特发性肺纤维化需要两种过氧化物酶体增殖激活受体(PPAR-β/δ 和 PPAR-γ)的共同作用。

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-09-23 DOI:10.1186/s12931-024-02935-7
Eistine Boateng, Rocio Bonilla-Martinez, Barbara Ahlemeyer, Vannuruswamy Garikapati, Mohammad Rashedul Alam, Omelyan Trompak, Gani Oruqaj, Natalia El-Merhie, Michael Seimetz, Clemens Ruppert, Andreas Günther, Bernhard Spengler, Srikanth Karnati, Eveline Baumgart-Vogt
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引用次数: 0

摘要

背景:特发性肺纤维化(IPF)的特点是肺上皮表型异常、成纤维细胞活化和细胞外基质沉积增加。转化生长因子-β(TGF-β)1 诱导的 Smad 信号转导和过氧化物酶体基因下调参与了发病机制,过氧化物酶体增殖激活受体(PPAR)-α 的激活可抑制这种信号转导。然而,已知三种 PPAR(即 PPAR-α、PPAR-β/δ 和 PPAR-γ)之间存在复杂的相互作用:方法:为了模拟肺纤维化的发病机制,用 TGF-β1 处理来自对照组和 IPF 患者的原代肺成纤维细胞 24 小时,然后单独或联合添加 PPAR 配体 24 小时。分析了TGF-β1处理后的纤维化标志物(细胞内和细胞外胶原蛋白水平、基质金属蛋白酶的表达和活性)和过氧化物酶体生物生成和代谢(过氧化物酶体生物生成和基质蛋白的基因表达、PEX13和过氧化氢酶的蛋白水平、靶向和非靶向脂质组图谱),并研究了PPAR配体的影响:结果:TGF-β1诱导了预期的表型,如增加了细胞内和细胞外胶原蛋白水平,减少了过氧化物酶体的生物生成和代谢。不同 PPARs 的激动剂可逆转 TGF-β1 诱导的纤维化,即使在 TGF-β1 24 小时后给药也是如此。这些效应包括:(1)通过抑制 COL1A2 启动子的活性(通过 PPAR-β/δ 激活)逆转胶原蛋白生成的增加;(2)降低基质金属蛋白酶的活性(通过 PPAR-β/δ 激活);(4)对照组(通过 PPAR-γ 激活)和 IPF(通过 PPAR-β/δ 和 PPAR-γ)成纤维细胞中过氧化氢酶蛋白水平的下降。进一步探索过氧化氢酶作用的实验表明,过氧化氢酶蛋白的过量表达减少了胶原蛋白的生成。此外,PPAR-γ 而非 PPAR-β/δ 激活对胶原合成的有益影响取决于过氧化氢酶的活性,因此对氧化还原反应敏感:我们的数据提供了 IPF 患者可能从 PPAR-β/δ 和 PPAR-γ 的联合激活中获益的证据。
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It takes two peroxisome proliferator-activated receptors (PPAR-β/δ and PPAR-γ) to tango idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung epithelial phenotypes, fibroblast activation, and increased extracellular matrix deposition. Transforming growth factor-beta (TGF-β)1-induced Smad signaling and downregulation of peroxisomal genes are involved in the pathogenesis and can be inhibited by peroxisome proliferator-activated receptor (PPAR)-α activation. However, the three PPARs, that is PPAR-α, PPAR-β/δ, and PPAR-γ, are known to interact in a complex crosstalk.

Methods: To mimic the pathogenesis of lung fibrosis, primary lung fibroblasts from control and IPF patients with comparable levels of all three PPARs were treated with TGF-β1 for 24 h, followed by the addition of PPAR ligands either alone or in combination for another 24 h. Fibrosis markers (intra- and extracellular collagen levels, expression and activity of matrix metalloproteinases) and peroxisomal biogenesis and metabolism (gene expression of peroxisomal biogenesis and matrix proteins, protein levels of PEX13 and catalase, targeted and untargeted lipidomic profiles) were analyzed after TGF-β1 treatment and the effects of the PPAR ligands were investigated.

Results: TGF-β1 induced the expected phenotype; e.g. it increased the intra- and extracellular collagen levels and decreased peroxisomal biogenesis and metabolism. Agonists of different PPARs reversed TGF-β1-induced fibrosis even when given 24 h after TGF-β1. The effects included the reversals of (1) the increase in collagen production by repressing COL1A2 promoter activity (through PPAR-β/δ activation); (2) the reduced activity of matrix metalloproteinases (through PPAR-β/δ activation); (3) the decrease in peroxisomal biogenesis and lipid metabolism (through PPAR-γ activation); and (4) the decrease in catalase protein levels in control (through PPAR-γ activation) and IPF (through a combined activation of PPAR-β/δ and PPAR-γ) fibroblasts. Further experiments to explore the role of catalase showed that an overexpression of catalase protein reduced collagen production. Additionally, the beneficial effect of PPAR-γ but not of PPAR-β/δ activation on collagen synthesis depended on catalase activity and was thus redox-sensitive.

Conclusion: Our data provide evidence that IPF patients may benefit from a combined activation of PPAR-β/δ and PPAR-γ.

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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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