scholarly journals P53 in lung vascular barrier dysfunction

2020 ◽  
Vol 2 (1) ◽  
pp. E1-E2 ◽  
Author(s):  
Nektarios Barabutis
Keyword(s):  
Distress Syndrome ◽  
Heat Shock Protein 90 ◽  
Tumor Suppressor Protein ◽  
Molecular Pathways ◽  
Barrier Dysfunction ◽  
Barrier Integrity ◽  
Beneficial Effects ◽  
Endothelial Barrier Dysfunction ◽  
Hormone Antagonists ◽  
Vascular Barrier Integrity

Endothelial barrier dysfunction is the hallmark of inflammatory lung disease, including Acute Lung Injury and Acute Respiratory Distress Syndrome. The purpose of the present editorial is to emphasize on recent advances in the corresponding field, as it relates to P53. This tumor suppressor protein has been shown to enhance the vascular barrier integrity via distinct molecular pathways. Further, it mediates the beneficial effects of heat shock protein 90 inhibitors and growth hormone releasing hormone antagonists in the lung microvasculature.

Brefeldin A and Kifunensine modulate the LPS-induced lung endothelial hyperpermeability in human and bovine cells

2021 ◽  
Author(s):  
Khadeja-Tul Kubra ◽  
Nektarios Barabutis
Keyword(s):  
Distress Syndrome ◽  
Brefeldin A ◽  
Respiratory Disorder ◽  
Molecular Pathways ◽  
Barrier Dysfunction ◽  
Unfolded Protein ◽  
Endothelial Barrier Dysfunction ◽  
Protein Response ◽  
Novel Therapeutic

Endothelial hyper-permeability is the hallmark of Acute Respiratory Distress Syndrome (ARDS). Laborious efforts in the investigation of the molecular pathways involved in the regulation of the vascular barrier, shall reveal novel therapeutic targets towards that respiratory disorder. Herein we investigate in vitro the effects of the alpha-1,2- mannosidase 1 inhibitor Kifunensine (KIF) and brefeldin A (BFA) in the LPS-induced endothelial breakdown. Our results suggest that BFA opposes the deteriorating effects of KIF (UPR suppressor) towards the lung microvasculature. Since KIF is an unfolded protein response (UPR) suppressor, and brefeldin A is a UPR inducer, we suggest that a carefully devised UPR manipulation may deliver novel therapeutic avenues in diseases related to endothelial barrier dysfunction (e.g. ARDS, sepsis).

scholarly journals Heme induces rapid endothelial barrier dysfunction via the MKK3/p38MAPK axis

Blood ◽  
2020 ◽  
Vol 136 (6) ◽  
pp. 749-754
Author(s):  
Joel James ◽  
Anup Srivastava ◽  
Mathews Valuparampil Varghese ◽  
Cody A. Eccles ◽  
Marina Zemskova ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Endothelial Barrier ◽  
Acute Chest Syndrome ◽  
Dependent Manner ◽  
Barrier Dysfunction ◽  
Barrier Integrity ◽  
Endothelial Barrier Dysfunction ◽  
Free Heme ◽  
P38mapk Pathway

Abstract Several studies demonstrate that hemolysis and free heme in circulation cause endothelial barrier dysfunction and are associated with severe pathological conditions such as acute respiratory distress syndrome, acute chest syndrome, and sepsis. However, the precise molecular mechanisms involved in the pathology of heme-induced barrier disruption remain to be elucidated. In this study, we investigated the role of free heme in the endothelial barrier integrity and mechanisms of heme-mediated intracellular signaling of human lung microvascular endothelial cells (HLMVECs). Heme, in a dose-dependent manner, induced a rapid drop in the endothelial barrier integrity of HLMVECs. An investigation into barrier proteins revealed that heme primarily affected the tight junction proteins zona occludens-1, claudin-1, and claudin-5, which were significantly reduced after heme exposure. The p38MAPK/HSP27 pathway, involved in the regulation of endothelial cytoskeleton remodeling, was also significantly altered after heme treatment, both in HLMVECs and mice. By using a knockout (KO) mouse for MKK3, a key regulator of the p38MAPK pathway, we showed that this KO effectively decreased heme-induced endothelial barrier dysfunction. Taken together, our results indicate that targeting the p38MAPK pathway may represent a crucial treatment strategy in alleviating hemolytic diseases.

scholarly journals Nox2-dependent glutathionylation of endothelial NOS leads to uncoupled superoxide production and endothelial barrier dysfunction in acute lung injury

2014 ◽  
Vol 307 (12) ◽  
pp. L987-L997 ◽  
Author(s):  
Feng Wu ◽  
William S. Szczepaniak ◽  
Sruti Shiva ◽  
Huanbo Liu ◽  
Yinna Wang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Superoxide Production ◽  
Endothelial Barrier ◽  
Tissue Homogenate ◽  
Protein Accumulation ◽  
Barrier Dysfunction ◽  
Barrier Integrity ◽  
Endothelial Barrier Dysfunction ◽  
Enos Uncoupling

Microvascular barrier integrity is dependent on bioavailable nitric oxide (NO) produced locally by endothelial NO synthase (eNOS). Under conditions of limited substrate or cofactor availability or by enzymatic modification, eNOS may become uncoupled, producing superoxide in lieu of NO. This study was designed to investigate how eNOS-dependent superoxide production contributes to endothelial barrier dysfunction in inflammatory lung injury and its regulation. C57BL/6J mice were challenged with intratracheal LPS. Bronchoalveolar lavage fluid was analyzed for protein accumulation, and lung tissue homogenate was assayed for endothelial NOS content and function. Human lung microvascular endothelial cell (HLMVEC) monolayers were exposed to LPS in vitro, and barrier integrity and superoxide production were measured. Biopterin species were quantified, and coimmunoprecipitation (Co-IP) assays were performed to identify protein interactions with eNOS that putatively drive uncoupling. Mice exposed to LPS demonstrated eNOS-dependent increased alveolar permeability without evidence for altered canonical NO signaling. LPS-induced superoxide production and permeability in HLMVEC were inhibited by the NOS inhibitor nitro-l-arginine methyl ester, eNOS-targeted siRNA, the eNOS cofactor tetrahydrobiopterin, and superoxide dismutase. Co-IP indicated that LPS stimulated the association of eNOS with NADPH oxidase 2 (Nox2), which correlated with augmented eNOS S-glutathionylation both in vitro and in vivo. In vitro, Nox2-specific inhibition prevented LPS-induced eNOS modification and increases in both superoxide production and permeability. These data indicate that eNOS uncoupling contributes to superoxide production and barrier dysfunction in the lung microvasculature after exposure to LPS. Furthermore, the results implicate Nox2-mediated eNOS- S-glutathionylation as a mechanism underlying LPS-induced eNOS uncoupling in the lung microvasculature.

scholarly journals STAT3 Signalling via the IL-6ST/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 187
Author(s):  
Lokman Pang ◽  
Jennifer Huynh ◽  
Mariah G. Alorro ◽  
Xia Li ◽  
Matthias Ernst ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Epithelial Integrity ◽  
Barrier Integrity ◽  
Gp130 Receptor ◽  
Stat3 Signalling

The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130∆STAT allele (GP130∆STAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.

scholarly journals Atrial Natriuretic Peptide Protects against Histamine-Induced Endothelial Barrier Dysfunction in Vivo

2008 ◽  
Vol 74 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Robert Fürst ◽  
Martin F. Bubik ◽  
Peter Bihari ◽  
Bettina A. Mayer ◽  
Alexander G. Khandoga ◽  
...  
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Endothelial Barrier ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction ◽  
Atrial Natriuretic

Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability

2008 ◽  
Vol 294 (4) ◽  
pp. L755-L763 ◽  
Author(s):  
Anuran Chatterjee ◽  
Connie Snead ◽  
Gunay Yetik-Anacak ◽  
Galina Antonova ◽  
Jingmin Zeng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Heat Shock ◽  
Lung Injury ◽  
Heat Shock Protein ◽  
Adherens Junction ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Barrier Dysfunction ◽  
Focal Adhesion Protein ◽  
Endothelial Hyperpermeability

Endothelial hyperperme ability leading to vascular leak is an important consequence of sepsis and sepsis-induced lung injury. We previously reported that heat shock protein (hsp) 90 inhibitor pretreatment improved pulmonary barrier dysfunction in a murine model of sepsis-induced lung injury. We now examine the effects of hsp90 inhibitors on LPS-mediated endothelial hyperpermeability, as reflected in changes in transendothelial electrical resistance (TER) of bovine pulmonary arterial endothelial cells (BPAEC). Vehicle-pretreated cells exposed to endotoxin exhibited a concentration-dependent decrease in TER, activation of pp60Src, phosphorylation of the focal adhesion protein paxillin, and reduced expression of the adherens junction proteins, vascular endothelial (VE)-cadherin and β-catenin. Pretreatment with the hsp90 inhibitor, radicicol, prevented the decrease in TER, maintained VE-cadherin and β-catenin expression, and inhibited activation of pp60Src and phosphorylation of paxillin. Similarly, when BPAEC hyperpermeability was induced by endotoxin-activated neutrophils, pretreatment of neutrophils and/or endothelial cells with radicicol protected against the activated neutrophil-induced decrease in TER. Increased paxillin phosphorylation and decreased expression of β-catenin and VE-cadherin were also observed in mouse lungs 12 h after intraperitoneal endotoxin and attenuated in mice pretreated with radicicol. These results suggest that hsp90 plays an important role in sepsis-associated endothelial barrier dysfunction.

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