scholarly journals The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1489
Author(s):  
Ruben M. L. Colunga Biancatelli ◽  
Pavel Solopov ◽  
Betsy Gregory ◽  
John D. Catravas
Keyword(s):  
Endothelial Cells ◽  
Hydrochloric Acid ◽  
Human Lung ◽  
Hsp90 Inhibitor ◽  
Endothelial Barrier ◽  
Microvascular Endothelial Cells ◽  
Dependent Manner ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction ◽  
Microvascular Endothelial

Exposure to hydrochloric acid (HCl) leads acutely to asthma-like symptoms, acute respiratory distress syndrome (ARDS), including compromised alveolo-capillary barrier, and respiratory failure. To better understand the direct effects of HCl on pulmonary endothelial function, we studied the characteristics of HCl-induced endothelial barrier dysfunction in primary cultures of human lung microvascular endothelial cells (HLMVEC), defined the involved molecular pathways, and tested the potentially beneficial effects of Heat Shock Protein 90 (HSP90) inhibitors. HCl impaired barrier function in a time- and concentration-dependent manner and was associated with activation of Protein Kinase B (AKT), Ras homolog family member A (RhoA) and myosin light chain 2 (MLC2), as well as loss of plasmalemmal VE-cadherin, rearrangement of cortical actin, and appearance of inter-endothelial gaps. Pre-treatment or post-treatment of HLMVEC with AUY-922, a third-generation HSP90 inhibitor, prevented and restored HCl-induced endothelial barrier dysfunction. AUY-922 increased the expression of HSP70 and inhibited the activation (phosphorylation) of extracellular-signal regulated kinase (ERK) and AKT. AUY-922 also prevented the HCl-induced activation of RhoA and MLC2 and the internalization of plasmalemmal VE-cadherin. We conclude that, by increasing the expression of cytoprotective proteins, interfering with actomyosin contractility, and enhancing the expression of junction proteins, inhibition of HSP90 may represent a useful approach for the management of HCl-induced endothelial dysfunction and acute lung injury.

scholarly journals Roles of VE-Cadherin in Hypoxia Induced Injury of Pulmonary Microvascular Endothelial Barrier

2021 ◽  
Vol 24 (4) ◽  
pp. E764-E768
Author(s):  
Lizhe Zhong ◽  
Xiurong Gao ◽  
Yongli Chen ◽  
Zhaoxiang Yu ◽  
Shuo Jin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Endothelial Barrier ◽  
Microvascular Endothelial Cells ◽  
Barrier Dysfunction ◽  
Barrier Methods ◽  
Endothelial Barrier Dysfunction ◽  
Microvascular Endothelial ◽  
Induced Apoptosis

Background: Hypoxia induced injury of pulmonary microvascular endothelial barrier is closely related to the pathogenesis of acute lung injury after lung transplantation. VE-cadherin is an important structural molecule for pulmonary microvascular endothelial barrier. In this study, we aim to investigate the roles of VE-cadherin in hypoxia induced injury of pulmonary microvascular endothelial barrier. Methods: Rat model of hypoxia and cultured pulmonary microvascular endothelial cells (PMVECs) were utilized. Determination of PMVECs apoptosis, skeleton combination was conducted to verify the effects of hypoxia on injury of pulmonary microvascular endothelial barrier. In addition, VE-cadherin expression was modulated by administration of siRNA in order to investigate the roles of VE-cadherin in hypoxia induced PMVECs apoptosis and skeleton recombination. Results: Our data indicated that expression of VE-cadherin was down-regulated in hypoxia-exposed PMVECs. Whereas, in the cells treated using siRNA, down-regulation of VE-cadherin did not trigger PMVECs apoptosis, but it increased the sensitivity of PMVECs to the hypoxia induced apoptosis. In cases of hypoxia, the expression of VE-cadherin was significantly down-regulated, together with endothelial skeleton recombination and increase of permeability, which then triggered endothelial barrier dysfunction. Conclusions: These data verify that VE-cadherin expression played an important role in hypoxia induced PMVECs apoptosis and cellular skeletal recombination.

scholarly journals Integrin α4β1/VCAM-1 Interaction Evokes Dynamic Cell Aggregation Between Immune Cells and Human Lung Microvascular Endothelial Cells at Infectious Hemolysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Hai-Yan Lou ◽  
Hai-Peng Yan ◽  
Long-Gui Yang ◽  
Jiang-hua Fan ◽  
William C. Cho ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
T Cell ◽  
Immune Cells ◽  
Human Lung ◽  
Cell Aggregation ◽  
Microvascular Endothelial Cells ◽  
T Cell Proliferation ◽  
Dependent Manner ◽  
Microvascular Endothelial

Bacterial and viral infection is a common cause of pneumonia, respiratory failure, and even acute respiratory distress syndrome. Increasing evidence indicates that red blood cells (RBCs) may contribute to immune response and inflammation. However, the precise molecular mechanisms that link RBC and hemolysis to the development and progression of inflammatory pathologies are not entirely understood. In this study, we used bacterial endotoxin, lipopolysaccharide (LPS), to mimic an infectious hemolysis and found that RBCs dynamically regulated cell aggregation between immune cells and human lung microvascular endothelial cells (HLMVEC). When RBCs were treated with LPS, integrin α4β1 was increased and was accompanied by cytokines and chemokines release (TNF-α, IL-1β, IL-6, IL-8, IFN-γ, CXCL12, CCL5, CCL7 and CCL4). Upon α4β1 elevation, RBCs not only facilitated mature monocyte derived dendritic cell (mo-DCs) adhesion but also promoted HLMVEC aggregation. Furthermore, co-culture of the supernatant of LPS pre-treated RBCs with mo-DCs could promote naïve CD4 T cell proliferation. Notably, the filtered culture from LPS-lysed RBCs further promoted mo-DCs migration in a concentration dependent manner. From a therapeutic perspective, cyclic peptide inhibitor of integrin α4β1 combined with methylprednisolone (α4β1/Methrol) remarkably blocked RBCs aggregation to mo-DCs, HLMVEC, or mo-DCs and HLMVEC mixture. Moreover, α4β1/Methrol dramatically reduced mo-DCs migration up-regulated glucocorticoid-induced leucine zipper in mo-DCs, and ultimately reversed immune cell dysfunction induced by hemolysis. Taken together, these results indicate that integrin α4β1 on RBCs could mediate cell-cell interaction for adaptive immunity through influencing cell adhesion, migration, and T cell proliferation.

scholarly journals Oxidized Hemoglobin Causes Human Lung Microvascular Endothelial Barrier Dysfunction

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Jamie E. Meegan ◽  
Toria Tomasek ◽  
Lorraine B. Ware ◽  
Julie A. Bastarache
Keyword(s):  
Human Lung ◽  
Endothelial Barrier ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction ◽  
Microvascular Endothelial

scholarly journals AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung Microvascular Endothelial Permeability through Activation of Rho Signaling Pathway and Phosphorylation of VE-Cadherin

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Junting Cai ◽  
Jianxin Wei ◽  
Shuang Li ◽  
Tomeka Suber ◽  
Jing Zhao
Keyword(s):  
Endothelial Cells ◽  
Lung Injury ◽  
Lysophosphatidic Acid ◽  
Endothelial Permeability ◽  
Endothelial Barrier ◽  
Dependent Manner ◽  
Gap Formation ◽  
Barrier Dysfunction ◽  
Lpa Receptor ◽  
Microvascular Endothelial

Maintenance of pulmonary endothelial barrier integrity is important for reducing severity of lung injury. Lysophosphatidic acid (LPA) regulates cell motility, cytoskeletal rearrangement, and cell growth. Knockdown of LPA receptor 1 (LPA1) has been shown to mitigate lung injury and pulmonary fibrosis. AM966, an LPA1 antagonist exhibiting an antifibrotic property, has been considered to be a future antifibrotic medicine. Here, we report an unexpected effect of AM966, which increases lung endothelial barrier permeability. An electric cell-substrate sensing (ECIS) system was used to measure permeability in human lung microvascular endothelial cells (HLMVECs). AM966 decreased the transendothelial electrical resistance (TEER) value immediately in a dose-dependent manner. VE-cadherin and f-actin double immunostaining reveals that AM966 increases stress fibers and gap formation between endothelial cells. AM966 induced phosphorylation of myosin light chain (MLC) through activation of RhoA/Rho kinase pathway. Unlike LPA treatment, AM966 had no effect on phosphorylation of extracellular signal-regulated kinases (Erk). Further, in LPA1 silencing cells, we observed that AM966-increased lung endothelial permeability as well as phosphorylation of VE-cadherin and focal adhesion kinase (FAK) were attenuated. This study reveals that AM966 induces lung endothelial barrier dysfunction, which is regulated by LPA1-mediated activation of RhoA/MLC and phosphorylation of VE-cadherin.

scholarly journals Pigment Epithelium-Derived Factor Induces Endothelial Barrier Dysfunction via p38/MAPK Phosphorylation

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Ting He ◽  
Liping Zhao ◽  
Dongxia Zhang ◽  
Qiong Zhang ◽  
Jiezhi Jia ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Umbilical Vein ◽  
Pigment Epithelium ◽  
Endothelial Barrier ◽  
Dependent Manner ◽  
Barrier Dysfunction ◽  
Edema Formation ◽  
Endothelial Barrier Dysfunction ◽  
Pigment Epithelium Derived Factor

Endothelial barrier dysfunction, which is a serious problem that occurs in various inflammatory conditions, permits extravasation of serum components into the surrounding tissues, leading to edema formation and organ failure. Pigment epithelium-derived factor (PEDF), which is a major endogenous antagonist, has been implicated in diverse biological process, but its role in endothelial barrier dysfunction has not been defined. To assess the role of PEDF in the vasculature, we evaluated the effects of exogenous PEDF using human umbilical vein endothelial cells (HUVECs)in vitro. Our results demonstrated that exogenous PEDF activated p38/MAPK signalling pathway in a dose- and time-dependent manner and induced vascular hyperpermeability as measured by the markedly increased FITC-dextran leakage and the decreased transendothelial electrical resistance (TER) across the monolayer cells, which was accompanied by microtubules (MTs) disassembly and F-actin rearrangement. However, the aforementioned alterations can be arrested by the application of low concentration of p38/MAPK inhibitor SB203580. These results reveal a novel role for PEDF as a potential vasoactive substance in inducing hyperpermeability. Furthermore, our results suggest that PEDF and p38/MAPK may serve as therapeutic targets for maintaining vascular integrity.

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