scholarly journals Atrial natriuretic peptide attenuates LPS-induced lung vascular leak: role of PAK1

2010 ◽  
Vol 299 (5) ◽  
pp. L652-L663 ◽  
Author(s):  
Anna A. Birukova ◽  
Junjie Xing ◽  
Panfeng Fu ◽  
Bakhtiyor Yakubov ◽  
Oleksii Dubrovskyi ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Atrial Natriuretic Peptide ◽  
Bronchoalveolar Lavage ◽  
Knockout Mice ◽  
Endothelial Barrier ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Vascular Leak ◽  
Evans Blue Extravasation

Increased levels of atrial natriuretic peptide (ANP) in the models of sepsis, pulmonary edema, and acute respiratory distress syndrome (ARDS) suggest its potential role in the modulation of acute lung injury. We have recently described ANP-protective effects against thrombin-induced barrier dysfunction in pulmonary endothelial cells (EC). The current study examined involvement of the Rac effector p21-activated kinase (PAK1) in ANP-protective effects in the model of lung vascular permeability induced by bacterial wall LPS. C57BL/6J mice or ANP knockout mice (Nppa−/−) were treated with LPS (0.63 mg/kg intratracheal) with or without ANP (2 μg/kg iv). Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count, Evans blue extravasation, and lung histology. Endothelial barrier properties were assessed by morphological analysis and measurements of transendothelial electrical resistance. ANP treatment stimulated Rac-dependent PAK1 phosphorylation, attenuated endothelial permeability caused by LPS, TNF-α, and IL-6, decreased LPS-induced cell and protein accumulation in bronchoalveolar lavage fluid, and suppressed Evans blue extravasation in the murine model of acute lung injury. More severe LPS-induced lung injury and vascular leak were observed in ANP knockout mice. In rescue experiments, ANP injection significantly reduced lung injury in Nppa−/− mice caused by LPS. Molecular inhibition of PAK1 suppressed the protective effects of ANP treatment against LPS-induced lung injury and endothelial barrier dysfunction. This study shows that the protective effects of ANP against LPS-induced vascular leak are mediated at least in part by PAK1-dependent signaling leading to EC barrier enhancement. Our data suggest a direct role for ANP in endothelial barrier regulation via modulation of small GTPase signaling.

scholarly journals Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction

2017 ◽  
Vol 57 (6) ◽  
pp. 662-673 ◽  
Author(s):  
Qing Lu ◽  
Miles Mundy ◽  
Eboni Chambers ◽  
Thilo Lange ◽  
Julie Newton ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Endothelial Barrier ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction

scholarly journals Platelet Extracellular Vesicles mediate Transfusion-related Acute Lung Injury by imbalancing the Sphingolipid Rheostat

Blood ◽  
2020 ◽  
Author(s):  
Mark J McVey ◽  
Sarah Weidenfeld ◽  
Mazharul Maishan ◽  
Chris Spring ◽  
Michael Kim ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Extracellular Vesicles ◽  
Endothelial Barrier ◽  
Barrier Dysfunction ◽  
Platelet Storage ◽  
Barrier Failure ◽  
Long Chain

Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5-15%. We previously showed that stored (5 days; D5) but not fresh platelets (1 day; D1) cause TRALI via ceramide mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induce TRALI. EVs formed during storage of murine platelets were enumerated, characterized for sphingolipids and applied in a murine TRALI model in vivo and for endothelial barrier assessment in vitro. D5-EVs were more abundant, had higher long chain ceramide (C16:0, C18:0, C20:0) and lower S1P content than D1-EVs. Transfusion of D5- but not D1-EVs induced characteristic signs of lung injury in vivo and endothelial barrier disruption in vitro. Inhibition or supplementation of ceramide-forming sphingomyelinase reduced or enhanced the formation of EVs, respectively, but did not alter the injuriousness per individual EV. Barrier failure was attenuated when EVs were abundant in or supplemented with S1P. Stored human platelet D4-EVs were more numerous compared with D2-EVs, contained more long chain ceramide and less S1P, and caused more EC barrier leak. Hence, platelet-derived EVs become more numerous and more injurious (more long chain ceramide, less S1P) during storage. Blockade of sphingomyelinase, EV elimination, or supplementation of S1P during platelet storage may present promising strategies for TRALI prevention.

Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats

2007 ◽  
Vol 293 (2) ◽  
pp. L446-L452 ◽  
Author(s):  
Takefumi Itoh ◽  
Hiroaki Obata ◽  
Shinsuke Murakami ◽  
Kaoru Hamada ◽  
Kenji Kangawa ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Total Protein ◽  
Intratracheal Instillation ◽  
Weight Ratio ◽  
Dry Weight ◽  
Alveolar Wall ◽  
Protective Effects ◽  
Tnf Α

Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 μg·kg−1·min−1) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-α and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

scholarly journals Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction

2015 ◽  
Vol 308 (5) ◽  
pp. L452-L463 ◽  
Author(s):  
Fanyong Meng ◽  
Angelo Meliton ◽  
Nurgul Moldobaeva ◽  
Gokhan Mutlu ◽  
Yoshihiro Kawasaki ◽  
...  
Keyword(s):  
Lung Injury ◽  
Adhesion Molecule ◽  
Endothelial Barrier ◽  
Intercellular Adhesion Molecule ◽  
Protective Effects ◽  
Nucleotide Exchange ◽  
Intercellular Adhesion Molecule 1 ◽  
Barrier Dysfunction ◽  
Gram Negative ◽  
Anti Inflammatory

Increased vascular endothelial permeability and inflammation are major pathological mechanisms of pulmonary edema and its life-threatening complication, the acute respiratory distress syndrome (ARDS). We have previously described potent protective effects of hepatocyte growth factor (HGF) against thrombin-induced hyperpermeability and identified the Rac pathway as a key mechanism of HGF-mediated endothelial barrier protection. However, anti-inflammatory effects of HGF are less understood. This study examined effects of HGF on the pulmonary endothelial cell (EC) inflammatory activation and barrier dysfunction caused by the gram-negative bacterial pathogen lipopolysaccharide (LPS). We tested involvement of the novel Rac-specific guanine nucleotide exchange factor Asef in the HGF anti-inflammatory effects. HGF protected the pulmonary EC monolayer against LPS-induced hyperpermeability, disruption of monolayer integrity, activation of NF-kB signaling, expression of adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and production of IL-8. These effects were critically dependent on Asef. Small-interfering RNA-induced downregulation of Asef attenuated HGF protective effects against LPS-induced EC barrier failure. Protective effects of HGF against LPS-induced lung inflammation and vascular leak were also diminished in Asef knockout mice. Taken together, these results demonstrate potent anti-inflammatory effects by HGF and delineate a key role of Asef in the mediation of the HGF barrier protective and anti-inflammatory effects. Modulation of Asef activity may have important implications in therapeutic strategies aimed at the treatment of sepsis and acute lung injury/ARDS-induced gram-negative bacterial pathogens.

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