8.) investigated 18 patients and reported that higher levels of plasma MMP-9 were found during the first 3 days in patients who underwent decompressive neurosurgery following TBI. More recently, Lorente et al.(1313 Lorente L, Martín MM, López P, Ramos L, Blanquer J, Cáceres JJ, et al. Association between serum tissue inhibitor of matrix metalloproteinase-1 levels and mortality in patients with severe brain trauma injury. PLoS One. 2014;9(4):e94370.) investigated serum levels of MMP-9 in a large cohort of 100 patients with severe TBI at hospital admission and did not show an association of MMP-9 with 30-day mortality. In contrast, Copin et al.(1212 Copin JC, Rebetez MM, Turck N, Robin X, Sanchez JC, Schaller K, et al. Matrix metalloproteinase 9 and cellular fibronectin plasma concentrations are predictors of the composite endpoint of length of stay and death in the intensive care unit after severe traumatic brain injury. Scand J Trauma Resusc Emerg Med. 2012;20:83.) demonstrated, in a cohort of 49 patients, that MMP-9 concentrations predicted death in the first 48 hours after severe TBI. Notably, in 2017, in a cohort of 80 patients with severe TBI, we also showed that increased plasma MMP-9 levels predicted short-term fatal outcomes, regardless of the presence of extracerebral injuries.(2121 Simon D, Evaldt J, Nabinger DD, Fontana MF, Klein MG, do Amaral Gomes J, et al. A. Plasma matrix metalloproteinase-9 levels predict intensive care unit mortality early after severe traumatic brain injury. Brain Inj. 2017;31(3):390-5.)

Accordingly, in the present study, we found that early higher plasma MMP-9 levels were associated with ICU mortality. Conversely, MMP-2 plasma levels did not predict short-term fatal outcomes. This observed divergence in the prognostic utility of MMP-2 and MMP-9 is in conformity with previous studies. Shi et al.(3737 Shi WZ, Ju JY, Xiao HJ, Xue F, Wu J, Pan MM, et al. Dynamics of MMP-9, MMP-2 and TIMP-1 in a rat model of brain injury combined with traumatic heterotopic ossification. Mol Med Rep. 2017;15(4):2129-35.) investigated early changes in the concentration of MMP-2, -9 and tissue inhibitor of metalloproteinase (TIMP-1 ) in a rat model of brain injury combined with trauma-induced heterotopic ossification and showed that MMP-9, but not MMP-2, contributed to the remodeling and calcification of the ECM, resulting in the induction of osteoblast precursor cells in heterotopic ossification. In a focal injury model, Guilfoyle et al.(3838 Guilfoyle MR, Carpenter KL, Helmy A, Pickard JD, Menon DK, Hutchinson PJ. Matrix metalloproteinase expression in contusional traumatic brain injury: a paired microdialysis study. J Neurotrauma. 2015;32(20):1553-9.) reported that, though MMP-9 concentrations were elevated in pericontusional brain tissue compared to normal brain tissue, no significant difference was found for MMP-2. Moreover, Underly et al.(3939 Underly RG, Levy M, Hartmann DA, Grant RI, Watson AN, Shih AY. Pericytes as inducers of rapid, matrix metalloproteinase-9-dependent capillary damage during ischemia. J Neurosci. 2017;37(1):129-40.) showed that coinjection of pericyte somata and a MMP-9 inhibitor, but not a MMP-2 inhibitor, was able to reduce BBB damage during cerebral ischemia. Distinct patterns of expression and activation of MMP-2 and MMP-9 may at least partially explain their different roles after TBI.(88 Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384-92.,4040 Rojas H, Ritter C, Pizzol FD. Mechanisms of dysfunction of the blood-brain barrier in critically ill patients: emphasis on the role of matrix metalloproteinases. Rev Bras Ter Intensiva. 2011;23(2):222-7.)

Overall, studies have indicated that both local and systemic trauma-induced upregulation of MMP-2 and MMP-9 during the acute phase postinjury are implicated in the pathophysiology of TBI.(88 Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384-92.,1414 del Zoppo GJ, Frankowski H, Gu Y, Osada T, Kanazawa M, Milner R, et al. Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab. 2012;32(5):919-32.

15 Suofu Y, Clark JF, Broderick JP, Kurosawa Y, Wagner KR, Lu A. Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience. 2012;212:180-9.

16 Zhao HD, Zhang YD. The effects of previous statin treatment on plasma matrix metalloproteinase-9 level in Chinese stroke patients undergoing trombolysis. J Stroke Cerebrovasc Dis. 2014;23(10):2788-93.

17 Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001;21(19):7724-32.

18 Shigemori Y, Katayama Y, Mori T, Maeda T, Kawamata T. Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats. Acta Neurochir Suppl. 2006;96:130-3.
-1919 Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci. 2000;20(18):7037-42.,2525 Suehiro E, Fujisawa H, Akimura T, Ishihara H, Kajiwara K, Kato S, et al. Increased matrix metalloproteinase-9 in blood in association with activation of interleukin-6 after traumatic brain injury: influence of hypothermic therapy. J Neurotrauma. 2004;21(12):1706-11.,3333 Mori T, Wang X, Aoki T, Lo HE. Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury. J Neurotrauma. 2002;19(11):1411-9.,4040 Rojas H, Ritter C, Pizzol FD. Mechanisms of dysfunction of the blood-brain barrier in critically ill patients: emphasis on the role of matrix metalloproteinases. Rev Bras Ter Intensiva. 2011;23(2):222-7.) For this reason, MMPs represent promising therapeutic targets. In effect, robust evidence has shown that pharmacological inhibitors of MMPs can reduce TBI-mediated edema formation, BBB impairment, inflammatory responses, and cerebral ischemia.(1414 del Zoppo GJ, Frankowski H, Gu Y, Osada T, Kanazawa M, Milner R, et al. Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab. 2012;32(5):919-32.

15 Suofu Y, Clark JF, Broderick JP, Kurosawa Y, Wagner KR, Lu A. Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience. 2012;212:180-9.

16 Zhao HD, Zhang YD. The effects of previous statin treatment on plasma matrix metalloproteinase-9 level in Chinese stroke patients undergoing trombolysis. J Stroke Cerebrovasc Dis. 2014;23(10):2788-93.

17 Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001;21(19):7724-32.

18 Shigemori Y, Katayama Y, Mori T, Maeda T, Kawamata T. Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats. Acta Neurochir Suppl. 2006;96:130-3.
-1919 Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci. 2000;20(18):7037-42.,2525 Suehiro E, Fujisawa H, Akimura T, Ishihara H, Kajiwara K, Kato S, et al. Increased matrix metalloproteinase-9 in blood in association with activation of interleukin-6 after traumatic brain injury: influence of hypothermic therapy. J Neurotrauma. 2004;21(12):1706-11.,3333 Mori T, Wang X, Aoki T, Lo HE. Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury. J Neurotrauma. 2002;19(11):1411-9.) Alternatively, it is important to consider the apparent positive effects of MMP-2 and MMP-9 in repair and regeneration after nervous system injury.(99 Abdul-Muneer PM, Pfister BJ, Haorah J, Chandra N. Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol. 2016;53(9):6106-23.,3636 Liu CL, Chen CC, Lee HC, Cho DY. Matrix metalloproteinase-9 in the ventricular cerebrospinal fluid correlated with the prognosis of traumatic brain injury. Turk Neurosurg. 2014;24(3):363-8.) As a matter of fact, Danilina et al.(4141 Danilina TI, Silachev DN, Pevzner IB, Gulyaev MV, Pirogov YA, Zorova LD, et al. The influence of proinflammatory factors on the neuroprotective efficiency of multipotent mesenchymal stromal cells in traumatic brain injury. Bull Exp Biol Med. 2017;163(4):528-34.) studied the neuroprotective potential of multipotent mesenchymal stromal cells exposed to inflammatory preconditioning in TBI. Culture conditions simulating inflammation increased the production of MMP-2 and MMP-9 but did not reduce their therapeutic effectiveness. Moreover, in some variants of inflammatory preconditioning, mesenchymal cells exhibited more pronounced neuroprotective properties, reducing the volume of brain lesions and promoting recovery of neurological functions after TBI.(4141 Danilina TI, Silachev DN, Pevzner IB, Gulyaev MV, Pirogov YA, Zorova LD, et al. The influence of proinflammatory factors on the neuroprotective efficiency of multipotent mesenchymal stromal cells in traumatic brain injury. Bull Exp Biol Med. 2017;163(4):528-34.)

Although we demonstrated that levels of plasma MMP-9 predicted short-term mortality and GOS scores following severe TBI, possible limitations of the present study were the limited sample size and the fact that we did not analyze the potential predictive value of MMP-2 or MMP-9 considering longer-term outcomes of disability and mortality.

CONCLUSION

In the present study, we demonstrated that higher plasma MMP-9, but not MMP-2, concentrations predicted short-term intensive care unit mortality and Glasgow Outcome Scale scores at discharge following severe traumatic brain injury regardless of the presence of associated multitrauma. Therefore, the translational potential of MMP-9 after traumatic brain injury is promising in both the diagnostic and treatment domains.

ACKNOWLEDGMENTS

This research was funded by Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS; research grant 03/2017 - PPSUS, Processo: 17/2551-0001382-4). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.

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    Suofu Y, Clark JF, Broderick JP, Kurosawa Y, Wagner KR, Lu A. Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience. 2012;212:180-9.
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    Zhao HD, Zhang YD. The effects of previous statin treatment on plasma matrix metalloproteinase-9 level in Chinese stroke patients undergoing trombolysis. J Stroke Cerebrovasc Dis. 2014;23(10):2788-93.
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    Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001;21(19):7724-32.
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    Shigemori Y, Katayama Y, Mori T, Maeda T, Kawamata T. Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats. Acta Neurochir Suppl. 2006;96:130-3.
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    Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci. 2000;20(18):7037-42.
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    Vajtr D, Benada O, Kukacka J, Prusa R, Houstava L, Toupalík P, et al. Correlation of ultrastructural changes of endothelial cells and astrocytes occurring during blood brain barrier damage after traumatic brain injury with biochemical markers of BBB leakage and inflammatory response. Physiol Res. 2009;58(2):263-8.
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    Simon D, Evaldt J, Nabinger DD, Fontana MF, Klein MG, do Amaral Gomes J, et al. A. Plasma matrix metalloproteinase-9 levels predict intensive care unit mortality early after severe traumatic brain injury. Brain Inj. 2017;31(3):390-5.
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    Gottschall PE, Yu X, Bing B. Increased production of gelatinase B (matrix metalloproteinase-9) and interleukin-6 by activated rat microglia in culture. J Neurosci Res. 1995;42(3):335-42.
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    Suehiro E, Fujisawa H, Akimura T, Ishihara H, Kajiwara K, Kato S, et al. Increased matrix metalloproteinase-9 in blood in association with activation of interleukin-6 after traumatic brain injury: influence of hypothermic therapy. J Neurotrauma. 2004;21(12):1706-11.
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    Harkness KA, Adamson P, Sussman JD, Davies-Jones GA, Greenwood J, Woodroofe MN. Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium. Brain. 2000;123(Pt 4):698-709.
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    Crespo AR, Da Rocha AB, Jotz GP, Schneider RF, Grivicich I, Pinheiro K, et al. Increased serum sFas and TNFalpha following isolated severe head injury in males. Brain Inj. 2007;21(4):441-7.
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    Ferreira LC, Regner A, Miotto KD, Moura SD, Ikuta N, Vargas AE, et al. Increased levels of interleukin-6, -8 and -10 are associated with fatal outcome following severe traumatic brain injury. Brain Inj. 2014;28(10):1311-6.
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    Kim JY, Kim N, Zheng Z, Lee JE, Yenari MA. The 70 kDa heat shock protein protects against experimental traumatic brain injury. Neurobiol Dis. 2013;58:289-95.
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    da Rocha AB, Zanoni C, de Freitas GR, André C, Himelfarb S, Schneider RF, et al. Serum Hsp70 as an early predictor of fatal outcome after severe traumatic brain injury in males. J Neurotrauma. 2005;22(9):966-77.
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    Alvarez-Sabín J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribó M, et al. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke. 2004;35(6):1316-22.
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    Rosell A, Ortega-Aznar A, Varez-Sabín J, Fernández-Cadenas I, Ribó M, Molina CA, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke. 2006;37(6):1399-406.
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    Mori T, Wang X, Aoki T, Lo HE. Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury. J Neurotrauma. 2002;19(11):1411-9.
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    Hadass O, Tomlinson BN, Gooyit M, Chen S, Purdy JJ, Walker JM, et al. Selective inhibition of matrix metalloproteinase-9 attenuates secondary damage resulting from severe traumatic brain injury. PLoS One. 2013;8(10):e76904.
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    Pijet B, Stefaniuk M, Kostrzewska-Ksiezyk A, Tsilibary PE, Tzinia A, Kaczmarek L. Elevation of MMP-9 levels promotes epileptogenesis after traumatic brain injury. Mol Neurobiol. 2018;55(12):9294-306.
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    Liu CL, Chen CC, Lee HC, Cho DY. Matrix metalloproteinase-9 in the ventricular cerebrospinal fluid correlated with the prognosis of traumatic brain injury. Turk Neurosurg. 2014;24(3):363-8.
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    Shi WZ, Ju JY, Xiao HJ, Xue F, Wu J, Pan MM, et al. Dynamics of MMP-9, MMP-2 and TIMP-1 in a rat model of brain injury combined with traumatic heterotopic ossification. Mol Med Rep. 2017;15(4):2129-35.
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    Guilfoyle MR, Carpenter KL, Helmy A, Pickard JD, Menon DK, Hutchinson PJ. Matrix metalloproteinase expression in contusional traumatic brain injury: a paired microdialysis study. J Neurotrauma. 2015;32(20):1553-9.
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    Danilina TI, Silachev DN, Pevzner IB, Gulyaev MV, Pirogov YA, Zorova LD, et al. The influence of proinflammatory factors on the neuroprotective efficiency of multipotent mesenchymal stromal cells in traumatic brain injury. Bull Exp Biol Med. 2017;163(4):528-34.

Edited by

Responsible editor: Felipe Dal-Pizzol

Publication Dates

  • Publication in this collection
    12 Oct 2020
  • Date of issue
    Jul-Sep 2020

History

  • Received
    09 Sept 2019
  • Accepted
    23 Mar 2020
Associação de Medicina Intensiva Brasileira - AMIB Rua Arminda, 93 - Vila Olímpia, CEP 04545-100 - São Paulo - SP - Brasil, Tel.: (11) 5089-2642 - São Paulo - SP - Brazil
E-mail: rbti.artigos@amib.com.br