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. Two phase 3 clinical trials failed to show that β2AR agonists provide a survival advantage in ALI patients. We hypothesized that IL‐8, an important mediator of ALI, 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 downregulation (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 (>; 4,000 pg/ml) were associated with impaired AFC in ALI patients. These results demonstrate a novel role for IL‐8 in inhibiting β2AR agonist‐stimulated alveolar epithelial fluid transport via GRK2/PI3K‐dependent mechanisms.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
