Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Biochem Pharmacol. 2010 Sep 15;80(6):920-31. doi: 10.1016/j.bcp.2010.05.025. Epub 2010 Jun 1.
Idiopathic pulmonary fibrosis (IPF) involves infiltration of leucocytes, pulmonary injury, fibrosis and resulting pulmonary dysfunction. Myofibroblasts and transforming growth factor (TGF)-beta1 have been suggested to play a major role in the pathology and the myofibroblasts are derived from both lung epithelial cells through epithelial-mesenchymal transition (EMT) and activation of lung fibroblasts. Heat shock protein 70 (HSP70) confers protection against various stressors and has the anti-inflammatory activity. In this study, we examined the effect of expression of HSP70 on bleomycin-induced pulmonary fibrosis in mice, a tentative animal model of IPF. Bleomycin-induced pulmonary injury and inflammatory response were ameliorated in transgenic mice overexpressing HSP70 compared to wild-type mice, even though bleomycin-induced pulmonary fibrosis and dysfunction were also suppressed in the transgenic mice. The production of TGF-beta1 and expression of pro-inflammatory cytokines was lower in cells from the transgenic mice than wild-type mice after the administration of bleomycin. In vitro, the suppression of HSP70 expression stimulated TGF-beta1-induced EMT-like phenotypes of epithelial cells but did not affect the TGF-beta1-dependent activation of fibroblasts. Orally administered geranylgeranylacetone (GGA), a clinically used drug with HSP-inducing activity, conferred protection against bleomycin-induced pulmonary injury, as well as against the inflammatory response, fibrosis and dysfunction. These results suggest that HSP70 plays a protective role against bleomycin-induced pulmonary injury, inflammation, fibrosis and dysfunction through cytoprotective effects and by inhibiting the production of TGF-beta1, TGF-beta1-dependent EMT of epithelial cells and expression of pro-inflammatory cytokines. Results also suggest that HSP70-inducing drugs, such as GGA, could be beneficial in the prophylaxis of IPF.
特发性肺纤维化（IPF）涉及白细胞浸润、肺损伤、纤维化和由此导致的肺功能障碍。肌成纤维细胞和成纤维细胞生长因子（TGF）-β1 被认为在病理学中起主要作用，肌成纤维细胞来源于肺上皮细胞，通过上皮-间充质转化（EMT）和肺成纤维细胞的激活。热休克蛋白 70（HSP70）赋予其抵抗各种应激的能力，并具有抗炎活性。在这项研究中，我们研究了 HSP70 的表达对博莱霉素诱导的肺纤维化的影响，这是 IPF 的一种动物模型。与野生型小鼠相比，过表达 HSP70 的转基因小鼠的博莱霉素诱导的肺损伤和炎症反应得到改善，尽管转基因小鼠的博莱霉素诱导的肺纤维化和功能障碍也受到抑制。博莱霉素给药后，来自转基因小鼠的细胞中 TGF-β1 的产生和促炎细胞因子的表达低于野生型小鼠。在体外，抑制 HSP70 表达刺激上皮细胞的 TGF-β1 诱导的 EMT 样表型，但不影响 TGF-β1 依赖性成纤维细胞的激活。口服使用具有 HSP 诱导活性的临床药物香叶基丙酮（GGA）可预防博莱霉素诱导的肺损伤以及炎症反应、纤维化和功能障碍。这些结果表明，HSP70 通过细胞保护作用和抑制 TGF-β1 的产生、TGF-β1 依赖性 EMT 的上皮细胞和促炎细胞因子的表达，对博莱霉素诱导的肺损伤、炎症、纤维化和功能障碍发挥保护作用。结果还表明，HSP70 诱导药物，如 GGA，可能有益于 IPF 的预防。
