Transforming Growth Factor-β1 Decreases Expression of the Epithelial Sodium Channel αENaC and Alveolar Epithelial Vectorial Sodium and Fluid Transport via an ERK1/2-dependent Mechanism
| Autor: | Yves Berthiaume, Jérémie Roux, George Su, Jean-Francois Pittet, Cecilia M. Canessa, André Dagenais, Xiaohui Fang, Hisaaki Kawakatsu, Marybeth Howard, Michael A. Matthay, James A. Frank, Dean Sheppard |
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| Rok vydání: | 2003 |
| Předmět: |
Epithelial sodium channel
Sodium Gene Expression chemistry.chemical_element Lung injury Biology Response Elements Transfection Biochemistry Dexamethasone Sodium Channels Amiloride Rats Sprague-Dawley Transforming Growth Factor beta1 Mice Transforming Growth Factor beta medicine Animals Humans RNA Messenger Epithelial Sodium Channels Luciferases Promoter Regions Genetic Glucocorticoids Molecular Biology Cells Cultured Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Water transport Lung Biological Transport Epithelial Cells Cell Biology respiratory system Apical membrane Fluid transport Epithelial fluid transport Body Fluids Rats Cell biology Enzyme Activation Pulmonary Alveoli medicine.anatomical_structure chemistry Immunology Mitogen-Activated Protein Kinases |
| Zdroj: | Journal of Biological Chemistry. 278:43939-43950 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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