Complement factor C5 deficiency significantly delays the progression of biliary fibrosis in bile duct-ligated mice

Abstract

Fibrogenesis represents the universal response of the liver to chronic liver injury. Complement factor C5 has been linked to fibrosis in murine toxic liver injury and human chronic hepatitis C. C5 may also play a central role in chronic cholestatic disorders, since the BA receptor FXR has been characterized as an activator of the C3 gene. We aimed to investigate, whether C5 deficiency is able to prevent biliary fibrosis in the mouse bile-duct-ligation model. BDL for 1-4weeks was performed in either Hc(0)/Hc(0) mice (deficient for C5) or WT controls. BA levels were measured by RIA. Histological examination included HE, sirius-red and immunohistochemistry. mRNA expression was quantified by RT-PCR. Protein expression levels were determined by Western blotting or ELISA. Enzymatic MMP-activity was analysed by zymography. One week BDL leads to fibrosis in WT (F2.0±0), while it is almost absent in Hc(0)/Hc(0) mice (F0.5±0.5). No differences in fibrosis can be detected at week-4. Together with delayed fibrogenesis at week-1, fibrotic markers are decreased in Hc(0)/Hc(0) mice. Expression of the inflammatory cytokine TNF-is decreased in Hc(0)/Hc(0) mice. In parallel C5 deficiency leads to an attenuated peribiliary infiltration of CD45(+) cells in fibrotic areas together with decreased MMP-9 expression and gelatinase activity. The present study proves a functional role of C5 during biliary fibrogenesis. C5 deficiency leads to attenuated inflammation and normalized MMP-9 activity concomitantly with a significant reduction of fibrosis. C5 appears to be an attractive target for future therapeutic intervention in chronic cholestatic liver disease. The present study proves a functional role of C5 during biliary fibrogenesis. C5 deficiency leads to attenuated inflammation and normalized MMP-9 activity concomitantly with a significant reduction of fibrosis. C5 appears to be an attractive target for future therapeutic intervention in chronic cholestatic liver disease.

Complement Activation and Inhibition in Wound Healing

“…However, elevated levels of C3, C3a, C3d, and MAC have been reported in chronic wounds and burn or traumatic wounds [27–32], indicating that uncontrolled complement activation occurs in such wounds. In addition, studies in animals with deficiencies in complement components and in patients treated with complement inhibiting agents confirmed the importance of controlling the complement system in wound healing and fibrosis [12–18, 108]. Specific inhibitors can balance the functional activities of the complement system and progress the healing process, as shown in patients with burn wounds treated with a C1 inhibitor or a soluble human recombinant complement receptor type 1 as well as in C4-deficient mice [15–18].…”

Therapeutic targets for cholestatic liver injury

“…Recently, it was established that cholangiocytes protect themselves against bile acid induced injury through a protective glycocalyx featuring an “umbrella” of bicarbonate secretion that lowers local pH values and reduces bile acid uptake through the anion exchange 1 transporter [106]. This new therapeutic area holds a great deal of potential as drugs specifically targeted towards the bile may be especially effective at preventing the adverse reactions associated with bile acid-induced cholangiocyte damage.…”

Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis

“…Several liver cells including hepatic stellate cells, portal fibroblasts, and myofibroblasts participate in the development of fibrosis. BDL is a unique animal model of hepatic fibrosis that the primary pathological changes started from the area around the biliary epithelium (23,50). Although the chronic obstruction of bile duct activates myofibroblasts in periductal areas, limited information exists regarding the role of cholangiocytes in the progression of biliary fibrosis (24).…”