BACKGROUND & AIMS: Hepatic stellate cells (HSCs) play a key role in the pathogenesis of liver fibrosis. Immigrating leukocytes can potentiate the progression of liver fibrosis by release of fibrogenic mediators and cytotoxic actions. The inducible production of neutrophil chemotactic activities in HSCs was investigated to understand the underlying mechanisms responsible for the attraction of leukocytes in the pathogenesis of liver fibrosis. METHODS: Cultured HSCs of different transformation grades and after transformation to myofibroblasts (MFBs) were stimulated with tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS), respectively. Induced leukocyte chemotactic activities were evaluated by chemotaxis assays, enzyme-linked immunosorbent assay, and Northern blot analysis. RESULTS: A transformation grade-dependent differential responsiveness of HSCs and MFBs was observed. TNF-alpha-inducible production of chemotactic mediators increased substantially with advancing transformation. Only transformed MFBs were LPS responsive. Macrophage inflammatory protein 2 was identified as one of the inducible chemokines. CONCLUSIONS: The results suggest that chemokines play an important role in the pathogenesis of liver fibrosis. Proinflammatory cytokines can initiate the production of chemotactic activities. The more HSCs are transformed to MFBs, e.g., by chronic injury, the more sensitive the cells become to LPS, which may lead to a vicious circle of enhanced fibrogenic and chemotactic mediator production.
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) play a key role in the pathogenesis of liver fibrosis. Immigrating leukocytes can potentiate the progression of liver fibrosis by release of fibrogenic mediators and cytotoxic actions. The inducible production of neutrophil chemotactic activities in HSCs was investigated to understand the underlying mechanisms responsible for the attraction of leukocytes in the pathogenesis of liver fibrosis. METHODS: Cultured HSCs of different transformation grades and after transformation to myofibroblasts (MFBs) were stimulated with tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS), respectively. Induced leukocyte chemotactic activities were evaluated by chemotaxis assays, enzyme-linked immunosorbent assay, and Northern blot analysis. RESULTS: A transformation grade-dependent differential responsiveness of HSCs and MFBs was observed. TNF-alpha-inducible production of chemotactic mediators increased substantially with advancing transformation. Only transformed MFBs were LPS responsive. Macrophage inflammatory protein 2 was identified as one of the inducible chemokines. CONCLUSIONS: The results suggest that chemokines play an important role in the pathogenesis of liver fibrosis. Proinflammatory cytokines can initiate the production of chemotactic activities. The more HSCs are transformed to MFBs, e.g., by chronic injury, the more sensitive the cells become to LPS, which may lead to a vicious circle of enhanced fibrogenic and chemotactic mediator production.
Authors: Chi Wei Lee; Jiin Haur Chuang; Pei Wen Wang; Nyuk Kong Chang; Hsiu Chuan Wang; Chao Cheng Huang; Mao Meng Tiao; Sing Kai Lo Journal: World J Surg Date: 2006-12 Impact factor: 3.352
Authors: Ekihiro Seki; Samuele De Minicis; Geum-Youn Gwak; Johannes Kluwe; Sayaka Inokuchi; Christina A Bursill; Josep M Llovet; David A Brenner; Robert F Schwabe Journal: J Clin Invest Date: 2009-07 Impact factor: 14.808