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IL‐8 Inhibits cAMP‐stimulated Alveolar Epithelial Fluid Transport via a GRK2/PI3K‐dependent Mechanism
Author(s) -
Wagener Brant M,
Roux Jeremie,
McNicholas Carmel M.,
Carles Michel,
Goolaerts Arnaud,
Houseman Benjamin T.,
Dickinson Dale A.,
Iles Karen E.,
Ware Lorraine B.,
Matthay Michael A.,
Pittet JeanFrancois
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.913.6
Subject(s) - agonist , chemistry , downregulation and upregulation , receptor , endocrinology , medicine , pi3k/akt/mtor pathway , signal transduction , pharmacology , microbiology and biotechnology , biology , biochemistry , gene
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 β 2 ‐adrenergic receptor (β 2 AR) agonists enhance AFC via a cAMP–dependent mechanism. Two phase 3 clinical trials failed to show that β 2 AR agonists provide a survival advantage in ALI patients. We hypothesized that IL‐8, an important mediator of ALI, antagonizes the alveolar epithelial response to β 2 AR agonists. Short‐circuit current and whole‐cell patch‐clamping experiments revealed that IL‐8 or its rat analog CINC‐1 decreases by 50% β 2 AR 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 β 2 AR desensitization and downregulation (50%) via the G‐protein coupled receptor kinase 2 (GRK2)/PI3K signaling pathway. Inhibition of CINC‐1 restored β 2 AR 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 (>; 4,000 pg/ml) were associated with impaired AFC in ALI patients. These results demonstrate a novel role for IL‐8 in inhibiting β 2 AR agonist‐stimulated alveolar epithelial fluid transport via GRK2/PI3K‐dependent mechanisms.

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