Stimulation by the ephrin-A1 ligand of the EphA2 receptor increases endothelial permeability. Lung injury increases the expression of EphA2, but the role of EphA2 in such injury is not well understood. To determine whether EphA2 contributes to changes in permeability and inflammation in the injured lung, we studied wild-type (WT) and EphA2 knockout (KO) mice, using isolated, perfused lung (IPL) preparations and a model of bleomycin-induced lung injury. We also studied the response of endothelial cells to ephrin-A1. In the IPL preparations, ephrin-A1 increased the filtration coefficient in WT mice, but not in EphA2 KO mice, demonstrating that EphA2 regulates vascular permeability. In early bleomycin injury in WT mice, the expression of both EphA2 and ephrin-A1 increased. EphA2 KO animals were protected from lung injury, showing less water and alveolar protein in the lungs than WT mice, consistent with reduced permeability. Bleomycin caused less accumulation of lung leukocytes in EphA2 KO animals than in WT animals, suggesting that EphA2 regulates inflammation. To determine whether EphA2 deficiency alters the production of chemokines, CXCL1 and CCL2 in the lungs were measured. After bleomycin injury, EphA2 KO animals produced less CXCL1 and CCL2 than WT animals. Because NF-kb mediates the production of chemokines, the effect of the ephrin-A1 ligand on the activation of NF-kb and the expression of chemokines was measured in endothelial cells. Ephrin-a1 significantly increased NFkb nuclear translocation and the expression of chemokine mRNA. This study demonstrates that the expression of EphA2 increases in the injured lung, and not only contributes to changes in permeability, but also plays a previously unrecognized role in promoting inflammatory responses.Keywords: chemokine; ephrin-A1; inflammation; vascular leakThe ephrins are a large family of receptor tyrosine kinases and ligands with demonstrated importance in both neural and vascular development. Ephrin ligands and Eph receptors are both cellsurface molecules, and as such, are primarily described to mediate cell-cell interactions, leading to either repulsive or attractive cell contacts and the regulation of behaviors such as axonal pathfinding in the central nervous system. Although less is known about the role of ephrins in the vasculature, some members of the family have been implicated in postnatal angiogenesis. In particular, the EphA2 receptor and its cognate ligand ephrin-A1 were shown to contribute to migration and tube formation in lung endothelial cells (1-3).Responses that promote cell migration and repulsive cell contacts are generally associated with a loss of cell-cell junctions, and might be expected to increase vascular permeability. We previously demonstrated that stimulation by the ephrin-A1 ligand leads both in vitro and in vivo to increases in lung endothelial permeability (4). These effects are associated with evidence of a breakdown of both adherens and tight junctions in endothelial cells. In addition, we recently presented data demonstra...

Larson J, Schomberg S, Schroeder W, Carpenter TC. Endothelial EphA receptor stimulation increases lung vascular permeability. Am J Physiol Lung Cell Mol Physiol 295: L431-L439, 2008. First published July 3, 2008 doi:10.1152/ajplung.90256.2008.-Mediators of angiogenesis such as VEGFs and angiopoietins may regulate pulmonary vascular permeability under normal and pathological conditions. Ephrin family receptor tyrosine kinases are expressed in the vasculature and also regulate angiogenesis under some circumstances, but whether they also modulate lung vascular permeability is unknown. We hypothesized that stimulation of lung endothelial EphA receptors with ephrin-a1 ligand would alter pulmonary vascular permeability and tested this idea in vivo and in vitro. We found that ephrin-a1 ligand and EphA2 receptors are expressed in distal normal lung vasculature and that their expression is increased in injured lung, suggesting a link to mechanisms of increased permeability. Intravenous injection of ephrin-a1 caused a large increase in the leakage of labeled albumin into the lungs of rats within 30 min (293 Ϯ 27 vs. 150 Ϯ 6 ng/mg dry lung, P Ͻ 0.01), along with histological evidence of the formation of endothelial disruptions. In cultured lung vascular endothelial cells, stimulation with ephrin-a1 increased monolayer permeability by 44% (P Ͻ 0.01), a permeability change similar to that seen with VEGF stimulation of the same cells. Ephrin-a1 stimulation in vivo and in vitro was associated with histological evidence for disruptions of tight and adherens junctions. These observations describe a novel role for ephrin-a1 and EphA receptors in the regulation of vascular permeability in the lung. ephrin; EphA2; pulmonary edema CONTROL OF PULMONARY VASCULAR permeability is a critical factor in the proper functioning of the lung, but the mechanisms regulating permeability remain incompletely understood. One interesting area that has drawn recent attention is the possible link between angiogenesis and vascular permeability (18). Current concepts of angiogenesis suggest that this process requires initial disruption followed by repair and stabilization of the endothelial barrier, which in turn suggests that "proangiogenic" mediators may have endothelial barrier regulatory properties. A growing body of evidence indicates that this is indeed the case.Three major families of receptor tyrosine kinases and ligands have been described to control the process of angiogenesis: VEGFs, angiopoietins, and ephrins. Members of two of these molecular families, VEGFs and angiopoietins, have been implicated in the control of vascular permeability and in the pathophysiology of human and experimental lung injuries (15,17,22,26). Although several ephrins are known to be expressed in pulmonary vascular cells, their physiological role in the lung is not known, and, in particular, whether ephrin family members regulate pulmonary vascular permeability has not been investigated. However, the EphA2 receptor and its cognate ligand ephrin-a1 have been reported...

Ephrin family receptor tyrosine kinases are mediators of angiogenesis that may also regulate endothelial barrier function in the lung. Previous work has demonstrated that stimulation of EphA ephrin receptors causes increased vascular leak in the intact lung and increased permeability in cultured endothelial cells. Whether EphA receptors are involved in the permeability changes associated with lung injury is unknown. We studied this question in young rats exposed to viral respiratory infection combined with exposure to moderate hypoxia, a previously described lung injury model. We found that the EphA2 receptor is expressed in normal lung and that EphA2 expression is markedly upregulated in the lungs of hypoxic infected (HV) rats compared with normal control animals. Immunohistochemistry showed increased EphA2 expression principally in areas of edematous alveolar septae. In HV rats, EphA2 antagonism with either the soluble decoy receptor EphA2/Fc or with monoclonal anti-EphA2 antibody reduced albumin extravasation and histological evidence of edema formation (P<0.01). Vascular leak in HV rats is mediated in large part by increased lung endothelin (ET) levels. In HV rats, ET receptor antagonism with bosentan resulted in reduced EphA2 mRNA and protein expression (P<0.01). Experiments with cultured rat lung microvascular endothelial cells demonstrated that ET increases endothelial EphA2 expression. These results suggest that EphA2 expression is increased in lung injury, contributes to vascular leak in the injured lung, and is regulated in endothelial cells by ET. EphA2 may be a previously unrecognized contributor to the pathophysiology of lung injury.

Flow cell batteries are of particular interest for applications of large-scale energy storage from renewable sources (e.g., wind, solar, etc.), as these energy sources are often intermittent or vary periodically. Recently, aqueous soluble organic redox species have been studied as alternative electrolytes to overcome the limitations of current vanadium chemistry, namely, low energy density, moderate charge/discharge efficiency, cost, and toxicity. Here, sulfonated derivatives of 4,4′-biphenol and 1,8-dihydroxy­anthraquinone were synthesized and electrochemically characterized to evaluate their potential battery performance. Long-term charge/discharge cycling measurements of the flow cell battery were obtained to determine the energy efficiency, charge capacity, and chemical stability of the electrolyte system. These electrolytes produced a standard cell potential of 0.905 V with a current density up to 0.8 A/cm2 and energy density of 45 Wh/L using 1 M electrolyte solutions, which is competitive with current vanadium-based electrolyte systems. The biphenol derivative appears to undergo a hydroxylation side reaction during charging cycles; however, once this reaction is complete Coulombic efficiency of the flow battery stabilizes at >95%.

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