White Kimberly E, Ding Qiang, Moore Bethany B, Peters-Golden Marc, Ware Lorraine B, Matthay Michael A, Olman Mitchell A
Department of Medicine, University of Alabama at Birmingham 35294, USA.
J Immunol. 2008 Jan 1;180(1):637-46. doi: 10.4049/jimmunol.180.1.637.
The fibroproliferative response to acute lung injury (ALI) results in severe, persistent respiratory dysfunction. We have reported that IL-1beta 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-1beta-mediated induction of cyclooxygenase-2 and PGE2, and evaluate the significance of individual E prostanoid (EP) receptors in mediating the fibroproliferative effects of IL-1beta in ALI. Blocking studies on human lung fibroblasts indicate that IL-1beta is the major cyclooxygenase-2 mRNA and PGE2-inducing factor in pulmonary edema fluid and accounts for the differential PGE2 induction noted in samples from ALI patients. Surprisingly, we found that PGE2 produced by IL-1beta-stimulated fibroblasts enhances fibroblast proliferation. Further studies revealed that the effect of fibroblast proliferation is biphasic, with the promitogenic effect of PGE2 noted at concentrations close to that detected in pulmonary edema fluid from ALI patients. The suppressive effects of PGE2 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 PGE2 were mimicked by the EP3-selective agent, sulprostone, by cAMP reduction, and lost upon inhibition of Gi-mediated signaling with pertussis toxin. Taken together, these data demonstrate that PGE2 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.
对急性肺损伤（ALI）的纤维增殖反应会导致严重且持续的呼吸功能障碍。我们曾报道，在ALI患者的肺水肿液中白细胞介素-1β（IL-1β）水平升高，并介导一条自分泌作用的成纤维细胞促有丝分裂途径。在本研究中，我们探究了IL-1β介导的环氧化酶-2（COX-2）和前列腺素E2（PGE2）诱导作用的作用，并评估了各前列腺素E受体（EP受体）在介导IL-1β对ALI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-1β是肺水肿液中主要的COX-2信使核糖核酸和PGE2诱导因子，并且是ALI患者样本中PGE2诱导差异的原因。令人惊讶的是，我们发现IL-1β刺激的成纤维细胞产生的PGE2会增强成纤维细胞增殖。进一步研究显示，成纤维细胞增殖效应具有双相性，在接近ALI患者肺水肿液中检测到的浓度时PGE2具有促有丝分裂作用。EP2选择性受体激动剂布他前列素通过激活环磷酸腺苷（cAMP）模拟了PGE2的抑制作用，而在缺乏EP2的小鼠肺成纤维细胞中这种作用消失。相反，中浓度PGE2的促有丝分裂作用被EP3选择性药物舒洛地尔通过降低cAMP模拟，并且在用百日咳毒素抑制Gi介导的信号传导后这种作用消失。综上所述，这些数据表明，PGE2在临床相关浓度下可分别通过EP3或EP2受体的优先信号传导刺激或抑制成纤维细胞增殖。此类机制可能驱动对ALI的纤维增殖反应。
