Transforming Growth Factor‐β1 Inhibits CFTR‐dependent cAMP‐stimulated Alveolar Epithelial Fluid Transport: Critical Role of Interleukin‐8

Abstract

β‐adrenergic agonist‐dependent stimulation of the lung fluid clearance is an important mechanism that protects the lung from alveolar flooding. In this study we hypothesized that critical mediators of acute lung injury (ALI), such as transforming growth factor‐β1 (TGF‐β1) and interleukin‐8 (IL‐8), could directly antagonize the epithelial response to β‐adrenergic agonists. Short circuit current experiments revealed that TGF‐β1 inhibits CFTR‐specific β‐agonist‐stimulated vectorial Cl‐transport across the apical membrane of primary rat and human alveolar epithelial type II (ATII). TGF‐β1 also significantly decreased β‐agonist‐stimulated cAMP production resulting in the inhibition of the CFTR promoter activity and gene expression in ATII cells. We found that this TGF‐β1‐dependent inhibition required IL‐8 and was mediated by desensitization the β‐adrenergic receptor through both TGF‐β1 and IL‐8 signaling pathways. Consistent with the in vitro results, we showed that TGF‐β1 requires IL‐8 to inhibit the β‐agonist‐stimulated fluid transport across the distal airspace epithelium in vivo in rats. In summary, the results show for the first time that TGF‐β1 and IL‐8 inhibit the stimulated vectorial chloride transport across the distal lung epithelium, thus impairing the β‐adrenergic‐dependent protective mechanism against alveolar flooding.NIH P50HL074005 (JFP), ALA Award and T32 GM008440 (JR)