Inhibition of transforming growth factor β decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice

Abstract

Transforming growth factor-b (TGF-b) 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-b receptor (AdTb-ExR), we investigated whether inhibition of TGF-b 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 lg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTb-ExR, or with a control adenoviral vector expressing bacterial b-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for a-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 AdTb-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTb-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTb-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-b action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.

Curcumin blocks activation of pancreatic stellate cells

“…Curcumin blocked TGF-b 0 s profibrotic actions through down-regulation of TGF-b receptor type II expression and inhibition of cjun activity [Gaedeke et al, 2004]. Because TGF-b plays a key role in the development of pancreatic fibrosis [Nagashio et al, 2004], it is interesting to see whether curcumin affects the TGF-b signaling cascade in PSCs.…”

Extracellular Matrix–Mediated Membrane-Type 1 Matrix Metalloproteinase Expression in Pancreatic Ductal Cells Is Regulated by Transforming Growth Factor-β1

“…Because type I collagen is the predominant matrix in the desmoplastic reaction (4,5), and because genetic studies have shown that MT1-MMP is a primary regulator of interstitial collagenolysis (16), our data suggest that inhibition of TGF-h1 signaling would also help to block tumor progression in vivo. Importantly, TGF-h1 has also been shown to promote a desmoplastic reaction in vivo following orthotopic transplantation of TGF-h1-transfected pancreatic cancer cells in an experimental model of human pancreatic carcinoma (46), whereas conditional loss of TGF-h1 signaling within the pancreas significantly ameliorated chemical-induced pancreatic fibrosis (47,48). Based on our data and on recent reports showing that the desmoplastic reaction is detrimental to the host (7,35), modulation of TGF-h1 signaling using small-molecule inhibitors, a number of which are currently under development (49), could be a potential approach for the treatment of this highly lethal cancer.…”

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

“…Among pancreatic stromal cells, PSCs attracted great attention due to their central role in pancreatic fibrosis, and multiple cytokines and growth factors have been reported to activate PSCs. For example, platelet-derived growth factor (PDGF), TGF-b, angiotensin II and tumor necrosis factor-a are well-known activators of PSCs [38][39][40][41]. These ligands activate downstream signaling pathways that promote cell proliferation, survival, migration and the ECM production of PSCs.…”