Transforming Growth Factor β1 Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-dependent cAMP-stimulated Alveolar Epithelial Fluid Transport via a Phosphatidylinositol 3-Kinase-dependent Mechanism
| Autor: | Marybeth Howard, Brian B. Chesebro, Walter E. Finkbeiner, Jérémie Roux, Kevan M. Shokat, Michael T. Ganter, Jean-Francois Pittet, Hidefumi Koh, Michel Carles, Arnaud Goolaerts, Michael A. Matthay, Benjamin T. Houseman, Agnes C. Paquet |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Cell Survival Blotting Western Cystic Fibrosis Transmembrane Conductance Regulator Shock Hemorrhagic Phosphatidylinositol 3-Kinases Biology Lung injury Biochemistry Rats Sprague-Dawley Transforming Growth Factor beta1 chemistry.chemical_compound Chlorides Adrenergic beta-2 Receptor Antagonists Internal medicine Cyclic AMP medicine Animals Humans Phosphatidylinositol Receptor Molecular Biology Cells Cultured Reverse Transcriptase Polymerase Chain Reaction Kinase Biological Transport Epithelial Cells Cell Biology respiratory system Epithelial fluid transport Cystic fibrosis transmembrane conductance regulator Rats Cell biology Pulmonary Alveoli Endocrinology chemistry biology.protein Receptors Adrenergic beta-2 Transforming growth factor |
| Zdroj: | Journal of Biological Chemistry. 285:4278-4290 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m109.036731 |
| Popis: | Exogenous or endogenous beta(2)-adrenergic receptor agonists enhance alveolar epithelial fluid transport via a cAMP-dependent mechanism that protects the lungs from alveolar flooding in acute lung injury. However, impaired alveolar fluid clearance is present in most of the patients with acute lung injury and is associated with increased mortality, although the mechanisms responsible for this inhibition of the alveolar epithelial fluid transport are not completely understood. Here, we found that transforming growth factor beta1 (TGF-beta1), a critical mediator of acute lung injury, inhibits beta(2)-adrenergic receptor agonist-stimulated vectorial fluid and Cl(-) transport across primary rat and human alveolar epithelial type II cell monolayers. This inhibition is due to a reduction in the cystic fibrosis transmembrane conductance regulator activity and biosynthesis mediated by a phosphatidylinositol 3-kinase (PI3K)-dependent heterologous desensitization and down-regulation of the beta(2)-adrenergic receptors. Consistent with these in vitro results, inhibition of the PI3K pathway or pretreatment with soluble chimeric TGF-beta type II receptor restored beta(2)-adrenergic receptor agonist-stimulated alveolar epithelial fluid transport in an in vivo model of acute lung injury induced by hemorrhagic shock in rats. The results demonstrate a novel role for TGF-beta1 in impairing the beta- adrenergic agonist-stimulated alveolar fluid clearance in acute lung injury, an effect that could be corrected by using PI3K inhibitors that are safe to use in humans. |
| Databáze: | OpenAIRE |
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