GSK-3Beta-Dependent Activation of GEF-H1/ROCK Signaling Promotes LPS-Induced Lung Vascular Endothelial Barrier Dysfunction and Acute Lung Injury

Abstract

The bacterial endotoxin or lipopolysaccharide (LPS) leads to the extensive vascular endothelial cells (EC) injury under septic conditions. Guanine nucleotide exchange factor-H1 (GEF-H1)/ROCK signaling not only involved in LPS-induced overexpression of pro-inflammatory mediator in ECs but also implicated in LPS-induced endothelial hyper-permeability. However, the mechanisms behind LPS-induced GEF-H1/ROCK signaling activation in the progress of EC injury remain incompletely understood. GEF-H1 localized on microtubules (MT) and is suppressed in its MT-bound state. MT disassembly promotes GEF-H1 release from MT and stimulates downstream ROCK-specific GEF activity. Since glycogen synthase kinase (GSK-3beta) participates in regulating MT dynamics under pathologic conditions, we examined the pivotal roles for GSK-3beta in modulating LPS-induced activation of GEF-H1/ROCK, increase of vascular endothelial permeability and severity of acute lung injury (ALI). In this study, we found that LPS induced human pulmonary endothelial cell (HPMEC) monolayers disruption accompanied by increase in GSK-3beta activity, activation of GEF-H1/ROCK signaling and decrease in beta-catenin and ZO-1 expression. Inhibition of GSK-3beta reduced HPMEC monolayers hyper-permeability and GEF-H1/ROCK activity in response to LPS. GSK-3beta/GEF-H1/ROCK signaling is implicated in regulating the expression of beta-catenin and ZO-1. In vivo, GSK-3beta inhibition attenuated LPS-induced activation of GEF-H1/ROCK pathway, lung edema and subsequent ALI. These findings present a new mechanism of GSK-3beta-dependent exacerbation of lung micro-vascular hyper-permeability and escalation of ALI via activation of GEF-H1/ROCK signaling and disruption of intracellular junctional proteins under septic condition.

Genistein‐3′‐sodium sulphonate protects against lipopolysaccharide‐induced lung vascular endothelial cell apoptosis and acute lung injury via BCL‐2 signalling

“…Although many previous studies have revealed the molecular mechanisms of sepsis-induced ALI, 25,26 the drugs used to treat ALI have too many side effects to be widely used in the clinic. Natural which promotes the development of ALI.…”

CX3CL1 Induces Vertebral Microvascular Barrier Dysfunction via the Src/P115-RhoGEF/ROCK Signaling Pathway

“…Furthermore, the ZO-1 which is belong to TJs acts as an intracellular scaffolding protein in ECs and regulates cell-cell tension and cytoskeletal organization (Matter and Balda, 2003). Our previous study has showed that ZO-1 plays an important role in the integrity of EC barrier (Yi et al, 2017). However, whether CX3CL1 induced vertebral vascular barrier disruption via the disruption of ZO-1 in VMECs is unclear.…”

“…The ECs barrier function was monitored by ECIS as previously described (Yi et al, 2017). Endothelial monolayer resistance was monitored with the ECIS (Electric Cell-substrate Impedance Sensing) method using the ECIS 1,600 instrument and 8W10E electrode arrays.…”

Lipoxin A4 Ameliorates Acute Pancreatitis-Associated Acute Lung Injury through the Antioxidative and Anti-Inflammatory Effects of the Nrf2 Pathway

“…Generally, lung edema due to the overexpression of inflammatory mediators is accepted as one of the major prerequisites for AP-ALI pathogenesis. HPMECs are attacked by inflammatory mediators, resulting in increased HPMEC permeability and barrier dysfunction [43]. After the alveolar barrier is damaged, a substantial amount of tissue fluid infiltration aggravates pulmonary edema, and the damaged lung function causes the blood oxygen saturation level to drop sharply, thus causing the body to be in a serious anoxic state and increasing the risk of mortality [6].…”