Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Ligand, Suppresses Bleomycin-Induced Acute Lung Injury and Fibrosis
Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Ligand, Suppresses Bleomycin-Induced Acute Lung Injury and Fibrosis
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DOI：
10.1159/000168676
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发表时间：
2009-01-01
期刊：
影响因子：
3.7
通讯作者：
Kurabayashi, Masahiko
中科院分区：
文献类型：
--
作者：
Aoki, Yasuhiro;Maeno, Toshitaka;Kurabayashi, Masahiko
背景：过氧化物酶体增殖物激活受体-γ（PPAR-gamma）配体已被证明具有有效的抗炎作用。特发性间质性肺炎被定义为慢性纤维化肺病的一种特殊形式，其特征在于进行性纤维化，导致肺的恶化和破坏。目标：研究过氧化物酶体增殖物激活受体γ配体吡格列酮（PGZ）是否抑制博莱霉素（BLM）诱导的急性肺损伤和随后的纤维化。方法：Wistar大鼠经气管内注射博莱霉素，再经前列环素（PGZ）处理。用BLM刺激大鼠肺泡巨噬细胞6 h，并与PGZ预处理18 h或不预处理18 h进行比较。MRC-5细胞（人肺成纤维细胞）用PGZ处理18小时。处理后，用转化生长因子-β（TGF-β）刺激细胞6小时。结果：PGZ从第7天开始抑制博莱霉素诱导的急性肺损伤和随后的肺纤维化。在第3天，PGZ治疗抑制了肺中炎性细胞的积聚和支气管肺泡灌洗液中肿瘤坏死因子-α（TNF-α）的浓度。PGZ还抑制BLM诱导的肺泡巨噬细胞中TNF-α的产生。此外，PGZ抑制肺纤维化的变化和羟脯氨酸含量的增加后，滴入博莱霉素，甚至当PGZ给药期间从第7天到第28天。北方印迹分析显示，PGZ抑制TGF-β诱导的MRC-5细胞中I型前胶原和结缔组织生长因子（CTGF）的表达。结论：这些结果表明，激活的过氧化物酶体增殖物激活物γ改善BLM诱导的急性炎症反应和纤维化的变化，至少部分通过抑制肿瘤坏死因子-α，前胶原I和CTGF的表达。这种PPAR γ配体对炎症和纤维化过程的有益作用为PPAR γ作为纤维增生性肺病分子靶点的潜在作用开辟了新的视角。版权所有（C）2008 S. Karger AG，巴塞尔
Background: Peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs. Objective: To investigate whether the PPAR gamma ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis. Methods: BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor-beta (TGF-beta) for 6 h. Results: PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day-7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-alpha production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-beta induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. Conclusion: These results suggest that activation of PPAR gamma ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-alpha, procollagen I and CTGF expression. Beneficial effects of this PPAR gamma ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPAR gamma as a molecular target in fibroproliferative lung diseases. Copyright (C) 2008 S. Karger AG, Basel