PAR1 regulates sepsis-induced vascular endothelial barrier dysfunction by mediating ERM phosphorylation via the RhoA/ROCK signaling pathway.

Sepsis begins with vascular endothelial barrier breakdown and causes widespread organ failure. Protease-activated receptor 1 (PAR1) is an important target for modulating vascular endothelial permeability; however, little research has been undertaken in sepsis, and its putative molecular mechanism remains unknown. The vascular endothelial permeability was examined by detecting FITC-dextran flux. F-actin was examined by immunofluorescence (IF). PAR1, ERM phosphorylation, and RhoA/ROCK signaling pathway expression in lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) line were examined by IF and Western blot. To develop the sepsis model, cecal ligation and puncture (CLP) were conducted. The PAR1 inhibitor SCH79797 was utilized to inhibit PAR1 expression in vivo. Vascular permeability in main organs weres measured by Evans blue dye extravasation. The pathological changes in main organs were examined by HE staining. The expression of PAR1, ERM phosphorylation, and the RhoA/ROCK signaling pathway was examined using IF, immunohistochemical and WB in CLP mice. In vitro, in response to LPS stimulation of HUVECs, PAR1 mediated the phosphorylation of ERM, promoted F-actin rearrangement, and increased endothelial hyperpermeability, all of which were prevented by inhibiting PAR1 or RhoA. Additionally, inhibiting PAR1 expression reduced RhoA and ROCK expression. In vivo, we showed that inhibiting PAR1 expression will reduce ezrin/radixin/moesin (ERM) phosphorylation to relieve vascular endothelial barrier dysfunction and thereby ameliorate multiorgan dysfunction syndrome (MODS) in CLP-induced septic mice. This study revealed that PAR1-mediated phosphorylation of ERM induced endothelial barrier dysfunction, which in turn led to MODS in sepsis, and that the RhoA/ROCK signaling pathway underlay these effects.

[Original materials of traditional Chinese medicinal names of "Jinchai" and "Jinchai Shihu" based on vegetative morphology].

"Jinchai Shihu" were called Jinchai and recoded in "Taishang Zhouhou Yujingfang" of Tang Dynasty, which first clearly documented the name of Shihu in complex Dendrobium medicines and were condiered as superior medicinal articles. Morphological features are one of the naming principles for Chinese medicines. In this paper, botanical origin plants under the names of "Jinchai" and "Jinchai Shihu" were investigated. Based on documents from the local Chronicles and historical accounts, the Chinese characters of Jinchai have the distinctive features of gold color and two hair clasps. Moreover, the hair clasps are usually cylindrical in shape with uniform thickness in middle and upper part, and tapers off to the foot. And its bottom part style is simple and head part is complex. Thus we speculated the herbal "Jinchai" and "Jinchai Shihu" should have similar morphologic features as Chinese characters of Jinchai, including golden color and hairpin shape of stems without braches, short and solid sterm. After comparing the dried vegetative morphology of 10 common medicinal Dendrobium species, we suggested that of Dendrobium flexicaule matches well with the morphological features from historical herbal records.