• Kodai Suzuki, Hideshi Okada, Genzou Takemura, Chihiro Takada, Ayumi Kuroda, Hirohisa Yano, Ryogen Zaikokuji, Kentaro Morishita, Hiroyuki Tomita, Kazumasa Oda, Saori Matsuo, Akihiro Uchida, Tetsuya Fukuta, So Sampei, Nagisa Miyazaki, Tomonori Kawaguchi, Takatomo Watanabe, Takahiro Yoshida, Hiroaki Ushikoshi, Shozo Yoshida, Yoichi Maekawa, and Shinji Ogura.
• Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
• Am. J. Pathol. 2019 Aug 1; 189 (8): 1526-1535.

AbstractNeutrophil elastase (NE) is necessary for effective sterilization of phagocytosed bacterial and fungal pathogens; however, NE increases alveolocapillary permeability and induces proinflammatory cytokine production in sepsis-induced acute respiratory distress syndrome. Under septic conditions, the pulmonary endothelial glycocalyx covering on the healthy endothelium surface is injured, but the contribution of NE to this injury remains unknown. Our aim was to examine whether NE-induced pulmonary endothelial injury is associated with endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 9- to 12-week-old granulocyte colony-stimulating factor knockout (G-CSFKO) mice, which harbor few neutrophils, and littermate control mice; in a second assay, mice were injected with the NE-inhibitor sivelestat (0.2 mg/kg) at 3, 6, 9, and 12 hours after LPS administration. Subsequently, vascular endothelial injury was evaluated through ultrastructural analysis. At 48 hours after LPS injection, survival rate was more than threefold higher among G-CSFKO than control mice, and degradation of both thrombomodulin and syndecan-1 was markedly attenuated in G-CSFKO compared with control mice. Ultrastructural analysis revealed attenuated vascular endothelial injury and clear preservation of the endothelial glycocalyx in G-CSFKO mice. Moreover, after LPS exposure, survival rate was approximately ninefold higher among sivelestat-injected mice than control mice, and sivelestat treatment potently preserved vascular endothelial structures and the endothelial glycocalyx. In conclusion, NE is associated with pulmonary endothelial injury under LPS-induced endotoxemic conditions.Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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