Expression of a Crry/p65 is reduced in acute lung injury induced by extracellular histones

Fumihiko Nagano, Tomohiro Mizuno, Masaki Imai, Kazuo Takahashi, Naotake Tsuboi, Shoichi Maruyama, Masashi Mizuno

研究成果: Article査読

1 被引用数 (Scopus)

抄録

Acute lung injury (ALI) occurs in patients with severe sepsis and has a mortality rate of 40%–60%. Severe sepsis promotes the release of histones from dying cells, which can induce platelet aggregation, activate coagulation and cause endothelial cell (EC) death. We previously reported that the expression of membrane complement receptor type 1-related gene Y (Crry)/p65, which plays a principal role in defence against abnormal activation of complement in the blood, is reduced in response to peritoneal mesothelial cell injury, and we hence hypothesized that a similar mechanism occurs in pulmonary ECs. In this study, we examined the role of Crry/p65 in histone-mediated ALI using an experimental animal model. In ALI model mice, exposure to extracellular histones induces lung injury and results in a decrease in Crry/p65 expression. The levels of lactic acid dehydrogenase (LDH), a marker of cell damage, were significantly increased in the serum of ALI model compared with vehicle mice. The significant inverse correlation between the expression of Crry/p65 and LDH levels in plasma revealed an association between Crry/p65 expression and cell damage. The levels of complement component 3a (C3a) were also significantly increased in the serum of the ALI model compared with vehicle mice. Notably, a C3a receptor antagonist ameliorated lung injury induced by histones. We hypothesize that extracellular histones induce complement activation via down-regulation of Crry/p65 and that C3a might serve as a therapeutic target for the treatment of ALI.

本文言語English
ページ(範囲)192-202
ページ数11
ジャーナルFEBS Open Bio
12
1
DOI
出版ステータスPublished - 01-2022

All Science Journal Classification (ASJC) codes

  • 生化学、遺伝学、分子生物学(全般)

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