Repetitive Acute Pancreatic Injury in the Mouse Induces Procollagen α1(I) Expression Colocalized to Pancreatic Stellate Cells

Abstract

SUMMARY:Pancreatic stellate cells may be a major source of extracellular matrix deposition during injury. This study was undertaken to establish whether pancreatic stellate cells are a source of Type I collagen in vivo and whether they continue to be a source of matrix production in the post-injury fibrotic pancreas. To induce pancreatic fibrogenesis, acute pancreatic injury was induced in mice three times weekly with supraphysiologic doses of cerulein. Animals were treated for 6 weeks and allowed to recover for an additional 6 weeks. Stellate cell activation and pancreatic collagen expression were measured by immunohistochemistry, whole tissue RNA analysis, and in situ hybridization. Histology and digital image analysis demonstrated the development of substantial pancreatic fibrosis after 6 weeks of treatment. During recovery, incomplete resolution of the fibrosis was found. Procollagen ␣ 1 (I) mRNA increased more than15-fold during treatment and continued to be 5-fold elevated during the post-injury phase. In situ hybridization studies demonstrated that collagen gene expression was colocalized to activated pancreatic stellate cells. Collagen expression and fibrosis persisted in focal areas during recovery. These findings show that pancreatic stellate cells are the major source of collagen during repetitive injury in vivo. Additionally, focal areas of sustained pancreatic fibrogenesis persist after cessation of cerulein treatment, and these areas may contribute to sustained total organ collagen expression in the absence of ongoing injury. (Lab Invest 2000, 80:143-150).

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

“…Because pancreatic stellate cells have been implicated as a major site of pancreatic fibrosis, we investigated whether they were present around acinar cells based on their property to positively stain for alpha smooth muscle actin once activated and transforming to fibroblastlike cells. 23 Alpha smooth muscle actin positive cells were exclusively observed in the vascular walls of arterioles and their number did not increase following azaserine treatment, indicating that inflammatory capillary neogenesis was small (Fig. 1c,d) and excluding the presence of activated stellate cells.…”

Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine

“…65,66 In conclusion, we were able to establish an immortal cell line from human pancreas, which is phenotypically and functionally indistinguishable from primary activated PSC with respect to the expression of stellate cell markers (vimentin, aSMA and GFAP) and their response to TGFb1 and PDGF treatment. Importantly, we were able to demonstrate that besides soluble factors, the matrix surrounding PSC plays a pivotal role in the maintenance of the activation process of PSC, as cultivation of activated PSC on a reconstituted basement membrane plus treatment with NAC was able to deactivate the cells, thus pointing to the possibility of an antifibrosis therapy in chronic pancreatitis.…”

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

“…Although collagen deposition increased after 2 weeks of cerulein treatment, 17 we performed repetitive Inhibiting TGF-b in chronic pancreatic injury Y Nagashio et al intraperitoneal injections of cerulein for 3 weeks to induce fibrosis in the pancreas. In normal pancreas, collagen was observed around the pancreatic ducts and blood vessels (Figure 1a).…”

“…15 Three days after adenoviral injections, the mice were submitted to repeated acute pancreatitis episodes to induce chronic pancreatic injury and pancreatic fibrosis as described previously. 17,18 Acute pancreatitis was elicited by hourly (6 times) intraperitoneal injections of 50 mg/kg body weight cerulein (Sigma-Aldrich, Tokyo, Japan), whereas control animals received a comparable amount of saline. Mice were submitted to three episodes of acute pancreatitis per week for 3 weeks.…”

“…[14][15][16] The use of AdTb-ExR can block the action of TGF-b in organs where direct gene transfer seems restrained. As an experimental pancreatic fibrosis model, we used mice treated with repeated cerulein injections, 17,18 an established animal model of chronic pancreatic injury and pancreatic fibrosis with a pathophysiology that closely resembles that of human chronic pancreatitis.…”