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Abstract：
BACKGROUND: Peel of Citrus reticulata, a Chinese herbal drug with functions of regulating Qi and expelling phlegm, has been used for the treatment of lung related diseases in Chinese medicine for a long time. Its detailed effects on collagen in anti-idiopathic pulmonary fibrosis (IPF) is still unclear.
OBJECTIVE: To explore the effects of citrus alkaline extract (CAE) on collagen synthesis, crosslinking and deposition in pulmonary fibrosis and understand the possible signal pathways involved in the activity.
METHODS: CAE was prepared from C. reticulata. Bleomycin-induced pulmonary fibrosis mouse model was applied. Pulmonary fibrosis of lung was estimated with histopathology analysis, and collagen deposition was evaluated with immunohistochemistry. Collagen crosslinking related biomarkers and enzymes were analyzed with chemical methods, immunohistochemical and western blot analyses.
RESULTS: CAE oral administration lowered hydroxyproline content, inhibited the collagen deposition including expressions of collagen I and III, and relieved bleomycin-induced pulmonary fibrosis in mice model. The productions of a collagen crosslink pyridinoline and crosslinking related enzymes including lysyl oxidase (LOX), lysyl oxidase-like protein 1 (LOXL1) in lung were suppressed by CAE treatment. Furthermore, the protein expressions of TGF-β1 and Smad3 levels in lungs were also downregulated by CAE.
CONCLUSIONS: This study demonstrated that CAE inhibited collagen synthesis, crosslinking and deposition, and ameliorated bleomycin-induced pulmonary fibrosis. Preliminary mechanism study revealed that CAE exerted its bioactivity at least via downregulation of TGF-β1/Smad3 pathway. Our findings provided a great potential in fighting IPF based on CAE.
OBJECTIVE: To explore the effects of citrus alkaline extract (CAE) on collagen synthesis, crosslinking and deposition in pulmonary fibrosis and understand the possible signal pathways involved in the activity.
METHODS: CAE was prepared from C. reticulata. Bleomycin-induced pulmonary fibrosis mouse model was applied. Pulmonary fibrosis of lung was estimated with histopathology analysis, and collagen deposition was evaluated with immunohistochemistry. Collagen crosslinking related biomarkers and enzymes were analyzed with chemical methods, immunohistochemical and western blot analyses.
RESULTS: CAE oral administration lowered hydroxyproline content, inhibited the collagen deposition including expressions of collagen I and III, and relieved bleomycin-induced pulmonary fibrosis in mice model. The productions of a collagen crosslink pyridinoline and crosslinking related enzymes including lysyl oxidase (LOX), lysyl oxidase-like protein 1 (LOXL1) in lung were suppressed by CAE treatment. Furthermore, the protein expressions of TGF-β1 and Smad3 levels in lungs were also downregulated by CAE.
CONCLUSIONS: This study demonstrated that CAE inhibited collagen synthesis, crosslinking and deposition, and ameliorated bleomycin-induced pulmonary fibrosis. Preliminary mechanism study revealed that CAE exerted its bioactivity at least via downregulation of TGF-β1/Smad3 pathway. Our findings provided a great potential in fighting IPF based on CAE.
摘要：
背景：柑橘皮，一种具有理气祛痰功能的中草药，长期以来,中医药一直用于肺部相关疾病的治疗。其在抗特发性肺纤维化（IPF）中对胶原蛋白的详细作用尚不清楚。
目的：探讨柑橘碱提取物（CAE）对胶原蛋白合成的影响，交联和沉积在肺纤维化中，并了解参与活动的可能的信号通路。
方法:从网状梭状芽孢杆菌制备CAE。应用博来霉素诱导的肺纤维化小鼠模型。通过组织病理学分析评估肺纤维化，用免疫组织化学评估胶原沉积。用化学方法分析了胶原交联相关的生物标志物和酶,免疫组织化学和蛋白质印迹分析。
结果：口服CAE降低了羟脯氨酸含量，抑制胶原蛋白沉积，包括胶原蛋白I和III的表达，减轻博莱霉素诱导的小鼠肺纤维化模型。胶原交联吡啶啉和交联相关酶的产生，包括赖氨酰氧化酶（LOX），CAE治疗抑制了肺中的赖氨酰氧化酶样蛋白1（LOXL1）。此外，CAE也下调了肺组织中TGF-β1和Smad3的蛋白表达水平。
结论：这项研究表明，CAE抑制胶原蛋白合成，交联和沉积，并改善博莱霉素诱导的肺纤维化。初步机制研究表明，CAE至少通过下调TGF-β1/Smad3途径发挥其生物活性。我们的发现为基于CAE对抗IPF提供了巨大的潜力。
目的：探讨柑橘碱提取物（CAE）对胶原蛋白合成的影响，交联和沉积在肺纤维化中，并了解参与活动的可能的信号通路。
方法:从网状梭状芽孢杆菌制备CAE。应用博来霉素诱导的肺纤维化小鼠模型。通过组织病理学分析评估肺纤维化，用免疫组织化学评估胶原沉积。用化学方法分析了胶原交联相关的生物标志物和酶,免疫组织化学和蛋白质印迹分析。
结果：口服CAE降低了羟脯氨酸含量，抑制胶原蛋白沉积，包括胶原蛋白I和III的表达，减轻博莱霉素诱导的小鼠肺纤维化模型。胶原交联吡啶啉和交联相关酶的产生，包括赖氨酰氧化酶（LOX），CAE治疗抑制了肺中的赖氨酰氧化酶样蛋白1（LOXL1）。此外，CAE也下调了肺组织中TGF-β1和Smad3的蛋白表达水平。
结论：这项研究表明，CAE抑制胶原蛋白合成，交联和沉积，并改善博莱霉素诱导的肺纤维化。初步机制研究表明，CAE至少通过下调TGF-β1/Smad3途径发挥其生物活性。我们的发现为基于CAE对抗IPF提供了巨大的潜力。
