Recombinant Thrombomodulin Protects Against Lipopolysaccharide-induced Acute Respiratory Distress Syndrome Via Preservation of Pulmonary Endothelial Glycocalyx.

BACKGROUND AND PURPOSE Endothelial glycocalyx (eGC) disruption is causally related to microvascular endothelial dysfunction, a characteristic of sepsis-induced acute respiratory distress syndrome (ARDS). Recombinant human thrombomodulin (rhTM) reportedly 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 sepsis. EXPERIMENTAL APPROACH Lipopolysaccharide (LPS, 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 RESULTS Survival rate of rhTM-treated mice was significantly higher than that of control mice 48 h after LPS injection. Serum interleukin-6 and high-mobility group box-1 concentrations were lower in the rhTM-treated group than in the control. eGC injury in the lung capillaries was attenuated by rhTM treatment. Gene set enrichment analysis revealed upregulation of gene sets corresponding to cell proliferation/differentiation and anti-inflammation, such as the transforming growth factor-β pathway, and negative regulation of interleukin-6, upon rhTM treatment. Gene expression of heparan sulphate 6-O-sulfotransferase-1 and endothelial cell specific molecule-1 (components of eGC) was significantly preserved by rhTM treatment, and their protein expression levels were retained in endothelial cells. CONCLUSION AND IMPLICATIONS Our 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.