Firestone Institure for Respiratory Health, St Joseph's Healthcare, Dept of Medicine, McMaster University, Hamilton, Ontario, Canada.
Eur Respir J. 2013 Feb;41(2):425-32. doi: 10.1183/09031936.00145009. Epub 2012 May 31.
Airway smooth muscle cells produce extracellular matrix proteins, which in turn can promote smooth muscle survival, proliferation and migration. Currently available therapies have little effect on airway smooth muscle matrix production and migration. Peroxisome proliferator-activated receptor (PPAR) ligands are reported to decrease migration and matrix production in various cell lines. In this study, we examined the effect of PPAR ligands on human airway smooth muscle (HASM) matrix production and migration. PPAR expression was examined by RT-PCR and Western blotting. Endogenous PPAR activity was examined by transfecting cells with a PPAR response element-luciferase reporter plasmid. We observed that HASM cells express PPARα, β and γ. A six-fold induction of luciferase activity was observed by stimulating cells with a pan-agonist, indicating endogenous PPAR activity. The PPAR ligands ciglitazone, 15-deoxy-Δ12,14-prostaglandin J(2) and WY-14643 decreased migration towards platelet-derived growth factor receptor. This was not mediated by inhibiting Akt phosphorylation or promoting PTEN activity, but partly through cyclooxygenase-2 induction and prostaglandin E(2) production that increased cyclic AMP levels in the cells. All three ligands also caused an inhibition of collagen and fibronectin secretion by cultured smooth muscle cells. We conclude that PPAR ligands decrease HASM migration and matrix production and are, therefore, potentially useful for modulating airway remodelling.
气道平滑肌细胞产生细胞外基质蛋白，这些蛋白反过来又可以促进平滑肌的存活、增殖和迁移。目前的治疗方法对气道平滑肌基质的产生和迁移几乎没有影响。过氧化物酶体增殖物激活受体（PPAR）配体被报道可以减少各种细胞系中的迁移和基质产生。在这项研究中，我们研究了 PPAR 配体对人气道平滑肌（HASM）基质产生和迁移的影响。通过 RT-PCR 和 Western blot 检查 PPAR 的表达。通过用 PPAR 反应元件-荧光素酶报告质粒转染细胞来检查内源性 PPAR 活性。我们观察到 HASM 细胞表达 PPARα、β 和γ。用泛激动剂刺激细胞，观察到荧光素酶活性增加了六倍，表明内源性 PPAR 活性。PPAR 配体 ciglitazone、15-deoxy-Δ12,14-prostaglandin J(2) 和 WY-14643 可降低对血小板衍生生长因子受体的迁移。这不是通过抑制 Akt 磷酸化或促进 PTEN 活性来介导的，而是部分通过诱导环加氧酶-2 和前列腺素 E(2) 的产生，从而增加细胞中环腺苷酸水平。这三种配体也导致培养的平滑肌细胞中胶原蛋白和纤维连接蛋白分泌减少。我们得出结论，PPAR 配体可减少 HASM 迁移和基质产生，因此对调节气道重塑具有潜在用途。
