Lipopolysaccharide-Activated Macrophages Stimulate the Synthesis of Collagen Type I and C-Fibronectin in Cultured Pancreatic Stellate Cells

Abstract

We have recently identified and characterized pancreatic stellate cells (PSC) in rats and humans (Gastroen-terologyChronic pancreatitis is characterized by the presence of chronic inflammatory lesions, the destruction of exocrine parenchyma, and fibrosis. 1 Until now the pathobiochemical and molecular mechanisms resulting in pancreas fibrosis have been controversial and largely unknown. Fibroblast and fibroblast-like cell activation was reported to be a common observation in acute and chronic pancreatitis. [2][3][4][5][6] It has been suggested that periacinar fibroblast-like cells might play a role in fibrogenesis by synthesizing significant amounts of extracellular matrix (ECM), in particular collagens. 7,8 Studies from our group have shown that in the cerulein-induced pancreatitis model, proliferation of acinar and centroacinar cells is associated with an increase in mitotic activity of fibroblasts, which is followed by a stimulated synthesis and deposition of collagen. 5,9 In an earlier study, we illustrated an enhanced expression of transforming growth factor ␤ (TGF␤) during regeneration from cerulein-induced pancreatitis in acinar cells and stromal cells of the rat pancreas, which was followed by stimulated matrix synthesis. 10 Furthermore, we identified and characterized the matrix-producing cell type responsible for pancreas fibrosis, the pancreatic stellate cell (PSC) in mice, rats and humans. 11,12 Phenotypic transformation of PSCs is characterized by a disappearance of fat droplets and retinyl-esters, development of a prominent endoplasmic reticulum, enhanced expression of smooth muscle ␣-actin, and increased synthesis of collagen types I and III and fibronectin. 11 Pancreas fibrosis is commonly associated with chronic inflammation. 4 In chronic pancreatitis and in pancreas carcinoma, infiltrating mononuclear cells 13 might potentiate fibrogenesis by the release of cytokines stimulating stromal cells 14 and by their cytotoxic effects. 15 The decreased intestinal motility during pancreatitis causes a bacterial translocation to the peritoneal fluid, lymph, blood, liver, and pancreas. 16 Bacterial lipopolysaccharides (LPS) and the LPS-binding protein form a complex that binds to the surface receptor CD14 of the invaded monocytes, triggering the cells to become activated. 17,18 Supported by Bausteinfö rderung University of Ulm (P.347) and Deutsche Forschungsgemeinschaft (SFB 518, Project A7) to M. G. B.

In Chronic Pancreatitis, Widespread Emergence of TRAIL Receptors in Epithelia Coincides with Neoexpression of TRAIL by Pancreatic Stellate Cells of Early Fibrotic Areas

“…We show here that at least one defined cell type that resides in areas of active fibrosis, namely the recently described PSC, a functional homolog to the hepatic "fat-storing" or Ito cell (Bachem et al, 1998;Schmid-Kotsas et al, 1999), expresses TRAIL in vivo and in vitro. As we further showed, these PSC represent the major subset of interstitial FLC in areas with active fibrosis.…”

“…As we further showed, these PSC represent the major subset of interstitial FLC in areas with active fibrosis. They are known to be fibrogenic in producing collagen types I and II, c-fibronectin, and laminin (Schmid-Kotsas et al, 1999). By local production of TRAIL, which is likely to be triggered by IFN-␥ derived from lymphohistiocytic infiltrates (Hasel et al, 2001), PSC may in addition profoundly modify TRAIL-sensitive pancreatic resident cells, eventually enforcing apoptosis and, by this route, promoting parenchymal regression during CP.…”

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

“…26,27,29,30 Moreover, previous studies strongly support the existence of autocrine and paracrine stimulatory loops of ECM protein synthesis in PSCs via TGF-b. [36][37][38] Thus, inhibition of TGF-b action may block these loops and thereby inhibit PSC activation and ECM protein deposition in the pancreas. However, the inhibitory effect of AdTb-ExR on pancreatic fibrosis was less impressive than that Mice were injected once intraperitoneally with either AdLacZ or AdTb-ExR, or with saline, and then treated with cerulein for 3 weeks.…”

Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

“…Fibronectin concentration in PSC supernatants was measured by time-resolved fluorescence immunoassay as described (16,23,24). Fibronectin concentration was put in reference to the DNA content in the corresponding culture well.…”