title: Differential regulation of matrix-metalloproteinases and their tissue inhibitors in patients with aneurysmal subarachnoid hemorrhage.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in vascular remodeling, (neuro)inflammation, blood-brain barrier breakdown and neuronal apoptosis. Proinflammatory mechanisms are suggested to play an important role during early brain injury and cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This study aimed to analyze MMP-3, MMP-9, TIMP-1 and TIMP-3 in patients with SAH and their respective association with cerebral vasospasm (CVS).
  
  
  METHODS
  Blood samples were collected in 20 SAH patients on days 1 to 7, 9, 11, 13 and 15 and 20 healthy age and gender matched volunteers. Serum MMPs and TIMPs were analyzed using enzyme-linked immunosorbent assay. Doppler sonographic CVS was defined as a mean blood flow velocity above 120 cm/sec in the middle cerebral artery. When discharged from hospital and at 6 month follow-up neurological outcome was evaluated using the Glasgow Outcome Score and the modified Rankin Scale.
  
  
  RESULTS
  MMP-9 was higher in SAH patients compared to healthy controls (p<0.001). Patients with CVS (n = 11) had elevated MMP-9 serum levels compared to patients without CVS (n = 9, p<0.05). Higher MMP-9 was observed in the presence of cerebral ischemia associated with cerebral vasospasm (p<0.05). TIMP-1 was increased in patients with SAH on day 4 (p<0.05). There was an imbalance of the MMP-9/TIMP-1 ratio in favor of MMP-9 in SAH patients, in particular those with CVS (p<0.001). MMP-3 and TIMP-3 were significantly lower in SAH patients throughout day 4 and day 7, respectively (p<0.05). We did not find an association between MMP-, TIMP levels and neurological outcome after 6 months.
  
  
  CONCLUSIONS
  MMP-3 and -9 are differentially regulated in SAH patients with both enzymes showing peak levels correlating with the development of CVS. The inhibitors TIMP-1 and -3 were low during the acute phase after SAH and increased later on which might suggest a preponderance of pro-inflammatory mechanisms.
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. mail: marlene.fischer@i-med.ac.at
authors.forename: Marlene
authors.initials: M
authors.lastname: Fischer
authors.forename: Anelia
authors.initials: A
authors.lastname: Dietmann
authors.forename: Ronny
authors.initials: R
authors.lastname: Beer
authors.forename: Gregor
authors.initials: G
authors.lastname: Broessner
authors.forename: Raimund
authors.initials: R
authors.lastname: Helbok
authors.forename: Bettina
authors.initials: B
authors.lastname: Pfausler
authors.forename: Erich
authors.initials: E
authors.lastname: Schmutzhard
authors.forename: Peter
authors.initials: P
authors.lastname: Lackner
mesh_terms: D000328:Adult; D000368:Aged; D002545:Brain Ischemia / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020782:Matrix Metalloproteinases / Q000097:blood*; D008875:Middle Aged; D013345:Subarachnoid Hemorrhage / Q000097:blood* / Q000235:genetics*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000097:blood; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial / Q000235:genetics* / Q000378:metabolism
chemical_list: C560822:TIMP1 protein, human; C088390:TIMP3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D020782:Matrix Metalloproteinases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
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