Department of Pulmonary and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China ; Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5910, USA.
Mediators Inflamm. 2013;2013:145197. doi: 10.1155/2013/145197. Epub 2013 Oct 8.
In the current study, we investigated the effect of a long-acting β -agonist (salmeterol) and a phosphodiesterase 4 (PDE4) inhibitor (cilomilast) on human lung fibroblast-mediated collagen gel contraction. Higher concentrations of salmeterol (10(-7) and 10(-6) M) inhibited fibroblast-mediated collagen gel contraction. No effect was observed with cilomilast alone (up to 10(-5) M). In the presence of 10(-8) M salmeterol, however, cilomilast could significantly inhibit fibroblast-mediated collagen gel contraction in a concentration-dependent manner (10(-7) ~10(-5) M). Blockade of endogenous PGE2 by indomethacin further potentiated the inhibitory effect of salmeterol on fibroblast-mediated collagen gel contraction, but it did not affect cilomilast's effect. Pretreatment with PGE2 abolished the inhibitory effect of salmeterol, but it potentiated the inhibitory effect of cilomilast on fibroblast-mediated collagen gel contraction. Finally, indomethacin slightly inhibited PDE4C expression, while PGE2 stimulated the expression of PDE4A and -4C in human lung fibroblasts. These findings suggest that long-acting β -agonist and PDE4 inhibitor have a synergistic effect in regulating fibroblast tissue repair functions and that PGE2 can modulate the effect of β -agonist and PDE4 inhibitor at least in part through the mechanism of regulating PDE4 expression.
在当前的研究中，我们研究了长效β-激动剂（沙美特罗）和磷酸二酯酶 4（PDE4）抑制剂（西罗莫司特）对人肺成纤维细胞介导的胶原凝胶收缩的影响。较高浓度的沙美特罗（10（-7）和 10（-6）M）抑制成纤维细胞介导的胶原凝胶收缩。单独使用西罗莫司特（高达 10（-5）M）没有观察到效果。然而，在 10（-8）M 沙美特罗存在的情况下，西罗莫司特可以显著地以浓度依赖的方式抑制成纤维细胞介导的胶原凝胶收缩（10（-7）~10（-5）M）。通过吲哚美辛阻断内源性 PGE2 进一步增强了沙美特罗对成纤维细胞介导的胶原凝胶收缩的抑制作用，但不影响西罗莫司特的作用。PGE2 的预处理消除了沙美特罗的抑制作用，但增强了西罗莫司特对成纤维细胞介导的胶原凝胶收缩的抑制作用。最后，吲哚美辛轻度抑制 PDE4C 的表达，而 PGE2 刺激人肺成纤维细胞中 PDE4A 和 -4C 的表达。这些发现表明，长效β-激动剂和 PDE4 抑制剂在调节成纤维细胞组织修复功能方面具有协同作用，PGE2 可以通过调节 PDE4 表达的机制至少部分地调节β-激动剂和 PDE4 抑制剂的作用。
