• Tetsuya Fukuta, Hideshi Okada, Genzou Takemura, Kodai Suzuki, Chihiro Takada, Hiroyuki Tomita, Akio Suzuki, Kazumasa Oda, Akihiro Uchida, Saori Matsuo, Hirotsugu Fukuda, Hirohisa Yano, Isamu Muraki, Ryogen Zaikokuji, Ayumi Kuroda, Ayane Nishio, So Sampei, Nagisa Miyazaki, Yasuaki Hotta, Noriaki Yamada, Takatomo Watanabe, Kentaro Morishita, Tomoaki Doi, Takahiro Yoshida, Hiroaki Ushikoshi, Shozo Yoshida, Yoichi Maekawa, and Shinji Ogura.
• Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu.
• Shock. 2020 Sep 1; 54 (3): 386-393.

AbstractMyocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48 hours after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12 hours after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2 mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12 hours after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxemia. Inhibition of NE may be a useful tool for the management of endotoxemia.

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