L-半胱氨酸给药通过抑制胰腺星状细胞的激活来减轻 TNBS 诱导的大鼠胰腺纤维化。
L-cysteine administration attenuates pancreatic fibrosis induced by TNBS in rats by inhibiting the activation of pancreatic stellate cell.
机构信息
Department of Gastroenterology, The First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
出版信息
PLoS One. 2012;7(2):e31807. doi: 10.1371/journal.pone.0031807. Epub 2012 Feb 16.
BACKGROUND AND AIMS
Recent studies have shown that activated pancreatic stellate cells (PSCs) play a major role in pancreatic fibrogenesis. We aimed to study the effect of L-cysteine administration on fibrosis in chronic pancreatitis (CP) induced by trinitrobenzene sulfonic acid (TNBS) in rats and on the function of cultured PSCs.
METHODS
CP was induced by TNBS infusion into rat pancreatic ducts. L-cysteine was administrated for the duration of the experiment. Histological analysis and the contents of hydroxyproline were used to evaluate pancreatic damage and fibrosis. Immunohistochemical analysis of α-SMA in the pancreas was performed to detect the activation of PSCs in vivo. The collagen deposition related proteins and cytokines were determined by western blot analysis. DNA synthesis of cultured PSCs was evaluated by BrdU incorporation. We also evaluated the effect of L-cysteine on the cell cycle and cell activation by flow cytometry and immunocytochemistry. The expression of PDGFRβ, TGFβRII, collagen 1α1 and α-SMA of PSCs treated with different concentrations of L-cysteine was determined by western blot. Parameters of oxidant stress were evaluated in vitro and in vivo. Nrf2, NQO1, HO-1, IL-1β expression were evaluated in pancreas tissues by qRT-PCR.
RESULTS
The inhibition of pancreatic fibrosis by L-cysteine was confirmed by histological observation and hydroxyproline assay. α-SMA, TIMP1, IL-1β and TGF-β1 production decreased compared with the untreated group along with an increase in MMP2 production. L-cysteine suppressed the proliferation and extracellular matrix production of PSCs through down-regulating of PDGFRβ and TGFβRII. Concentrations of MDA+4-HNE were decreased by L-cysteine administration along with an increase in GSH levels both in tissues and cells. In addition, L-cysteine increased the mRNA expression of Nrf2, NQO1 and HO-1 and reduced the expression of IL-1β in L-cysteine treated group when compared with control group.
CONCLUSION
L-cysteine treatment attenuated pancreatic fibrosis in chronic pancreatitis in rats.
背景与目的
最近的研究表明，激活的胰腺星状细胞（PSCs）在胰腺纤维化中起着重要作用。我们旨在研究 L-半胱氨酸给药对三硝基苯磺酸（TNBS）诱导的大鼠慢性胰腺炎（CP）纤维化的影响及其对培养的 PSCs 功能的影响。
方法
将 TNBS 注入大鼠胰管中诱导 CP。L-半胱氨酸在整个实验过程中给予。通过羟脯氨酸含量和组织学分析评估胰腺损伤和纤维化。通过免疫组织化学分析检测体内 PSCs 的激活。通过 Western blot 分析测定胶原沉积相关蛋白和细胞因子。通过 BrdU 掺入评估培养的 PSCs 的 DNA 合成。我们还通过流式细胞术和免疫细胞化学评估 L-半胱氨酸对细胞周期和细胞激活的影响。通过 Western blot 确定不同浓度 L-半胱氨酸处理的 PSCs 的 PDGFRβ、TGFβRII、胶原 1α1 和α-SMA 的表达。通过 qRT-PCR 评估胰腺组织中 Nrf2、NQO1、HO-1 和 IL-1β 的表达。
结果
通过组织学观察和羟脯氨酸测定证实了 L-半胱氨酸对胰腺纤维化的抑制作用。与未处理组相比，α-SMA、TIMP1、IL-1β 和 TGF-β1 的产生减少，而 MMP2 的产生增加。L-半胱氨酸通过下调 PDGFRβ 和 TGFβRII 抑制 PSCs 的增殖和细胞外基质产生。L-半胱氨酸给药可降低 MDA+4-HNE 的浓度，并增加组织和细胞中的 GSH 水平。此外，与对照组相比，L-半胱氨酸处理组的 Nrf2、NQO1 和 HO-1 的 mRNA 表达增加，IL-1β 的表达减少。
结论
L-半胱氨酸治疗可减轻大鼠慢性胰腺炎中的胰腺纤维化。
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