1 Department of Biochemistry.
2 Department of Internal Medicine, and.
Am J Respir Crit Care Med. 2017 Jul 15;196(2):186-199. doi: 10.1164/rccm.201604-0712OC.
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.
急性呼吸窘迫综合征的特征是肺泡上皮细胞损伤、水肿形成和肺泡内接触相激活。
探索内源性接触相抑制剂 C1 酯酶抑制剂（C1INH）是否可能在体内保护肺免受损伤，并阐明介导保护作用的可能潜在机制。
研究了 C1INH 在体内和体外控制炎症过程的能力。
在这里，我们证明 C1INH 通过与细胞外组蛋白的直接相互作用来减轻博来霉素诱导的肺损伤。体外研究发现 C1INH 与所有类型的组蛋白结合。与组蛋白的相互作用不依赖于其蛋白酶抑制活性，如使用活性中心切割的 C1INH 所证明的，但依赖于其糖基化状态。C1INH 的唾液酸化-N-和-O-聚糖不仅是其与组蛋白相互作用的必要条件，也是保护细胞免受组蛋白诱导的细胞死亡的必要条件。在体内，急性呼吸窘迫综合征患者和多种肺损伤模型的支气管肺泡灌洗液中检测到组蛋白-C1INH 复合物。此外，活性中心切割的 C1INH 可减轻静脉注射组蛋白引起的肺损伤。
总的来说，C1INH 的给药为与组蛋白释放相关的疾病提供了一种新的治疗选择。
