Background Complement factor C5 contributes to hepatic fibrogenesis as
C5-deficient mice display less fibrosis after challenge with CCl4 (Hillebrandt et
al. 2005). During inflammation C5 is cleaved and the small chemoattractive peptide
C5a binds to the receptors C5aR and C5L2. Our aim was to assess the specific roles
of the C5 receptors during CCl4-induced liver damage and regeneration.
Methods C5aR- and C5L2-deficient mice and wild-type (WT) controls were treated
with CCl4 for 6 weeks. In addition, mice were challenged with CCl4 for 6 weeks and
left untreated for another 6 weeks (regression model). Expression of Th1 and Th2
cytokines was determined by qRT-PCR, and hepatic collagen contents were measured via
hydroxyproline. Mice were also objected to bile duct ligation (BDL) and unilateral
ureteral obstruction (UUO) to compare fibrosis progression in liver and kidney.
Results Chronic fibrosis in liver and kidney was least pronounced in
C5aR-deficient mice in comparison to the other lines. Of note, 6 weeks after the
last injection C5aR-deficient mice developed highest hepatic collagen levels,
indicating response and ongoing damage after cessation of fibrotic stimuli. This is
resembled by cytokine profiles, with IL6, IL10, IL12, IL23 and IL27 being reduced
in
mice deficient for C5 receptors in the chronic model but elevated in C5aR-/-
mice during fibrosis regression in the liver.
Conclusions C5aR is critical during chronic fibrogenesis. The novel
observation of fibrosis progression in C5aR-deficient mice the after removal of the
fibrotic stimulus points to its critical role during wound healing and fibrosis
regression.
