title: Transforming growth factor-beta1 decreases expression of the epithelial sodium channel alphaENaC and alveolar epithelial vectorial sodium and fluid transport via an ERK1/2-dependent mechanism.
abstract: Acute lung injury (ALI) is characterized by the flooding of the alveolar airspaces with protein-rich edema fluid and diffuse alveolar damage. We have previously reported that transforming growth factor-beta1 (TGF-beta1) is a critical mediator of ALI after intratracheal administration of bleomycin or Escherichia coli endotoxin, at least in part due to effects on lung endothelial and alveolar epithelial permeability. In the present study, we hypothesized that TGF-beta1 would also decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we studied the effect of active TGF-beta1 on 22Na+ uptake across monolayers of primary rat and human alveolar type II (ATII) cells. TGF-beta1 significantly reduced the amiloride-sensitive fraction of 22Na+ uptake and fluid transport across monolayers of both rat and human ATII cells. TGF-beta1 also significantly decreased alphaENaC mRNA and protein expression and inhibited expression of a luciferase reporter downstream of the alphaENaC promoter in lung epithelial cells. The inhibitory effect of TGF-beta1 on sodium uptake and alphaENaC expression in ATII cells was mediated by activation of the MAPK, ERK1/2. Consistent with the in vitro results, TGF-beta1 inhibited the amiloride-sensitive fraction of the distal airway epithelial fluid transport in an in vivo rat model at a dose that was not associated with any change in epithelial protein permeability. These data indicate that increased TGF-beta1 activity in the distal airspaces during ALI promotes alveolar edema by reducing distal airway epithelial sodium and fluid clearance. This reduction in sodium and fluid transport is attributable in large part to a reduction in apical membrane alphaENaC expression mediated through an ERK1/2-dependent inhibition of the alphaENaC promoter activity.
authors.affiliation: Laboratory of Surgical Research, Cardiovascular Research Institute, Lung Biology Center, Departments of Anesthesia, Surgery, and Medicine, University of California, San Francisco, California 94110, USA.
authors.forename: James
authors.initials: J
authors.lastname: Frank
authors.forename: Jérémie
authors.initials: J
authors.lastname: Roux
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Kawakatsu
authors.forename: George
authors.initials: G
authors.lastname: Su
authors.forename: André
authors.initials: A
authors.lastname: Dagenais
authors.forename: Yves
authors.initials: Y
authors.lastname: Berthiaume
authors.forename: Marybeth
authors.initials: M
authors.lastname: Howard
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Canessa
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Fang
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pittet
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001826:Body Fluids / Q000378:metabolism*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D053503:Epithelial Sodium Channels; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000032:analysis / Q000235:genetics*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
chemical_list: D053503:Epithelial Sodium Channels; D005938:Glucocorticoids; D012333:RNA, Messenger; C440894:Scnn1a protein, rat; D015222:Sodium Channels; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000584:Amiloride; D003907:Dexamethasone; D012964:Sodium; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases