Microvascular barrier integrity is dependent on bioavailable nitric oxide (NO) produced locally by endothelial NO synthase (eNOS). Under conditions of limited substrate or cofactor availability or by enzymatic modification, eNOS may become uncoupled, producing superoxide in lieu of NO. This study was designed to investigate how eNOS-dependent superoxide production contributes to endothelial barrier dysfunction in @entity651 and its regulation. C57BL/6J @entity19 were challenged with intratracheal @entity558 . Bronchoalveolar lavage fluid was analyzed for protein accumulation, and lung tissue homogenate was assayed for @entity13471 content and function. @entity1 lung microvascular endothelial cell (HLMVEC) monolayers were exposed to @entity558 in vitro, and barrier integrity and superoxide production were measured. Biopterin species were quantified, and coimmunoprecipitation (Co-IP) assays were performed to identify protein interactions with eNOS that putatively drive uncoupling. @entity19 exposed to @entity558 demonstrated eNOS-dependent @entity133 without evidence for altered canonical NO signaling. @entity558 -induced superoxide production and permeability in HLMVEC were inhibited by the NOS inhibitor nitro-l-arginine methyl ester, eNOS-targeted siRNA, the eNOS cofactor tetrahydrobiopterin, and superoxide dismutase. Co-IP indicated that @entity558 stimulated the association of eNOS with @entity8930 ( @entity8930 ), which correlated with augmented eNOS S-glutathionylation both in vitro and in vivo. In vitro, @entity8930 -specific inhibition prevented @entity558 -induced eNOS modification and increases in both superoxide production and permeability. These data indicate that eNOS uncoupling contributes to superoxide production and barrier dysfunction in the lung microvasculature after exposure to @entity558 . Furthermore, the results implicate @entity8930 -mediated eNOS-S-glutathionylation as a mechanism underlying @entity558 -induced eNOS uncoupling in the lung microvasculature.

@entity8930 -dependent glutathionylation of XXXX leads to uncoupled superoxide production and endothelial barrier dysfunction in acute lung injury.

@entity1 :: ('9606', 'Species') :: ['Human'] @entity558 :: ('MESH:C536528', 'Disease') :: ['LPS'] @entity19 :: ('10090', 'Species') :: ['mice', 'Mice'] @entity133 :: ('MESH:D002282', 'Disease') :: ['increased alveolar permeability'] @entity651 :: ('MESH:D055370', 'Disease') :: ['inflammatory lung injury'] @entity8930 :: ('13058(Tax:10090)', 'Gene') :: ['NADPH oxidase 2', 'Nox2'] @entity13471 :: ('18127(Tax:10090)', 'Gene') :: ['endothelial NOS']
@entity13471 :: (18127(Tax:10090),Gene) :: ['endothelial NOS']
