Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China.
Respiration. 2012;84(6):509-17. doi: 10.1159/000340041. Epub 2012 Sep 20.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease without beneficial therapy, except for lung transplantation. A high oral dose of N-acetylcysteine (NAC) added to prednisone and azathioprine has been found to improve lung function in IPF patients, though the mechanism of action remains poorly understood.
Based on our previous findings showing elevation of glutathione (GSH) content associated with downregulation of lysyl oxidase (LOX) activity, which is essential for collagen deposition, the aim of the present study was to test the hypothesis that NAC alleviates IPF by regulating LOX function.
We firstly analyzed the time course of collagen deposition in lung tissue, hydroxyproline content, LOX activity, GSH levels, and transforming growth factor-β(1) (TGF-β(1)) and α-smooth muscle actin (α-SMA) expression in bleomycin (BLM)-induced pulmonary fibrosis in a rat model. Then, we focused our studies on NAC modulation of LOX activity.
LOX activity was increased on day 9 and peaked 14 days after BLM administration, while TGF-β(1) protein peaked on day 9. Interestingly, NAC treatment for 14 days from day 0 reversed LOX activity to normal levels and increased GSH levels in the lung of BLM-dosed rats. Consistently, NAC partially attenuated pulmonary fibrosis and inhibited TGF-β(1) and α-SMA expression in this model.
Our study supports a novel mechanism of NAC alleviating IPF by inhibition of LOX activity via elevation of lung GSH in BLM-induced pulmonary fibrosis. The TGF-β(1)/α-SMA pathway may also play an important role in modulation of LOX activity.
特发性肺纤维化（IPF）是一种进行性和致命性肺病，除了肺移植之外，没有有效的治疗方法。已经发现，高剂量的 N-乙酰半胱氨酸（NAC）联合泼尼松和硫唑嘌呤可改善 IPF 患者的肺功能，但作用机制仍不清楚。
基于我们之前的研究结果表明，NAC 可通过调节赖氨酰氧化酶（LOX）的功能来缓解 IPF，该酶与胶原蛋白沉积有关。本研究旨在验证 NAC 通过调节 LOX 功能缓解 IPF 的假说。
我们首先分析了博来霉素（BLM）诱导的大鼠肺纤维化模型中肺组织胶原沉积、羟脯氨酸含量、LOX 活性、GSH 水平、转化生长因子-β1（TGF-β1）和α-平滑肌肌动蛋白（α-SMA）表达的时间过程。然后，我们集中研究了 NAC 对 LOX 活性的调节作用。
LOX 活性在 BLM 给药后第 9 天增加，并在第 14 天达到峰值，而 TGF-β1 蛋白在第 9 天达到峰值。有趣的是，从第 0 天开始用 NAC 治疗 14 天可将 LOX 活性逆转至正常水平，并增加 BLM 处理大鼠肺中的 GSH 水平。一致地，NAC 部分减轻了该模型中的肺纤维化，并抑制了 TGF-β1 和α-SMA 的表达。
我们的研究支持 NAC 通过增加 BLM 诱导的肺纤维化中肺 GSH 来抑制 LOX 活性从而缓解 IPF 的新机制。TGF-β1/α-SMA 途径也可能在 LOX 活性的调节中发挥重要作用。
