BACKGROUND & AIMS: Monocytes/macrophages infiltrate into injured livers. We tried to clarify their roles in inflammation and subsequent fibrogenesis by inhibiting their infiltration with a mutated form (7ND; 7 amino acids at the N-terminal were deleted) of monocyte chemoattractant protein 1, which may function as a dominant-negative mutant. METHODS: Rats were injected via the tail vein with an adenovirus expressing either human 7ND (Ad7ND), a truncated type II transforming growth factor beta receptor (AdTbeta-TR), which works as a dominant-negative receptor, bacterial beta-galactosidase (AdLacZ), or saline. Seven days later, the rats were treated with dimethylnitrosamine for 1-21 days. RESULTS: Within 24 hours after a single dimethylnitrosamine injection, macrophages were observed in livers. With a 3-day dimethylnitrosamine treatment, activated hepatic stellate cells were detectable in livers in AdLacZ-, AdTbeta-TR-, and saline-injected rats. In contrast, in the Ad7ND-treated rats, infiltration of macrophages was markedly reduced, and activated hepatic stellate cells were not detectable. After a 3-week dimethylnitrosamine treatment, fibrogenesis was almost completely inhibited, and activated hepatic stellate cells were hardly seen in livers in both Ad7ND- and AdTbeta-TR-treated rats. CONCLUSIONS: Our results show that blockade of macrophage infiltration inhibits activation of hepatic stellate cells and leads to suppression of liver fibrogenesis. The presence of activated hepatic stellate cells in the initial phase after injury and its absence at a later phase in the AdTbeta-TR-treated livers indicate that transforming growth factor beta is not an activating factor for hepatic stellate cells, and this suggests that transforming growth factor beta is required for the survival of activated hepatic stellate cells. Our study suggests that infiltrated macrophages may themselves produce an activating factor for hepatic stellate cells.
BACKGROUND & AIMS: Monocytes/macrophages infiltrate into injured livers. We tried to clarify their roles in inflammation and subsequent fibrogenesis by inhibiting their infiltration with a mutated form (7ND; 7 amino acids at the N-terminal were deleted) of monocyte chemoattractant protein 1, which may function as a dominant-negative mutant. METHODS:Rats were injected via the tail vein with an adenovirus expressing either human 7ND (Ad7ND), a truncated type II transforming growth factor beta receptor (AdTbeta-TR), which works as a dominant-negative receptor, bacterial beta-galactosidase (AdLacZ), or saline. Seven days later, the rats were treated with dimethylnitrosamine for 1-21 days. RESULTS: Within 24 hours after a single dimethylnitrosamine injection, macrophages were observed in livers. With a 3-day dimethylnitrosamine treatment, activated hepatic stellate cells were detectable in livers in AdLacZ-, AdTbeta-TR-, and saline-injected rats. In contrast, in the Ad7ND-treated rats, infiltration of macrophages was markedly reduced, and activated hepatic stellate cells were not detectable. After a 3-week dimethylnitrosamine treatment, fibrogenesis was almost completely inhibited, and activated hepatic stellate cells were hardly seen in livers in both Ad7ND- and AdTbeta-TR-treated rats. CONCLUSIONS: Our results show that blockade of macrophage infiltration inhibits activation of hepatic stellate cells and leads to suppression of liver fibrogenesis. The presence of activated hepatic stellate cells in the initial phase after injury and its absence at a later phase in the AdTbeta-TR-treated livers indicate that transforming growth factor beta is not an activating factor for hepatic stellate cells, and this suggests that transforming growth factor beta is required for the survival of activated hepatic stellate cells. Our study suggests that infiltrated macrophages may themselves produce an activating factor for hepatic stellate cells.
Authors: Sandra March; Mariona Graupera; María Rosa Sarrias; Francisco Lozano; Pilar Pizcueta; Jaume Bosch; Pablo Engel Journal: Am J Pathol Date: 2007-01 Impact factor: 4.307
Authors: K Tomita; G Tamiya; S Ando; K Ohsumi; T Chiyo; A Mizutani; N Kitamura; K Toda; T Kaneko; Y Horie; J-Y Han; S Kato; M Shimoda; Y Oike; M Tomizawa; S Makino; T Ohkura; H Saito; N Kumagai; H Nagata; H Ishii; T Hibi Journal: Gut Date: 2005-09-20 Impact factor: 23.059
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
Authors: Caroline C Duwaerts; Stephan Gehring; Chao-Wen Cheng; Nico van Rooijen; Stephen H Gregory Journal: Liver Int Date: 2012-12-13 Impact factor: 5.828
Authors: Ekihiro Seki; Samuele de Minicis; Sayaka Inokuchi; Kojiro Taura; Katsumi Miyai; Nico van Rooijen; Robert F Schwabe; David A Brenner Journal: Hepatology Date: 2009-07 Impact factor: 17.425
Authors: Henning W Zimmermann; Sebastian Seidler; Jacob Nattermann; Nikolaus Gassler; Claus Hellerbrand; Alma Zernecke; Jens J W Tischendorf; Tom Luedde; Ralf Weiskirchen; Christian Trautwein; Frank Tacke Journal: PLoS One Date: 2010-06-10 Impact factor: 3.240