Inhibition of transforming growth factor β decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice
Inhibition of transforming growth factor β decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice
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DOI：
10.1038/labinvest.3700191
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发表时间：
2004-12-01
影响因子：
5
通讯作者：
Otsuki, M
中科院分区：
文献类型：
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作者：
Nagashio, Y;Ueno, H;Otsuki, M
转化生长因子-β（TGF-β）是包括胰腺在内的许多器官中纤维形成的重要细胞因子。使用表达II型人TGF-β受体（AdTbeta-ExR）的整个细胞外结构域的腺病毒载体，我们研究了抑制TGF-β作用是否对持续性胰腺纤维化有效，以及它是否在慢性损伤过程中对胰腺产生有益作用。为了诱导慢性胰腺损伤和胰腺纤维化，小鼠经历三次急性胰腺炎发作，所述急性胰腺炎发作是通过每周每小时腹膜内注射六次50 μ g/kg体重的雨蛙肽诱导的，连续3周。用AdTbeta-ExR或表达细菌β-半乳糖苷酶的对照腺病毒载体（AdLacZ）感染小鼠一次。以组织学和羟脯氨酸含量评价胰腺纤维化。通过α-平滑肌肌动蛋白的免疫染色评估胰腺星状细胞（PSC）的活化。腺泡细胞凋亡和增殖分别通过ssDNA和Ki-67的免疫染色来评估。三周蛙皮素注射诱导胰腺纤维化和胰腺萎缩，并伴有活化的PSC增殖。在注射AdTbeta-ExR的小鼠中，胰腺纤维化显著减弱，而注射AdLacZ的小鼠则没有。这一发现伴随着活化PSC的减少。AdTbeta-ExR，而不是AdLacZ，在慢性胰腺损伤后显著增加胰腺重量。AdTbeta-ExR没有改变增殖腺泡细胞的比例，但它减少了凋亡腺泡细胞的数量。我们的研究结果表明，抑制TGF-β的作用不仅减少胰腺纤维化，而且还通过防止腺泡细胞凋亡保护胰腺免受慢性损伤。
Transforming growth factor-beta (TGF-beta) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-beta receptor (AdTbeta-ExR), we investigated whether inhibition of TGF-beta action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 mug/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTbeta-ExR, or with a control adenoviral vector expressing bacterial beta-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for alpha-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTbeta-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTbeta-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTbeta-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-beta action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.