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Am J Respir Crit Care Med. 2017 Jul 15;196(2):186-199. doi: 10.1164/rccm.201604-0712OC.

Antihistone Properties of C1 Esterase Inhibitor Protect against Lung Injury.

Author information

1
1 Department of Biochemistry.
2
2 Department of Internal Medicine, and.
3
3 Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin, Berlin, Germany.
4
4 Goethe University School of Medicine, University Hospital, Frankfurt am Main, Germany.
5
5 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
6
6 Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany.
7
7 Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.
8
8 CSL Behring GmbH, Marburg, Germany; and.
9
9 Bio21 Institute, CSL Limited, Victoria, Australia.

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.

KEYWORDS:

ARDS; C1 esterase inhibitor; cell death; extracellular histones

PMID:
28005404
DOI:
10.1164/rccm.201604-0712OC
[Indexed for MEDLINE]

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