Lipoxin A4 Attenuates Constitutive and TGF-β1-Dependent Profibrotic Activity in Human Lung Myofibroblasts.
Lipoxin A4 Attenuates Constitutive and TGF-β1-Dependent Profibrotic Activity in Human Lung Myofibroblasts.
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DOI：
10.4049/jimmunol.1500936
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Bradding P
中科院分区：
文献类型：
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作者：
Roach KM;Feghali-Bostwick CA;Amrani Y;Bradding P
特发性肺纤维化（IPF）是一种常见的、进行性的、总是致命的间质性肺疾病，目前尚无有效的治疗方法。驱动纤维化发展的关键细胞是肌成纤维细胞。脂氧素 A4 (LXA4) 是一种抗炎脂质，对于消退炎症很重要，并且具有潜在的抗纤维化活性。然而，之前尚未研究过 LXA4 对原代人肺肌成纤维细胞 (HLMF) 的影响。因此，本研究的目的是检查 LXA4 对 IPF 和非纤维化对照 (NFC) 衍生的 HLMF 中 TGF-β1 依赖性反应的影响。 HLMF 从 IPF 和 NFC 患者中分离出来并在体外生长。在 TGF-β1 刺激后，组成性检查了 LXA4 对 HLMF 增殖、胶原蛋白分泌、α-平滑肌肌动蛋白 (αSMA) 表达和 Smad2/3 激活的影响。 LXA4 受体 (ALXR) 在 NFC 和 IPF 衍生的 HLMF 中表达。 LXA4（10−10 和 10−8 mol）减少组成型 αSMA 表达、肌动蛋白应力纤维形成、收缩和核 Smad2/3，表明从肌成纤维细胞表型回归到成纤维细胞表型。 LXA4 还显着抑制 IPF 衍生的 HLMF 中 FBS 依赖性增殖和 TGF-β1 依赖性胶原分泌、αSMA 表达和 Smad2/3 核转位。 LXA4 不抑制 Smad2/3 磷酸化。总之，LXA4 减弱了促纤维化 HLMF 活性，并促进 HLMF 退化为静止的成纤维细胞表型。通过气雾剂输送的 LXA4 或其稳定类似物可能为治疗 IPF 提供一种新方法。
Idiopathic pulmonary fibrosis (IPF) is a common, progressive, and invariably lethal interstitial lung disease with no effective therapy. The key cell driving the development of fibrosis is the myofibroblast. Lipoxin A4 (LXA4) is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts (HLMFs) have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on TGF-β1–dependent responses in IPF- and nonfibrotic control (NFC)–derived HLMFs. HLMFs were isolated from IPF and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, α-smooth muscle actin (αSMA) expression, and Smad2/3 activation were examined constitutively and following TGF-β1 stimulation. The LXA4 receptor (ALXR) was expressed in both NFC- and IPF-derived HLMFs. LXA4 (10−10 and 10−8 mol) reduced constitutive αSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and TGF-β1–dependent collagen secretion, αSMA expression, and Smad2/3 nuclear translocation in IPF-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of IPF.