Redox Regulation of Reactive Oxygen Species-Induced p38 MAP Kinase Activation and Barrier Dysfunction in Lung Microvascular Endothelial Cells

Usatyuk, Peter V.; Vepa, Suryanarayana; Watkins, Tonya; He, Donghong; Parinandi, Narasimham L.; Natarajan, Viswanathan

doi:10.1089/152308603770380025

Cited by 131 publications

(107 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nevertheless, our data do not rule out ROS- independent mechanisms by which sustained adenosine activates p38 and JNK in mitochondria, leading to barrier dysfunction. We and others have previously shown that p38 mediates EC barrier dysfunction and lung edema (34,57). The p38 downstream targetHSP27 modulates actin filament dynamics via its phosphorylation, thus affecting endothelial permeability.…”

Section: Discussionmentioning

confidence: 93%

Sustained Adenosine Exposure Causes Lung Endothelial Barrier Dysfunction via Nucleoside Transporter–Mediated Signaling

Lü

Newton

Hsiao

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Previous studies by our group as well as others have shown that acute adenosine exposure enhances lung vascular endothelial barrier integrity and protects against increased permeability lung edema. In contrast, there is growing evidence that sustained adenosine exposure has detrimental effects on the lungs, including lung edema. It is well established that adenosine modulates lung inflammation. However, little is known concerning the effect of sustained adenosine exposure on lung endothelial cells (ECs), which are critical to the maintenance of the alveolar-capillary barrier. We show that exogenous adenosine plus adenosine deaminase inhibitor caused sustained elevation of adenosine in lung ECs. This sustained adenosine exposure decreased EC barrier function, elevated cellular reactive oxygen species levels, and activated p38, JNK, and RhoA. Inhibition of equilibrative nucleoside transporters (ENTs) prevented sustained adenosine-induced p38 and JNK activation and EC barrier dysfunction. Inhibition of p38, JNK, or RhoA also partially attenuated sustained adenosine-induced EC barrier dysfunction. These data indicate that sustained adenosine exposure causes lung EC barrier dysfunction via ENT-dependent intracellular adenosine uptake and subsequent activation of p38, JNK, and RhoA. The antioxidant N-acetylcysteine and the NADPH inhibitor partially blunted sustained adenosine-induced JNK activation but were ineffective in attenuation of p38 activation or barrier dysfunction. p38 was activated exclusively in mitochondria, whereas JNK was activated in mitochondria and cytoplasm by sustained adenosine exposure. Our data further suggest that sustained adenosine exposure may cause mitochondrial oxidative stress, leading to activation of p38, JNK, and RhoA in mitochondria and resulting in EC barrier dysfunction.Keywords: adenosine deaminase; equilibrative nucleoside transporters; oxidative stress; MAP kinases; RhoA Increased permeability pulmonary edema is a life-threatening complication characteristic of acute lung injury (ALI) and acute respiratory distress syndrome. The purine nucleoside adenosine has been shown to protect (1-4) and cause (5) pulmonary edema and inflammation in animal models of ALI. The mechanisms governing these paradoxical effects of adenosine are poorly understood.Adenosine is a potent signaling molecule. Under homeostatic conditions, extracellular adenosine concentrations are low (40-600 nM) (6). However, extracellular adenosine levels are increased in response to tissue injury. High plasma adenosine (10-190 mM) has been reported in patients with sepsis-induced ALI (7, 8) and tissue ischemia (9). Adenosine is also significantly elevated in the lungs of animals with ALI caused by acute hypoxia (10-13), high tidal volume ventilation (14), endotoxin (15), and bleomycin (16). Acutely elevated adenosine has been shown to have a protective, antiinflammatory effect in various animal models of ALI (1-4). However, nonsurviving patients with sepsis have much higher plasma adenosine than survivors (7), suggesti...

show abstract

Section: Discussionmentioning

confidence: 93%

Sustained Adenosine Exposure Causes Lung Endothelial Barrier Dysfunction via Nucleoside Transporter–Mediated Signaling

Lü

Newton

Hsiao

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…Indeed, oxidative stress is known to induce signaling cascades and subsequent cytoskeletal remodeling in a number of neural and non-neural cell systems (Bundy et al, 2005;Carvalho et al, 2004;Choi et al, 2004;Huot et al, 1998;Kevil et al, 2001;Kurata, 2000;Usatyuk and Natarajan, 2004;Usatyuk et al, 2003). In dopaminergic neurons, phosphorylation of p38 MAPK by oxidative stress is linked to activation of caspases and apoptotic pathways (Choi et al, 2004) and p38 MAPK mediates the formation of actin stress fibers induced by β-amyloid peptide (Song et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative stress has been reported to stimulate signaling pathways including the mitogen-activated protein kinases (MAPK) (Choi et al, 2004;Huot et al, 1998;Kurata, 2000;Rosenberger et al, 2001;Song et al, 2002;Usatyuk et al, 2003). In this study, western blot analysis was used to demonstrate that H 2 O 2 triggers the p38 MAPK pathway in astrocytes and phosphorylation of p38 MAPK increased with increasing dose of H 2 O 2 ( Fig.…”

Section: H 2 O 2 Stimulates P38 Mapk In Astrocytesmentioning

confidence: 94%

Hydrogen peroxide alters membrane and cytoskeleton properties and increases intercellular connections in astrocytes

Zhu

Tan

Zhang

et al. 2005

Journal of Cell Science

225

152

View full text Add to dashboard Cite

Excess hydrogen peroxide (H2O2) is produced in the pathogenesis of brain injuries and neurodegenerative diseases. H2O2 may damage cells through direct oxidation of lipids, proteins and DNA or it can act as a signaling molecule to trigger intracellular pathways leading to cell death. In this study, H2O2 caused plasma membranes of primary astrocytes to become more gel-like, while artificial membranes of vesicles composed of rat brain lipid extract became more liquid crystalline-like. Besides the effects on membrane phase properties, H2O2 promoted actin polymerization, induced the formation of cell-to-cell tunneling nanotube (TNT)-like connections among astrocytes and increased the colocalization of myosin Va with F-actin. Myosin Va was also observed in the H2O2-induced F-actin-enriched TNT-like connections. Western blot analysis suggests that H2O2 triggered the phosphorylation of the p38 mitogen-activated protein kinase (MAPK), and that SB203580, a specific inhibitor of p38 MAPK, suppressed the changes in membrane phase properties and cytoskeleton resulting from H2O2 treatment. These results suggest that H2O2 alters astrocyte membranes and the cytoskeleton through activation of the p38 MAPK pathway.

show abstract

“…In rat AT2 cells and immortalised human airway epithelial cells (A549), cyclic mechanical strain increases ROS production in a dose-dependent manner once a critical threshold is reached [100], and the same has been seen in bovine pulmonary arteries [101]. A number of targets for ROS-induced permeability changes have been suggested, and include vascular endothelial growth factor (VEGF), endothelial growth factor and subsets of the mitogen-activated protein kinase cascades [102], yet the actual effector mechanisms downstream remain elusive.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Ventilator-associated lung injury: a search for better therapeutic targets

Oeckler¹,

Hubmayr²

2007

European Respiratory Journal

View full text Add to dashboard Cite

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a continuum of injury that may arise from a number of primary insults.Localised injury may progress due to trauma from mechanical ventilation, a finding that has led to intense debate in the clinical and experimental literature over optimal ventilator management. The implementation of low tidal volume strategies has led to an improvement in outcomes; however, mortality remains unacceptably high.In the current review, ventilator-associated lung injury is examined, as it relates to the pathophysiological changes beyond direct airway trauma in ALI and ARDS, and an attempt is made to provide a historical perspective to outline potential current and future pitfalls in the use of surrogate end-points and the discovery of potential biomarkers. The systemic responses that lead to multi-organ dysfunction, the leading causes of morbidity and mortality in ALI and ARDS, are caused by pro-inflammatory signalling cascades and the activation of such diverse mediators as reactive oxygen species, immune response elements, apoptotic constituents and coagulation proteins.These areas are examined, including key mediators, and possible future areas of interest are discussed, including the potential of an ''acute lung injury chip'' to integrate measured surrogate biomarkers with real-time clinical information to improve patient outcomes.

show abstract

Redox Regulation of Reactive Oxygen Species-Induced p38 MAP Kinase Activation and Barrier Dysfunction in Lung Microvascular Endothelial Cells

Cited by 131 publications

References 38 publications

Sustained Adenosine Exposure Causes Lung Endothelial Barrier Dysfunction via Nucleoside Transporter–Mediated Signaling

Sustained Adenosine Exposure Causes Lung Endothelial Barrier Dysfunction via Nucleoside Transporter–Mediated Signaling

Hydrogen peroxide alters membrane and cytoskeleton properties and increases intercellular connections in astrocytes

Ventilator-associated lung injury: a search for better therapeutic targets

Contact Info

Product

Resources

About