title: Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage.
abstract: OBJECTIVE
  Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH.
  
  
  METHODS
  ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3.
  
  
  RESULTS
  Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions.
  
  
  CONCLUSIONS
  Our findings reveal the importance of rADAMTS 13 in regulating pathological inflammation and BBB function and suggest that rADAMTS 13 may provide a new therapeutic strategy for ICH.
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Ping
authors.initials: P
authors.lastname: Cai
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Haiyu
authors.initials: H
authors.lastname: Luo
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Haochen
authors.initials: H
authors.lastname: Xu
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Ximin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Dai
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Jin
authors.initials: J
authors.lastname: Xiao
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.).
authors.forename: Yuwu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.). wenyingf@fudan.edu.cn bingqiaoz@fudan.edu.cn.
authors.forename: Bing-Qiao
authors.initials: BQ
authors.lastname: Zhao
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science and School of Basic Medical Sciences, Fudan University, Shanghai, China (P.C., H.L., H.X., X.Z., W.X., Y.D., J.X., Y.C., B.-Q.Z.,W.F.); Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fujian, China (P.C.); and Neurologic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China (Y.Z.). wenyingf@fudan.edu.cn bingqiaoz@fudan.edu.cn.
authors.forename: Wenying
authors.initials: W
authors.lastname: Fan
mesh_terms: D000071120:ADAMTS13 Protein; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D002543:Cerebral Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D008666:Metalloendopeptidases / Q000494:pharmacology*; D051379:Mice
chemical_list: D000893:Anti-Inflammatory Agents; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein
keywords: ADAMTS 13; blood–brain barrier disruption; edema and brain injury; inflammation; intracerebral hemorrhage