title: Antihistone Properties of C1 Esterase Inhibitor Protect against Lung Injury.
abstract: Acute respiratory distress syndrome is characterized by alveolar epithelial cell injury, edema formation, and intraalveolar contact phase activation.
  
  
  
  To explore whether C1 esterase inhibitor (C1INH), an endogenous inhibitor of the contact phase, may protect from lung injury in vivo and to decipher the possible underlying mechanisms mediating protection.
  
  
  
  The ability of C1INH to control the inflammatory processes was studied in vitro and in vivo.
  
  
  
  Here, we demonstrate that application of C1INH alleviates bleomycin-induced lung injury via direct interaction with extracellular histones. In vitro, C1INH was found to bind all histone types. Interaction with histones was independent of its protease inhibitory activity, as demonstrated by the use of reactive-center-cleaved C1INH, but dependent on its glycosylation status. C1INH sialylated-N- and -O-glycans were not only essential for its interaction with histones but also to protect against histone-induced cell death. In vivo, histone-C1INH complexes were detected in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome and multiple models of lung injury. Furthermore, reactive-center-cleaved C1INH attenuated pulmonary damage evoked by intravenous histone instillation.
  
  
  
  Collectively, C1INH administration provides a new therapeutic option for disorders associated with histone release.
authors.affiliation: 1 Department of Biochemistry.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.affiliation: 2 Department of Internal Medicine, and.
authors.forename: Djuro
authors.initials: D
authors.lastname: Kosanovic
authors.affiliation: 1 Department of Biochemistry.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wujak
authors.affiliation: 3 Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Reppe
authors.affiliation: 2 Department of Internal Medicine, and.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Henneke
authors.affiliation: 4 Goethe University School of Medicine, University Hospital, Frankfurt am Main, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Frey
authors.affiliation: 1 Department of Biochemistry.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Didiasova
authors.affiliation: 5 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.affiliation: 5 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Leigh M
authors.initials: LM
authors.lastname: Marsh
authors.affiliation: 6 Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany.
authors.forename: Nelli
authors.initials: N
authors.lastname: Baal
authors.affiliation: 6 Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Hackstein
authors.affiliation: 1 Department of Biochemistry.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Zakrzewicz
authors.affiliation: 3 Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Holger C
authors.initials: HC
authors.lastname: Müller-Redetzky
authors.affiliation: 7 Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: de Maat
authors.affiliation: 7 Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.affiliation: 8 CSL Behring GmbH, Marburg, Germany; and.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
authors.affiliation: 9 Bio21 Institute, CSL Limited, Victoria, Australia.
authors.forename: Con
authors.initials: C
authors.lastname: Panousis
authors.affiliation: 2 Department of Internal Medicine, and.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: 2 Department of Internal Medicine, and.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: 3 Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.affiliation: 4 Goethe University School of Medicine, University Hospital, Frankfurt am Main, Germany.
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.affiliation: 2 Department of Internal Medicine, and.
authors.forename: Philipp
authors.initials: P
authors.lastname: Markart
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D050718:Complement C1 Inhibitor Protein / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D055370:Lung Injury / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D012128:Respiratory Distress Syndrome / Q000503:physiopathology*
chemical_list: D050718:Complement C1 Inhibitor Protein; D006657:Histones
keywords: ARDS; C1 esterase inhibitor; cell death; extracellular histones