• Malgorzata Wygrecka, Djuro Kosanovic, Lukasz Wujak, Katrin Reppe, Ingrid Henneke, Helena Frey, Miroslava Didiasova, Grazyna Kwapiszewska, Leigh M Marsh, Nelli Baal, Holger Hackstein, Dariusz Zakrzewicz, Holger C Müller-Redetzky, Steven de Maat, Coen Maas, Marc W Nolte, Con Panousis, Ralph T Schermuly, Werner Seeger, Martin Witzenrath, Liliana Schaefer, and Philipp Markart.
• 1 Department of Biochemistry.
• Am. J. Respir. Crit. Care Med. 2017 Jul 15; 196 (2): 186-199.

RationaleAcute respiratory distress syndrome is characterized by alveolar epithelial cell injury, edema formation, and intraalveolar contact phase activation.ObjectivesTo 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.MethodsThe ability of C1INH to control the inflammatory processes was studied in vitro and in vivo.Measurements And Main ResultsHere, 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.ConclusionsCollectively, C1INH administration provides a new therapeutic option for disorders associated with histone release.

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