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

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

scholarly journals Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury

2013 ◽  
Vol 305 (11) ◽  
pp. L844-L855 ◽  
Author(s):  
Ming-Yuan Jian ◽  
Mikhail F. Alexeyev ◽  
Paul E. Wolkowicz ◽  
Jaroslaw W. Zmijewski ◽  
Judy R. Creighton
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Ex Vivo ◽  
Endothelial Permeability ◽  
Beneficial Effects ◽  
Isolated Lung

Acute lung injury secondary to sepsis is a leading cause of mortality in sepsis-related death. Present therapies are not effective in reversing endothelial cell dysfunction, which plays a key role in increased vascular permeability and compromised lung function. AMP-activated protein kinase (AMPK) is a molecular sensor important for detection and mediation of cellular adaptations to vascular disruptive stimuli. In this study, we sought to determine the role of AMPK in resolving increased endothelial permeability in the sepsis-injured lung. AMPK function was determined in vivo using a rat model of endotoxin-induced lung injury, ex vivo using the isolated lung, and in vitro using cultured rat pulmonary microvascular endothelial cells (PMVECs). AMPK stimulation using N1-(α-d-ribofuranosyl)-5-aminoimidizole-4-carboxamide or metformin decreased the LPS-induced increase in permeability, as determined by filtration coefficient ( Kf) measurements, and resolved edema as indicated by decreased wet-to-dry ratios. The role of AMPK in the endothelial response to LPS was determined by shRNA designed to decrease expression of the AMPK-α1 isoform in capillary endothelial cells. Permeability, wounding, and barrier resistance assays using PMVECs identified AMPK-α1 as the molecule responsible for the beneficial effects of AMPK in the lung. Our findings provide novel evidence for AMPK-α1 as a vascular repair mechanism important in the pulmonary response to sepsis and identify a role for metformin treatment in the management of capillary injury.

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

Apple polyphenol protects against cigarette smoke-induced acute lung injury

Nutrition ◽  
2013 ◽  
Vol 29 (1) ◽  
pp. 235-243 ◽  
Author(s):  
Meng-Jing Bao ◽  
Jian Shen ◽  
Yong-Liang Jia ◽  
Fen-Fen Li ◽  
Wen-Jiang Ma ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cigarette Smoke

Endothelial NOS Uncoupling Contributes To Endothelial Permeability In Inflammatory Acute Lung Injury

2012 ◽  
Author(s):  
William S. Szczepaniak ◽  
Eric E. Kelley ◽  
Sruti Shiva ◽  
Mark T. Gladwin ◽  
Bryan J. McVerry
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Endothelial Permeability
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