Journal Article

Antihistone Properties of C1 Esterase Inhibitor Protect against Lung Injury

Markart, Philipp, Zakrzewicz, Dariusz, Schermuly, Ralph T., de Maat, Steven, Panousis, Con, Didiasova, Miroslava, Witzenrath, Martin, Baal, Nelli, Frey, Helena, Marsh, Leigh M., Schaefer, Liliana, Nolte, Marc W., Seeger, Werner, Henneke, Ingrid, Maas, Coen, Wujak, Lukasz, Müller-Redetzky, Holger C., Wygrecka, Malgorzata, Hackstein, Holger, Kosanovic, Djuro, Reppe, Katrin, Kwapiszewska, Grazyna

2017

Overview

Abstract Rationale Acute respiratory distress syndrome is characterized by alveolar epithelial cell injury, edema formation, and intraalveolar contact phase activation. Objectives 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. Methods The ability of C1INH to control the inflammatory processes was studied in vitro and in vivo. Measurements and Main Results 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. Conclusions Collectively, C1INH administration provides a new therapeutic option for disorders associated with histone release.

• Publisher: Oxford University Press
• Subject: Animals / Apoptosis / Bronchoalveolar Lavage Fluid / Complement C1 Inhibitor Protein - metabolism / Complement C1 Inhibitor Protein - pharmacology / Disease Models, Animal / Edema / Histones - metabolism / Humans / Lung - metabolism / Lung - physiopathology / Lung Injury - physiopathology / Lung Injury - prevention & control / Medical prognosis / Mice / Mice, Inbred C57BL / Neutrophils / Patients / Proteins / Respiratory distress syndrome / Respiratory Distress Syndrome, Adult - physiopathology / Rodents / Sepsis / Streptococcus infections / Tumor necrosis factor-TNF