Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan China.
Central laboratory, Kunming Medical University Second Hospital, Kunming, Yunnan, China.
Mol Immunol. 2020 Aug;124:109-116. doi: 10.1016/j.molimm.2020.05.017. Epub 2020 Jun 15.
Disordered collagen production by fibroblasts in response to tissue injury contributes to pulmonary fibrosis (PF). Therefore, elimination of collagen deposition has becoming a potential target in PF treatment which despite standard anti-fibrosis regiment still remains challenge. Curcumin and curcumol are regarded as the main active components extraction from the rhizomes of Curcuma zedoaria, which is widely used for inhibition the proliferation of multiple cells. However, the molecular basis for the function of curcumin and curcumol in limiting fibrogenesis still unknown. In this study, we have investigated the effects of curcumin and curcumol in the fibroblast overproliferation model human lung fibroblast (HLF) inducing by TGF-β1. The growth-inhibitory effects of the components wasn't observed from 8 to 64 μg/ml. Administration of curcumin or curcumol significantly diminished the level of hydroxyproline hydroxyproline and α-smooth muscle actin (α-SMA), also the collagen Ⅰ (Col-Ⅰ) and collagen Ⅲ (Col-Ⅲ) deposition were reduced in the HLF. Furthermore, related to the collagen synthesis proteins including N-terminal pro-peptide for Type Ⅰ collagen (PⅠNP), N-terminal pro-peptide for Type Ⅲ collagen (PⅢNP) and prolyl-hydroxylase (PHD) were degraded gracefully at dose-dependent manner. Autophagy as the scavenger was crippled in TGF-β1-fibroblast overproliferation HLF, conversely the increased autophagosomes have been spotted in cytoplasm under transmission electron microscope which is consistent with up-regulation of Beclin1 and ATG7 after treatment with curcumin or curcumol in this study. Additionally, blocking autophagy by inhibitor chloroquine (CQ) caused collagen deposition, providing further evidence regard to autophagy activation capacity of curcumin and curcumol. Our findings provide a detailed understanding that the function of curcumin and curcumol on decreasing collagen deposition mediating by autophagy mechanism, which may also inspire the further research on PF at different perspectives.
成纤维细胞对组织损伤的异常胶原产生导致肺纤维化（PF）。因此，消除胶原沉积已成为 PF 治疗的潜在靶点，尽管采用了标准的抗纤维化方案，但仍然具有挑战性。姜黄素和莪术醇被认为是从莪术根茎中提取的主要活性成分，广泛用于抑制多种细胞的增殖。然而，姜黄素和莪术醇在限制纤维化形成中的功能的分子基础仍然未知。在这项研究中，我们研究了姜黄素和莪术醇在 TGF-β1 诱导的人肺成纤维细胞（HLF）过度增殖模型中的作用。在 8 至 64μg/ml 的浓度范围内，没有观察到这些成分的生长抑制作用。姜黄素或莪术醇的给药显著降低了羟脯氨酸和α-平滑肌肌动蛋白（α-SMA）的水平，同时也减少了 HLF 中的胶原 Ⅰ（Col-Ⅰ）和胶原 Ⅲ（Col-Ⅲ）的沉积。此外，与胶原合成蛋白相关的包括Ⅰ型前胶原 N 端肽（PⅠNP）、Ⅲ型前胶原 N 端肽（PⅢNP）和脯氨酰-羟化酶（PHD）在内的相关蛋白也以剂量依赖的方式被降解。自噬作为清除剂在 TGF-β1-成纤维细胞过度增殖的 HLF 中受到破坏，相反，在透射电子显微镜下可以看到细胞质中增加的自噬体，这与本研究中用姜黄素或莪术醇处理后 Beclin1 和 ATG7 的上调一致。此外，通过抑制剂氯喹（CQ）阻断自噬会导致胶原沉积，这进一步证明了姜黄素和莪术醇激活自噬的能力。我们的研究结果提供了一个详细的认识，即姜黄素和莪术醇通过自噬机制减少胶原沉积的功能，这也可能从不同角度激发对 PF 的进一步研究。
