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

Abstract

Background and Purpose Disruption 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 Approach 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 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 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.

Vascular endothelial injury exacerbates coronavirus disease 2019: The role of endothelial glycocalyx protection

“…58 Although further experiments are required to understand how rhTM affects endothelial glycocalyx biosynthesis, it has been suggested that there is an interaction between thrombomodulin and endothelial glycocalyx thrombomodulin at least. 54…”

“…A very recent report revealed that recombinant human thrombomodulin (rhTM) protects endothelial glycocalyx from lipopolysaccharide (LPS)-induced pulmonary injury. 54 This mechanism may be involved with not only the reduction of the damage associated with inflammation but also the acceleration of the biosynthesis of the glycocalyx itself. Thrombomodulin exists at the luminal surface of all vessel segments and especially at venular endothelial cell junctions, 34 binds to thrombin to inhibit its pro-coagulant activity, and promotes anticoagulant protein C activation.…”

“…61,62 In addition, rhTM attenuates endothelial dysfunction by endothelial glycocalyx restoration through its biosynthesis. 54 During this COVID-19 pandemic, many scientists are researching on SARS-CoV-2 and the associated host immune defenses.…”

“…A very recent report revealed that recombinant human thrombomodulin (rhTM) protects endothelial glycocalyx from lipopolysaccharide (LPS)‐induced pulmonary injury 54 . This mechanism may be involved with not only the reduction of the damage associated with inflammation but also the acceleration of the biosynthesis of the glycocalyx itself.…”

“…rhTM also promotes protein C activation 55‐57 and reduces the secretion of inflammatory cytokines, including interleukin‐6 and tumor necrosis factor‐α, under septic conditions 58 . Although further experiments are required to understand how rhTM affects endothelial glycocalyx biosynthesis, it has been suggested that there is an interaction between thrombomodulin and endothelial glycocalyx thrombomodulin at least 54 …”