Transforming growth factor beta1 inhibits cystic fibrosis transmembrane conductance regulator-dependent cAMP-stimulated alveolar epithelial fluid transport via a phosphatidylinositol 3-kinase-dependent mechanism.
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.
Roux
Jérémie
J
Laboratory of Surgical Research, Department of Anesthesia, University of California, San Francisco, California 94110, USA. Jeremie.Roux@gmail.com
Carles
Michel
M
Koh
Hidefumi
H
Goolaerts
Arnaud
A
Ganter
Michael T
MT
Chesebro
Brian B
BB
Howard
Marybeth
M
Houseman
Benjamin T
BT
Finkbeiner
Walter
W
Shokat
Kevan M
KM
Paquet
Agnès C
AC
Matthay
Michael A
MA
Pittet
Jean-François
JF
D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
D058672:Adrenergic beta-2 Receptor Antagonists; D002712:Chlorides; D018343:Receptors, Adrenergic, beta-2; D053773:Transforming Growth Factor beta1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases