Prostaglandin E2 mediates IL-1β-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors
Prostaglandin E2 mediates IL-1β-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors
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DOI：
10.4049/jimmunol.180.1.637
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发表时间：
2008-01-01
影响因子：
4.4
通讯作者：
Olman, Mitchell A.
中科院分区：
文献类型：
--
作者：
White, Kimberly E.;Ding, Qiang;Olman, Mitchell A.
急性肺损伤（ALI）的纤维增生反应导致严重的、持续的呼吸功能障碍。我们已经报道，IL-1 β在ALI患者的肺水肿液中升高，并介导自分泌作用的成纤维细胞有丝分裂途径。在这项研究中，我们检测了IL-1 β介导的环氧合酶-2和PGE（2）的诱导作用，并评估了单个E前列腺素（EP）受体在介导IL-1 β在ALI中的纤维增殖作用中的意义。对人肺成纤维细胞的阻断研究表明，IL-1 β是肺水肿液中主要的环氧合酶-2 mRNA和PGE（2）诱导因子，并解释了在ALI患者样本中观察到的不同PGE（2）诱导。令人惊讶的是，我们发现由IL-1 β刺激的成纤维细胞产生的PGE（2）增强成纤维细胞增殖。进一步的研究表明，成纤维细胞增殖的作用是双相的，PGE（2）的促有丝分裂作用在接近ALI患者肺水肿液中检测到的浓度下观察到。PGE（2）的抑制作用被EP 2选择性受体激动剂布他前列素通过cAMP激活模拟，并且在缺乏EP 2的小鼠肺成纤维细胞中丧失。相反，中等浓度的PGE的促有丝分裂作用被EP 3选择剂硫前列酮通过cAMP还原模拟，并且在用百日咳毒素抑制G（i）介导的信号传导后丧失。总之，这些数据表明，PGE（2）可以刺激或抑制成纤维细胞增殖在临床相关浓度，通过优先信号通过EP 3或EP 2受体，分别。这些机制可能驱动对ALI的纤维增生反应。
The fibroproliferative response to acute lung injury (ALI) results in severe, persistent respiratory dysfunction. We have reported that IL-1 beta is elevated in pulmonary edema fluid in those with ALI and mediates an autocrine-acting, fibroblast mitogenic pathway. In this study, we examine the role of IL-1 beta-mediated induction of cyclooxygenase-2 and PGE(2), and evaluate the significance of individual E prostanoid (EP) receptors in mediating the fibroproliferative effects of IL-1 beta in ALI. Blocking studies on human lung fibroblasts indicate that IL-1 beta is the major cyclooxygenase-2 mRNA and PGE(2)-inducing factor in pulmonary edema fluid and accounts for the differential PGE(2) induction noted in samples from ALI patients. Surprisingly, we found that PGE(2) produced by IL-1 beta-stimulated fibroblasts enhances fibroblast proliferation. Further studies revealed that the effect of fibroblast proliferation is biphasic, with the promitogenic effect of PGE(2) noted at concentrations close to that detected in pulmonary edema fluid from ALI patients. The suppressive effects of PGE(2) were mimicked by the EP2-selective receptor agonist, butaprost, by cAMP activation, and were lost in murine lung fibroblasts that lack EP2. Conversely, the promitogenic effects of mid-range concentrations of PGE, were mimicked by the EP3-selective agent, sulprostone, by cAMP reduction, and lost upon inhibition of G(i)-mediated signaling with pertussis toxin. Taken together, these data demonstrate that PGE(2) can stimulate or inhibit fibroblast proliferation at clinically relevant concentrations, via preferential signaling through EP3 or EP2 receptors, respectively. Such mechanisms may drive the fibroproliferative response to ALI.