Transforming Growth Factor β1 Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-dependent cAMP-stimulated Alveolar Epithelial Fluid Transport via a Phosphatidylinositol 3-Kinase-dependent Mechanism

Abstract

Exogenous or endogenous ␤ 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 ␤1 (TGF-␤1), a critical mediator of acute lung injury, inhibits ␤ 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 ␤ 2 -adrenergic receptors. Consistent with these in vitro results, inhibition of the PI3K pathway or pretreatment with soluble chimeric TGF-␤ type II receptor restored ␤ 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-␤1 in impairing the ␤-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.

Transforming Growth Factor-β1 and Cigarette Smoke Inhibit the Ability of β2-Agonists to Enhance Epithelial Permeability

“…CS is known to induce TGF-b1 signaling (26,31). Addition of a TGF-b receptor (TGFBR)-2 neutralizing antibody to the apical and basolateral side of cultures before smoke exposure prevented the effects of CS described previously here, and restored the ability of albuterol to increase epithelial permeability compared with cells treated with goat IgG alone ( Figure 6A).…”

Cytoprotective-Selective Activated Protein C Attenuates Pseudomonas aeruginosa–Induced Lung Injury in Mice

“…One of the major mechanisms mediating the activation of TGF-b1 in the distal lung epithelium is the activation of RhoA by IL-1b or thrombin agonists, resulting in a avb6-integrin-mediated activation of TGF-b1 in alveolar epithelial cells (15). Furthermore, TGF-b1 mediates an increase in protein permeability and an inhibition of baseline and c-AMP-dependent vectorial fluid transport across the alveolar-epithelial barrier in experimental rodent models of acute lung injury (23). Finally, we recently demonstrated that P. aeruginosa increased protein permeability across rat alveolar epithelial Type II cell monolayers, an effect that was inhibited by a specific inhibitor of RhoA or a soluble Type II receptor for TGF-b1 (13,14).…”

Transforming growth factor-β1 impairs CFTR-mediated anion secretion across cultured porcine vas deferens epithelial monolayer via the p38 MAPK pathway

“…TGF-␤1 exposure led to a significant reduction in the magnitude of the response to forskolin or a cAMP analog in colonic epithelia, T84 and HT-29 cells, and in kidney epithelia, MadinDarby canine kidney cells, by changing the expression and distribution of CFTR (18,19). A similar role of TGF-␤1 to reduce cAMP-driven anion secretion and CFTR expression has been identified in lung and airway epithelial cells (38,39). The present report demonstrates that TGF-␤1 downregulates the gene expression of CFTR, its protein abundance, and especially the protein abundance of functional CFTR in the cell surface.…”

“…the effect of TGF-␤1 on vas deferens epithelia (18,19,38,39). TGF-␤1 exposure led to a significant reduction in the magnitude of the response to forskolin or a cAMP analog in colonic epithelia, T84 and HT-29 cells, and in kidney epithelia, MadinDarby canine kidney cells, by changing the expression and distribution of CFTR (18,19).…”

“…TGF-␤1 inhibited fluid transport across ATII monolayers through a phosphatidylinositol 3-kinase-dependent mechanism (39). Sodium and fluid transport across ATII monolayers were decreased by TGF-␤1 through an ERK1/2-dependent mechanism (13).…”