IL-8 inhibits cAMP-stimulated alveolar epithelial fluid transport via a GRK2/PI3K-dependent mechanism

FASEB J. 2013 Mar;27(3):1095-106. doi: 10.1096/fj.12-219295. Epub 2012 Dec 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / metabolism
  • Acute Lung Injury / pathology
  • Adrenergic beta-2 Receptor Agonists / pharmacology
  • Animals
  • Biological Transport, Active / drug effects
  • Cells, Cultured
  • Chemokine CXCL1 / metabolism
  • Chlorides / metabolism
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Extracellular Fluid / metabolism*
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • Humans
  • Interleukin-8 / metabolism*
  • Interleukin-8 / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Pulmonary Alveoli / metabolism*
  • Pulmonary Alveoli / pathology
  • Rats
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology

Substances

  • Adrenergic beta-2 Receptor Agonists
  • CXCL8 protein, human
  • Chemokine CXCL1
  • Chlorides
  • Cxcl1 protein, rat
  • Interleukin-8
  • GRK2 protein, human
  • Grk2 protein, rat
  • G-Protein-Coupled Receptor Kinase 2