scholarly journals Cigarette Smoke Disrupted Lung Endothelial Barrier Integrity and Increased Susceptibility to Acute Lung Injury via Histone Deacetylase 6

2016 ◽  
Vol 54 (5) ◽  
pp. 683-696 ◽  
Author(s):  
Diana Borgas ◽  
Eboni Chambers ◽  
Julie Newton ◽  
Junsuk Ko ◽  
Stephanie Rivera ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Histone Deacetylase ◽  
Cigarette Smoke ◽  
Endothelial Barrier ◽  
Histone Deacetylase 6 ◽  
Barrier Integrity ◽  
Increased Susceptibility

scholarly journals Histone Deacetylase 6 Mediates Cigarette Smoke‐Induced Increase in Lung Endothelial Permeability and Susceptibility to Acute Lung Injury

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Diana Borgas ◽  
Pavlo Sakhatskyy ◽  
Julie Newton ◽  
Eboni Chambers ◽  
Mandy Xi ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Histone Deacetylase ◽  
Cigarette Smoke ◽  
Endothelial Permeability ◽  
Histone Deacetylase 6

scholarly journals Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

2015 ◽  
Vol 309 (12) ◽  
pp. L1410-L1419 ◽  
Author(s):  
Atul D. Joshi ◽  
Nektarios Barabutis ◽  
Charalampos Birmpas ◽  
Christiana Dimitropoulou ◽  
Gagan Thangjam ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Heat Shock ◽  
Lung Injury ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Heat Shock Protein 90 ◽  
Selective Inhibitor ◽  
Endothelial Barrier ◽  
Rhoa Activity ◽  
Chaperone Function

Transendothelial hyperpermeability caused by numerous agonists is dependent on heat shock protein 90 (Hsp90) and leads to endothelial barrier dysfunction (EBD). Inhibition of Hsp90 protects and restores transendothelial permeability. Hyperacetylation of Hsp90, as by inhibitors of histone deacetylase (HDAC), suppresses its chaperone function and mimics the effects of Hsp90 inhibitors. In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS)-induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 chaperone function, and attenuated RhoA activity and signaling crucial to endothelial barrier function. Treatment with the HDAC3-selective inhibitor RGFP-966 or the HDAC6-selective inhibitor tubastatin A provided partial protection against LPS-mediated transendothelial hyperpermeability. Similarly, knock down of HDAC3 and HDAC6 by specific small-interfering RNAs provided significant protection against LPS-induced EBD. Furthermore, combined pharmacological inhibition of both HDAC3 and -6 attenuated the inflammation, capillary permeability, and structural abnormalities associated with LPS-induced ALI in mice. Together these data indicate that HDAC mediate increased transendothelial hyperpermeability caused by LPS and that inhibition of HDAC protects against LPS-mediated EBD and ALI by suppressing Hsp90-dependent RhoA activity and signaling.

Impaired airway epithelial barrier integrity was mediated by PI3Kδ in a mouse model of lipopolysaccharide-induced acute lung injury

2021 ◽  
Vol 95 ◽  
pp. 107570
Author(s):  
Lihong Yao ◽  
Ying Tang ◽  
Junjie Chen ◽  
Jiahui Li ◽  
Hua Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Barrier Integrity

Abstract 73: Bone Morphogenetic Protein Activity Modulates Endothelial Barrier Function

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Thomas Helbing ◽  
Elena Ketterer ◽  
Bianca Engert ◽  
Jennifer Heinke ◽  
Sebastian Grundmann ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Barrier Function ◽  
Endothelial Permeability ◽  
Bmp Signaling ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function

Introduction: Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome, are associated with high morbidity and mortality in patients. During the progression of ALI, the endothelial cell barrier of the pulmonary vasculature becomes compromised, leading to pulmonary edema, a characteristic feature of ALI. It is well-established that EC barrier dysfunction is initiated by cytoskeletal remodeling, which leads to disruption of cell-cell contacts and formation of paracellular gaps, allowing penetration of protein-rich fluid and inflammatory cells. Bone morphogenetic proteins (BMPs) are important players in endothelial dysfunction and inflammation but their effects on endothelial permeability in ALI have not been investigated until now. Methods and Results: As a first approach to assess the role of BMPs in acute lung injury we analysed BMP4 and BMPER expression in an infectious (LPS) and a non-infectious (bleomycin) mouse models of acute lung injury. In both models BMP4 and BMPER protein expression levels were reduced demonstrated by western blots, suggesting that BMPs are involved in progression ALI. To assess the role of BMPs on vascular leakage, a key feature of ALI, BMP activity in mice was inhibited by i.p. administration of LDN193189, a small molecule that blocks BMP signalling. After 3 days Evans blue dye (EVB) was administered i.v. and dye extravasation into the lungs was quantified as a marker for vascular leakage. Interestingly, LDN193189 significantly increased endothelial permeability compared to control lungs, indicating that BMP signaling is involved in maintenance of endothelial barrier function. To quantify effects of BMP inhibition on endothelial barrier function in vitro, HUVECs were seeded onto transwell filters and were exposed to LDN193189. After 3 days FITC-dextrane was added and passage into the lower chamber was quantified as a marker for endothelial barrier function. Thrombin served as a positive control. As expected from our in vivo experiments inhibition of BMP signaling by LDN193189 enhanced FITC-dextrane passage. To study specific effects of BMPs on endothelial barrier function, two protagonist of the BMP family, BMP2 and BMP4, or BMP modulator BMPER were tested in the transwell assay in vitro. Interestingly BMP4 and BMPER, but not BMP2, reduced FITC-dextrane passage demonstrating that BMP4 and BMPER improved endothelial barrier function. Vice versa, specific knock down of BMP4 or BMPER increased leakage in transwell assays. Im immuncytochemistry silencing of BMPER or BMP4 induced hyperpermeability as a consequence of a pro-inflammatory endothelial phenotype characterised by reduced cell-cell contacts and increased actin stress fiber formation. Additionally, the pro-inflammatory endothelial phenotype was confirmed by real-time revealing increased expression of adhesion molecules ICAM-1 or proinflammatory cytokines such as IL-6 and IL-8 in endothelial cells after BMPER or BMP4 knock down. Confirming these in vitro results BMPER +/- mice exhibit increased extravasation of EVB into the lungs, indicating that partial loss of BMPER impairs endothelial barrier function in vitro and in vivo. Conclusion: We identify BMPER and BMP4 as local regulators of vascular permeability. Both are protective for endothelial barrier function and may open new therapeutic avenues in the treatment of acute lung injury.

Gene silencing of receptor-interacting protein 2 protects against cigarette smoke-induced acute lung injury

2019 ◽  
Vol 139 ◽  
pp. 560-568 ◽  
Author(s):  
Jinrui Dong ◽  
Wupeng Liao ◽  
Lay Hong Tan ◽  
Amy Yong ◽  
Wen Yan Peh ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Gene Silencing ◽  
Cigarette Smoke ◽  
Interacting Protein

CRTH2 antagonist, CT‑133, effectively alleviates cigarette smoke-induced acute lung injury

Life Sciences ◽  
2019 ◽  
Vol 216 ◽  
pp. 156-167 ◽  
Author(s):  
Musaddique Hussain ◽  
Chengyun Xu ◽  
Minli Yao ◽  
Qin Zhang ◽  
Junsong Wu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cigarette Smoke

Effects of Eucalyptol in respiratory system mechanics on acute lung injury after exposure to short-term cigarette smoke

2019 ◽  
Vol 266 ◽  
pp. 33-38 ◽  
Author(s):  
Fladimir de Lima Gondim ◽  
Daniel Silveira Serra ◽  
Francisco Sales Ávila Cavalcante
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cigarette Smoke ◽  
Respiratory System ◽  
Short Term ◽  
Respiratory System Mechanics
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