Recombinant thrombomodulin protects against LPS‐induced acute respiratory distress syndrome via preservation of pulmonary endothelial glycocalyx

• DOI: 10.1111/bph.15153
• Publication Date: 2020-06-04T16:40:31Z
• Authors: Kodai Suzuki; Hideshi Okada; Genzou Takemura; Chihiro Takada; Hiroyuki Tomita; Hirohisa Yano; Isamu Muraki; Ryogen Zaikokuji; Ayumi Kuroda; Hirotsugu Fukuda; Ayane Nishio; Shigeo Takashima; Akio Suzuki; Nagisa Miyazaki; Tetsuya Fukuta; Noriaki Yamada; Takatomo Watanabe; Tomoaki Doi; Takahiro Yoshida; Keisuke Kumada; Hiroaki Ushikoshi; Shozo Yoshida; Shinji Ogura
• Keywords: Lipopolysaccharides; Male; 0301 basic medicine; Respiratory Distress Syndrome; Thrombomodulin; Endothelial Cells; Glycocalyx; Research Papers; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals; Lung

Background and PurposeDisruption of the endothelial glycocalyx is causally related to microvascular endothelial dysfunction, a characteristic of sepsis‐induced acute respiratory distress syndrome (ARDS). Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries, but the underlying mechanism remains elusive. Here, we investigated the structural basis and molecular mechanisms of rhTM effects on vascular endothelial injury in a model of sepsis.Experimental ApproachLPS (20 mg·kg−1) was intraperitoneally injected into 10‐week‐old male C57BL6 mice, and saline or rhTM was intraperitoneally injected 3 and 24 h after LPS injection. Using serum and/or lung tissue, histological, ultrastructural, and microarray analyses were performed.Key ResultsSurvival rate of rhTM‐treated mice was significantly higher than that of control mice 48 h after LPS injection. Serum concentrations of IL‐6 and high‐mobility group box 1 were lower in the rhTM‐treated group than in the control. Injury to the endothelial glycocalyx in pulmonary capillaries was attenuated by rhTM treatment. Gene set enrichment analysis revealed up‐regulation of gene sets corresponding to cell proliferation/differentiation and anti‐inflammation, such as the TGF‐β pathway, and negative regulation of IL‐6, upon rhTM treatment. Gene expression of heparan sulfate 6‐O‐sulfotransferase 1 and endothelial cell‐specific molecule 1 (components of the endothelial glycocalyx) was significantly preserved by rhTM treatment, and their protein expression levels were maintained in endothelial cells.Conclusion and ImplicationsOur findings show that rhTM treatment affected inflammation, cell proliferation/differentiation, and glycocalyx synthesis in serum and lung tissue, subsequently attenuating ARDS caused by endothelial injury.