title: Systemic inflammation impairs tissue reperfusion through endothelin-dependent mechanisms in cerebral ischemia.
abstract: OBJECTIVE
  Systemic inflammation contributes to diverse acute and chronic brain pathologies, and extensive evidence implicates inflammation in stroke susceptibility and poor outcome. Here we investigate whether systemic inflammation alters cerebral blood flow during reperfusion after experimental cerebral ischemia.
  
  
  METHODS
  Serial diffusion and perfusion-weighted MRI was performed after reperfusion in Wistar rats given systemic (intraperitoneal) interleukin-1β or vehicle before 60-minute transient middle cerebral artery occlusion. The expression and location of endothelin-1 was assessed by polymerase chain reaction, ELISA, and immunofluorescence.
  
  
  RESULTS
  Systemic interleukin-1 caused a severe reduction in cerebral blood flow and increase in infarct volume compared with vehicle. Restriction in cerebral blood flow was observed alongside activation of the cerebral vasculature and upregulation of the vasoconstricting peptide endothelin-1 in the ischemic penumbra. A microthrombotic profile was also observed in the vasculature of rats receiving interleukin-1. Blockade of endothelin-1 receptors reversed this hypoperfusion, reduced tissue damage, and improved functional outcome.
  
  
  CONCLUSIONS
  These data suggest patients with a raised inflammatory profile may have persistent deficits in perfusion after reopening of an occluded vessel. Future therapeutic strategies to interrupt the mechanism identified could lead to enhanced recovery of penumbra in patients with a heightened inflammatory burden and a better outcome after stroke.
authors.affiliation: From the Faculty of Life Sciences (K.N.M., S.M.A.) and Centre for Imaging Science (L.M.P., S.R.W.), University of Manchester, Manchester, United Kingdom; Sainte-Justine Hospital Research Centre, University of Montreal, Canada (S.G.); Glasgow Experimental MRI Centre, The University of Glasgow, Glasgow, United Kingdom (W.M.H.); and University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom (A.R.P.-J.).
authors.forename: Katie N
authors.initials: KN
authors.lastname: Murray
authors.affiliation: From the Faculty of Life Sciences (K.N.M., S.M.A.) and Centre for Imaging Science (L.M.P., S.R.W.), University of Manchester, Manchester, United Kingdom; Sainte-Justine Hospital Research Centre, University of Montreal, Canada (S.G.); Glasgow Experimental MRI Centre, The University of Glasgow, Glasgow, United Kingdom (W.M.H.); and University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom (A.R.P.-J.).
authors.forename: Sylvie
authors.initials: S
authors.lastname: Girard
authors.affiliation: From the Faculty of Life Sciences (K.N.M., S.M.A.) and Centre for Imaging Science (L.M.P., S.R.W.), University of Manchester, Manchester, United Kingdom; Sainte-Justine Hospital Research Centre, University of Montreal, Canada (S.G.); Glasgow Experimental MRI Centre, The University of Glasgow, Glasgow, United Kingdom (W.M.H.); and University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom (A.R.P.-J.).
authors.forename: William M
authors.initials: WM
authors.lastname: Holmes
authors.affiliation: From the Faculty of Life Sciences (K.N.M., S.M.A.) and Centre for Imaging Science (L.M.P., S.R.W.), University of Manchester, Manchester, United Kingdom; Sainte-Justine Hospital Research Centre, University of Montreal, Canada (S.G.); Glasgow Experimental MRI Centre, The University of Glasgow, Glasgow, United Kingdom (W.M.H.); and University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom (A.R.P.-J.).
authors.forename: Laura M
authors.initials: LM
authors.lastname: Parkes
authors.affiliation: From the Faculty of Life Sciences (K.N.M., S.M.A.) and Centre for Imaging Science (L.M.P., S.R.W.), University of Manchester, Manchester, United Kingdom; Sainte-Justine Hospital Research Centre, University of Montreal, Canada (S.G.); Glasgow Experimental MRI Centre, The University of Glasgow, Glasgow, United Kingdom (W.M.H.); and University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom (A.R.P.-J.).
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Williams
authors.affiliation: From the Faculty of Life Sciences (K.N.M., S.M.A.) and Centre for Imaging Science (L.M.P., S.R.W.), University of Manchester, Manchester, United Kingdom; Sainte-Justine Hospital Research Centre, University of Montreal, Canada (S.G.); Glasgow Experimental MRI Centre, The University of Glasgow, Glasgow, United Kingdom (W.M.H.); and University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom (A.R.P.-J.). adrian.parry-jones@manchester.ac.uk.
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Parry-Jones
authors.affiliation: From the Faculty of Life Sciences (K.N.M., S.M.A.) and Centre for Imaging Science (L.M.P., S.R.W.), University of Manchester, Manchester, United Kingdom; Sainte-Justine Hospital Research Centre, University of Montreal, Canada (S.G.); Glasgow Experimental MRI Centre, The University of Glasgow, Glasgow, United Kingdom (W.M.H.); and University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom (A.R.P.-J.).
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D016232:Endothelins / Q000096:biosynthesis*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000633:toxicity; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016232:Endothelins; D053583:Interleukin-1beta
keywords: brain ischemia; endothelin-1; inflammation; interleukin-1; magnetic resonance imaging; reperfusion