Acute respiratory distress syndrome (ARDS) is a life-threatening illness characterized by decreased alveolar-capillary barrier function, pulmonary edema consisting of proteinaceous fluid, and inhibition of net alveolar fluid transport responsible for resolution of pulmonary edema. There is currently no pharmacotherapy that has proven useful to prevent or treat ARDS, and two trials using beta-agonist therapy to treat ARDS demonstrated no effect. Prior studies indicated that IL-8-induced heterologous desensitization of the beta2-adrenergic receptor (β₂-AR) led to decreased beta-agonist-induced mobilization of cyclic adenosine monophosphate (cAMP). Interestingly, phosphodiesterase (PDE) 4 inhibitors have been used in human airway diseases characterized by low intracellular cAMP levels and increases in specific cAMP hydrolyzing activity. Therefore, we hypothesized that PDE4 would mediate IL-8-induced heterologous internalization of the β₂-AR and that PDE4 inhibition would restore beta-agonist-induced functions. We determined that CINC-1 (a functional IL-8 analog in rats) induces internalization of β₂-AR from the cell surface, and arrestin-2, PDE4, and β₂-AR form a complex during this process. Furthermore, we determined that cAMP associated with the plasma membrane was adversely affected by β₂-AR heterologous desensitization. Additionally, we determined that rolipram, a PDE4 inhibitor, reversed CINC-1-induced derangements of cAMP and also caused β₂-AR to successfully recycle back to the cell surface. Finally, we demonstrated that rolipram could reverse CINC-1-mediated inhibition of beta-agonist-induced alveolar fluid clearance in a murine model of trauma-shock. These results indicate that PDE4 plays a role in CINC-1-induced heterologous internalization of the β₂-AR; PDE4 inhibition reverses these effects and may be a useful adjunct in particular ARDS patients.

中文翻译：

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磷酸二酯酶 4 介导白细胞介素 8 诱导的 β2 肾上腺素能受体异源脱敏

急性呼吸窘迫综合征 (ARDS) 是一种危及生命的疾病，其特征是肺泡-毛细血管屏障功能下降、由蛋白质液体组成的肺水肿以及导致肺水肿消退的肺泡液体净运输受到抑制。目前还没有药物疗法被证明对预防或治疗 ARDS 有用，两项使用 β 受体激动剂疗法治疗 ARDS 的试验证明没有效果。先前的研究表明，IL-8 诱导的 β2-肾上腺素能受体（_β2-AR) 导致β-激动剂诱导的环磷酸腺苷 (cAMP) 动员减少。有趣的是，磷酸二酯酶 (PDE) 4 抑制剂已用于以细胞内 cAMP 水平低和特定 cAMP 水解活性增加为特征的人类气道疾病。因此，我们假设 PDE4 会介导 IL-8 诱导的 β ₂ -AR 的异源内化，并且 PDE4 抑制会恢复 β 激动剂诱导的功能。我们确定 CINC-1（大鼠中的一种功能性 IL-8 类似物）诱导 β ₂ -AR 从细胞表面内化，并且在此过程中抑制蛋白 2、PDE4 和 β ₂ -AR 形成复合物。此外，我们确定与质膜相关的 cAMP 受到 β _{2的不利影响}-AR异源脱敏。此外，我们确定咯利普兰（一种 PDE4 抑制剂）逆转了 CINC-1 诱导的 cAMP 紊乱，并且还导致 β ₂ -AR 成功循环回细胞表面。最后，我们证明咯利普兰可以在创伤休克小鼠模型中逆转 CINC-1 介导的对 β 受体激动剂诱导的肺泡液清除的抑制作用。这些结果表明 PDE4 在 CINC-1 诱导的 β ₂ -AR 异源内化中起作用；PDE4 抑制可逆转这些作用，并可能成为特定 ARDS 患者的有用辅助手段。