Neutrophil Elastase Damages the Pulmonary Endothelial Glycocalyx in Lipopolysaccharide-Induced Experimental Endotoxemia

Neutrophil 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 pu...

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Veröffentlicht in:The American journal of pathology 2019-08, Vol.189 (8), p.1526-1535
Hauptverfasser: Suzuki, Kodai, Okada, Hideshi, Takemura, Genzou, Takada, Chihiro, Kuroda, Ayumi, Yano, Hirohisa, Zaikokuji, Ryogen, Morishita, Kentaro, Tomita, Hiroyuki, Oda, Kazumasa, Matsuo, Saori, Uchida, Akihiro, Fukuta, Tetsuya, Sampei, So, Miyazaki, Nagisa, Kawaguchi, Tomonori, Watanabe, Takatomo, Yoshida, Takahiro, Ushikoshi, Hiroaki, Yoshida, Shozo, Maekawa, Yoichi, Ogura, Shinji
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Sprache:eng
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Zusammenfassung:Neutrophil 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.
ISSN:0002-9440
1525-2191
DOI:10.1016/j.ajpath.2019.05.002