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. 2012:2012:452143.
doi: 10.1155/2012/452143. Epub 2011 Jul 7.

Novel approach to bile duct damage in primary biliary cirrhosis: participation of cellular senescence and autophagy

Motoko Sasaki  1 , Yasuni Nakanuma
Affiliations

Novel approach to bile duct damage in primary biliary cirrhosis: participation of cellular senescence and autophagy

Motoko Sasaki et al. Int J Hepatol. 2012.

Abstract

Primary biliary cirrhosis (PBC) is characterized by antimitochondrial autoantibodies (AMAs) in patients' sera and histologically by chronic nonsuppurative destructive cholangitis in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. The autoimmune-mediated pathogenesis of bile duct lesions, including the significance of AMAs, triggers of the autoimmune process, and so on remain unclear. We have reported that cellular senescence in biliary epithelial cells (BECs) may be involved in bile duct lesions and that autophagy may precede the process of biliary epithelial senescence in PBC. Interestingly, BECs in damaged bile ducts show characteristicsof cellular senescence and autophagy in PBC. A suspected causative factor of biliary epithelial senescence is oxidative stress. Furthermore, senescent BECs may modulate the microenvironment around bile ducts by expressing various chemokines and cytokines called senescence-associated secretory phenotypes and contribute to the pathogenesis in PBC.

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Figures

Figure 1
Figure 1
Biliary epithelial senescence in PBC. BECs in small bile ducts involved in chronic nonsuppurative destructive cholangitis (CNSDC) show histological features of senescence, such as cytoplasmic eosinophilia, cellular and nuclear enlargement, and uneven nuclear spacing (a). SA-β-gal activity is detected in BECs in PBC (b). Senescent markers, p21WAF1/Cip1 and p16INK4a, were expressed in BECs in damaged small bile ducts in PBC (c) and (d). Immunostaining for p21WAF1/Cip1 and p16INK4a. Original magnification: ×400.
Figure 2
Figure 2
Double immunostaining for senescence markers (p16INK4a or p21WAF1/Cip1) and cell cycle markers (G1-phase, cyclin D; S-phase, cyclin A) (red) and NCAM (green) in PBC, stage 4. (a), (c) The expression of senescent markers p16INK4a and p21WAF1/Cip1 is seen in NCAM-positive ductular cells (arrows) in PBC, stage 4. (b), (d) Most NCAM-positive ductular cells (arrows) express cyclin D, whereas there is no cyclin A expression in DRs in PBC, stage 4. Original magnification ×400.
Figure 3
Figure 3
Biliary epithelial autophagy in PBC. (a) The expression of autophagy marker LC3 was not observed in BECs in noninflammed bile ducts (arrow) in PBC. (b) The expression of autophagy marker LC3 was detected in intracytoplasmic vesicles (arrows) in BECs involved in inflamed and damaged small bile ducts in PBC. Immunostaining for LC3. Original magnification, ×400 (inset, ×1000).
Figure 4
Figure 4
Increased expression of CCL2 in inflamed and damaged bile ducts in PBC. (a) The expression of CCL2 was absent or faint in biliary epithelial cells (BECs) in the small bile duct (arrow) in normal liver (top). CCL2 was extensively expressed in the membrane and cytoplasm of damaged and senescent BECs (arrows) in the early stage of PBC (bottom). Immunostaining for CCL2. Original magnification, ×400. (b) The expression of CCL2 was significantly more frequent and intense in inflamed small bile ducts in PBC, when compared with noninflamed small bile ducts in PBC and small bile ducts in control livers (P < .01). CVH: chronic viral hepatitis; NASH: nonalcoholic steatohepatitis; EBO: extrahepatic biliary obstruction; NL: normal liver.
Figure 5
Figure 5
Possible regulation of microenvironment by senescent BECs expressing SASPs in PBC. Senescent BECs may function in modulation of the inflammatory microenvironment by recruiting monocytes and possibly other inflammatory cells by secreting chemokines and cytokines as SASPs. Senescent BECs may also participate in the induction of senescence in surrounding cells and progression of fibrosis via SASPs.
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