Connective Tissue Growth Factor is Involved in Pancreatic Repair and Tissue Remodeling in Human and Rat Acute Necrotizing Pancreatitis

Autor: Murray Korc, Helmut Friess, Markus W. Büchler, Erick Riesle, Alexander Koliopanos, Fabio F. di Mola, Peter Büchler, David R. Brigstock, Zhaowen Zhu
Rok vydání: 2002
Předmět:
Zdroj: Annals of Surgery. 235:60-67
ISSN: 0003-4932
DOI: 10.1097/00000658-200201000-00008
Popis: Acute pancreatitis is an episodic inflammation of the pancreas that can develop as a mild form (edematous pancreatitis) or as a severe form (necrotizing pancreatitis). Inflamed pancreatic tissue, surviving the primary damage, can heal with a “restitutio ad integrum” after edematous pancreatitis. In contrast, in the case of necrotizing pancreatitis, recovery is often associated with fibrosis and scarring. Patients with necrotizing pancreatitis have in general a more severe clinical course, and intensive care treatment and surgery are often required. 1 The reparative process after acute inflammation of the pancreas is characterized by cell proliferation as well as synthesis and transient deposition of extracellular matrix. 1 In fact, after acute necrotizing pancreatitis (ANP), the necrotic areas are sealed off by granulation tissue, which mainly consists of collagen fibers. In addition, a coordinated release of inflammatory mediators and growth factors by activated platelets and endothelial cells is postulated to contribute to mesenchymal cell recruitment and proliferation. Among these early cellular products, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-β) are the major candidates that initiate and afterward support fibroblast proliferation and chemotactic activity, resulting in the replacement of necrosis and formation of a scar. 2–5 A previous study in human ANP tissues reported that TGF-β and its signaling receptors are overexpressed in a concomitant fashion with collagen type 1 mRNA in the remaining parenchyma, suggesting that these growth factors play a critical role in pancreatic tissue remodeling and in the fibrotic repair of the necrotic areas. 5 In addition, similar results were reported in rat acute edematous pancreatitis, where TGF-β upregulation has been described. 6–9 Expression levels of TGF-β mRNA were biphasically increased, with an initial early peak probably related to the acute pancreatic damage and inflammatory cell infiltration, and a second peak probably related to the intense extracellular matrix synthesis and tissue repair. 6–9 A recent report studying concomitant overexpression of connective tissue growth factor (CTGF), a novel peptide that exhibits PDGF-like chemotactic and mitogenic activities for mesenchymal cells, and TGF-β1 and collagen type 1 in patients with chronic pancreatitis showed that CTGF may play a central role in fibrogenesis during chronic pancreatic damage. 10 In addition, TGF-β1 is at present the only known inducer of CTGF in human tissue, and several studies have confirmed that CTGF is a downstream component of the TGF-β signaling cascade that stimulates extracellular matrix synthesis in several fibrotic disorders. 11–13 However, TGF-β1 is a multifunctional peptide, and its expression in the pancreas has been found in different cell types, such as islet cells, inflammatory cells, and acinar cells. In agreement with their multifunctional capacity, different mediators for specific biologic actions are induced by TGF-β. 14 Connective tissue growth factor represents a more selective peptide that plays a unique role in fibrogenesis in various disorders, and this peculiarity makes CTGF a potential target for new therapy that might regulate and finally modulate fibrogenesis in various human disorders. 10,15,16 In view of these observations, in the present study we analyzed CTGF in human ANP and in a rat model of ANP to further evaluate its potential involvement in fibrogenesis in these disorders.
Databáze: OpenAIRE
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