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L-cysteine administration attenuates pancreatic fibrosis induced by TNBS in rats by inhibiting the activation of pancreatic stellate cell.

ABSTRACT: 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 ?-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 PDGFR?, TGF?RII, collagen 1?1 and ?-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-1? 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. ?-SMA, TIMP1, IL-1? and TGF-?1 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 PDGFR? and TGF?RII. 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-1? in L-cysteine treated group when compared with control group. CONCLUSION:L-cysteine treatment attenuated pancreatic fibrosis in chronic pancreatitis in rats.

SUBMITTER: Yang L

PROVIDER: S-EPMC3281011 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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L-cysteine administration attenuates pancreatic fibrosis induced by TNBS in rats by inhibiting the activation of pancreatic stellate cell.

Yang LiJuan L Shen JiaQing J He ShanShan S Hu GuoYong G Shen Jie J Wang Feng F Xu Ling L Dai WeiQi W Xiong Jie J Ni JianBo J Guo ChuanYong C Wan Rong R Wang XingPeng X

PloS one 20120216 2

<h4>Background and aims</h4>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.<h4>Methods</h4>CP was induced by TNBS infusion into rat pancreatic ducts. L-cysteine was administrated for the duration of the experiment. Histological analysi ...[more]

PMID: 22359633

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Project description:Pancreatic cancer is characterized by a hypoxic tumor microenvironment, which is primarily caused by massive fibrosis with pancreatic stellate cells (PSCs) as a main component. Our previous studies have shown that resveratrol can significantly inhibit pancreatic cancer. However, whether resveratrol can inhibit hypoxia-induced cancer development remains unclear. The objective of this study was to explore whether PSCs and hypoxia synergistically mediate aggressiveness in pancreatic cancer and detect the potential pleiotropic protective effects of resveratrol on hypoxia-induced pancreatic cancer progression. Human PSCs were treated with vehicle or resveratrol under normoxic or hypoxic conditions (3% O2), and PSC activation was assessed by immunofluorescence staining. SiRNA was used to silence hypoxia-inducible factor 1 (HIF-1) expression. The invasive capacity of Panc-1 and Mia Paca-2 cells cocultured with conditioned medium from PSCs was assessed by Transwell assays. To examine tumor formation kinetics, KPC (LSL-KrasG12D/+, Trp53fl/+, and Pdx1-Cre) mice were sacrificed at different time points. To investigate the antitumor effects of resveratrol in vivo, 8-wk-old KPC mice were divided into two groups and treated daily with or without 50 mg/kg resveratrol. Our data indicate that hypoxia induces PSC activation via HIF-1 and that the interleukin 6, vascular endothelial growth factor A, and stromal cell-derived factor 1 derived from activated PSCs promote both invasion and the epithelial-mesenchymal transition and inhibit apoptosis in pancreatic cancer cells. However, resveratrol inhibits hypoxia-induced PSC activation, blocks the interplay between PSCs and pancreatic cancer cells, and suppresses the malignant progression of pancreatic cancer and stromal desmoplasia in a KPC mouse model. Our data highlight that activated PSCs and intratumoral hypoxia are essential targets for novel strategies to prevent tumor-microenvironment interactions. Furthermore, the polyphenolic compound resveratrol effectively ameliorates the malignant progression of pancreatic ductal adenocarcinoma.

Project description:BackgroundPancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions.MethodWe evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone's combination therapy on subcutaneous tumor formation and splenic xenografted mouse models.ResultsIn vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone's combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level.ConclusionNAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.

Dataset Information

L-cysteine administration attenuates pancreatic fibrosis induced by TNBS in rats by inhibiting the activation of pancreatic stellate cell.

Publications

L-cysteine administration attenuates pancreatic fibrosis induced by TNBS in rats by inhibiting the activation of pancreatic stellate cell.

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