title: IL-8 inhibits cAMP-stimulated alveolar epithelial fluid transport via a GRK2/PI3K-dependent mechanism.
abstract: Patients with acute lung injury (ALI) who retain maximal alveolar fluid clearance (AFC) have better clinical outcomes. Experimental and small clinical studies have shown that β2-adrenergic receptor (β2AR) agonists enhance AFC via a cAMP-dependent mechanism. However, two multicenter phase 3 clinical trials failed to show that β2AR agonists provide a survival advantage in patients with ALI. We hypothesized that IL-8, an important mediator of ALI, directly antagonizes the alveolar epithelial response to β2AR agonists. Short-circuit current and whole-cell patch-clamping experiments revealed that IL-8 or its rat analog CINC-1 decreases by 50% β2AR agonist-stimulated vectorial Cl(-) and net fluid transport across rat and human alveolar epithelial type II cells via a reduction in the cystic fibrosis transmembrane conductance regulator activity and biosynthesis. This reduction was mediated by heterologous β2AR desensitization and down-regulation (50%) via the G-protein-coupled receptor kinase 2 (GRK2)/PI3K signaling pathway. Inhibition of CINC-1 restored β2AR agonist-stimulated AFC in an experimental model of ALI in rats. Finally, consistent with the experimental results, high pulmonary edema fluid levels of IL-8 (>4000 pg/ml) were associated with impaired AFC in patients with ALI. These results demonstrate a novel role for IL-8 in inhibiting β2AR agonist-stimulated alveolar epithelial fluid transport via GRK2/PI3K-dependent mechanisms.-Roux, J., McNicholas, C. M., Carles, M., Goolaerts, A., Houseman, B. T., Dickinson, D. A., Iles, K. E., Ware, L. B., Matthay, M. A., Pittet, J.-F. IL-8 inhibits cAMP-stimulated alveolar epithelial fluid transport via a GRK2/PI3K-dependent mechanism.
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, San Francisco, California, USA.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Roux
authors.forename: Carmel M
authors.initials: CM
authors.lastname: McNicholas
authors.forename: Michel
authors.initials: M
authors.lastname: Carles
authors.forename: Arnaud
authors.initials: A
authors.lastname: Goolaerts
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Houseman
authors.forename: Dale A
authors.initials: DA
authors.lastname: Dickinson
authors.forename: Karen E
authors.initials: KE
authors.lastname: Iles
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pittet
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D045604:Extracellular Fluid / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D054360:Chemokine CXCL1; D002712:Chlorides; D054769:G-Protein-Coupled Receptor Kinase 2; D016209:Interleukin-8; D019869:Phosphatidylinositol 3-Kinases; C508606:CXCL8 protein, human; C513297:Cxcl1 protein, rat; C496567:GRK2 protein, human; C496569:Grk2 protein, rat