Acta Biologica Hungarica

, Volume 63, Issue 3, pp 321–332 | Cite as

Ductular Reaction at the Early Terms of Common Bile Duct Ligation in the Rats

  • Elza Azmaiparashvili
  • Ekaterine Berishvili
  • Z. Kakabadze
  • O. Pilishvili
  • Ekaterine Mikautadze
  • R. Solomonia
  • M. Jangavadze
  • D. KordzaiaEmail author


Ductular reaction (DR) in bile duct ligated rats generally appears from 2nd day after biliary obstruction (BO). However, we show that increased amount of ductular profiles is evident already in 6 hours after BDL. The study aims to explain the origin of such an early DR in response to BO. Male Lewis rats were subjected to common bile duct ligation (CBDL) for 3, 6, 12 and 24 hours and sham operation. Liver samples were studied histologically, immunohistochemically (Ki67, pan-Cytokeratin/AE1+AE3/ and OV-6) and by immunoblotting analyses. It appeared that number of ductular profiles increase in time-related manner after BO. These ductular profiles are formed by biliary epitheliocyte-like cells; No mitotic activity was revealed. Part of hepatocytes reveals pan-Cytokeratin positivity on 12 and 24 hours after BO. Total cytokeratins content at 24 hours after CBDL was 37% higher in comparison with control data. The significant increase was observed for the cytokeratins with molecular weights: 61, 56 and 40 KDa. Thus, early DR after BDL is mediated by widening of the existed finest biliary ramifications and is not associated with proliferation activities. This DR is accompanied by differentiation of hepatocytes toward bile duct-like cells.


Ductular reaction biliary obstruction cytokeratins bile ductules rats 


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  1. 1.
    Alpini, G., McGill, J. M., Larusso, N. F. (2002) The pathobiology of biliary epithelia. Hepatology 35, 1256–1268.PubMedGoogle Scholar
  2. 2.
    Azmaiparashvili, E., Kordzaia, D., Dzidziguri, D. (2009) Biliary hypertension as the cell proliferation trigger in bile duct ligated rats. Georgian Med. News 111–116.Google Scholar
  3. 3.
    Benedetti, A., Bassotti, C., Rapino, K., Marucci, L., Jezequel, A. M. (1996) A morphometric study of the epithelium lining the rat intrahepatic biliary tree. J. Hepatol. 24, 335–342.PubMedGoogle Scholar
  4. 4.
    Burt, A. D., MacSween, R. N. (1993) Bile duct proliferation - its true significance? Histopathology 23, 599–602.PubMedGoogle Scholar
  5. 5.
    Demetris, A. J., Sakamoto, T., Liu, Z., Yokomuro, S., Ezure, T., Murase, N., Blakolmer, K. (1999) The ductular reaction in liver disease - emphasis on a type I response. In: Fleig, W. E. (ed.) Normal and Malignant Liver Cell Growth. Dordrecht; Boston: Kluwer Academic, pp. 156–170.Google Scholar
  6. 6.
    Desmet, V., Roskams, T., Van Eyken, P. (1995) Ductular reaction in the liver. Pathology, research and practice 191, 513–524.PubMedGoogle Scholar
  7. 7.
    Desmet, V. J. (1992) Modulation of the liver in cholestasis. J. Gastroenterol. Hepatol. 7, 313–323.PubMedGoogle Scholar
  8. 8.
    Desmet, V. J. (2011) Ductal plates in hepatic ductular reactions. Hypothesis and implications. I. Types of ductular reaction reconsidered. Virchows Archiv 458, 251–259.PubMedGoogle Scholar
  9. 9.
    Dirlik, M., Canbaz, H., Dusmez Apa, D., Caglikulekci, M., Yaylak, F., Balli, E., Tamer, L., Kanik, A., Aydin, S. (2009) The monitoring of progress in apoptosis of liver cells in bile duct-ligated rats. The Turkish Gastroenterol. 20, 247–256.Google Scholar
  10. 10.
    Dittmer, A., Dittmer, J. (2006) Beta-actin is not a reliable loading control in Western blot analysis. Electrophoresis 27, 2844–2845.PubMedGoogle Scholar
  11. 11.
    Dutra, R. A., Dos Santos, J. S., de Araujo, W. M., Simoes, M. V., de Paixao-Becker, A. N., Neder, L. (2008) Evaluation of hepatobiliary excretion and enterobiliary reflux in rats with biliary obstruction submitted to bilioduodenal or biliojejunal anastomosis. Dig. Dis. Sci. 53, 1138–1145.PubMedGoogle Scholar
  12. 12.
    Georgiev, P., Jochum, W., Heinrich, S., Jang, J. H., Nocito, A., Dahm, F., Clavien, P. A. (2008) Characterization of time-related changes after experimental bile duct ligation. Br. J. Surg. 95, 646–656.PubMedGoogle Scholar
  13. 13.
    Glaser, S. S., Gaudio, E., Miller, T., Alvaro, D., Alpini, G. (2009) Cholangiocyte proliferation and liver fibrosis. Expert Reviews Mol. Med. 11:e7.Google Scholar
  14. 14.
    Glaser, S. S., Onori, P., Wise, C., Yang, F., Marzioni, M., Alvaro, D., Franchitto, A., Mancinelli, R., Alpini, G., Munshi, M. K., Gaudio, E. (2010) Recent advances in the regulation of cholangiocyte proliferation and function during extrahepatic cholestasis. Dig. Liver. Dis. 42, 245–252.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Greenbaum, L. E., Wells, R. G. (2011) The role of stem cells in liver repair and fibrosis. Int. Biochem. Cell Biol. 43, 222–229.Google Scholar
  16. 16.
    Jeong, J. Y., Kang, D. Y., Noh, S. M. (1993) A morphologic study on the bile duct changes induced by common bile duct ligation in rats. Korean J. Pathol. 27, 618–629.Google Scholar
  17. 17.
    Kordzaia, D. (1990) Extrahepatic cholestasis. Ganatleba, Tbilisi, Georgia.Google Scholar
  18. 18.
    Lee, J. H., Tschai, H. J., Lee, S. C., Tu, Y. C. (1981) Liver histologic changes in bile ligated rats. Med. Sci. 4, 9.Google Scholar
  19. 19.
    Libbrecht, L., Desmet, V., Van Damme, B., Roskams, T. (2000) The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J. Hepatol. 33, 76–84.PubMedGoogle Scholar
  20. 20.
    Liu, Z., Sakamoto, T., Ezure, T., Yokomuro, S., Murase, N., Michalopoulos, G., Demetris, A. J. (1998) Interleukin-6, hepatocyte growth factor, and their receptors in biliary epithelial cells during a type I ductular reaction in mice: interactions between the periductal inflammatory and stromal cells and the biliary epithelium. Hepatology 28, 1260–1268.PubMedGoogle Scholar
  21. 21.
    Mancinelli, R., Onori, R, Gaudio, E., DeMorrow, S., Franchitto, A., Francis, F.L., Glaser, S., Carpino, G., Venter, J., Alvaro, D., Kopriva, S., White, M., Kossie, A., Savage, J., Alpini, G. (2009) Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G11–G26.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Marucci, L., Baroni, G. S., Mancini, R., Benedetti, A., Jezequel, A. M., Orlandi, F. (1993) Cell proliferation following extrahepatic biliary obstruction. Evaluation by immunohistochemical methods. J. Hepatol. 17, 163–169.PubMedGoogle Scholar
  23. 23.
    Michalopoulos, G. K., Barua, L., Bowen, W. C. (2005) Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41, 535–544.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Motta, R. M., Muto, M., Fujita, T. (1978) The liver: an atlas of scanning electron microscopy. Igaku-Shoin.Google Scholar
  25. 25.
    Murakami, T., Sato, F.L., Nakatani, S., Taguchi, T., Ohtsuka, A. (2001) Biliary tract of the rat as observed by scanning electron microscopy of cast samples. Arch. Histol. Cytol. 64, 439–447.Google Scholar
  26. 26.
    Nakano, S., Haratake, J., Hashimoto, H. (1995) Alterations in bile ducts and peribiliary microcirculation in rats after common bile duct ligation. Hepatology 21, 1380–1386.PubMedGoogle Scholar
  27. 27.
    Nishikawa, Y., Doi, Y., Watanabe, F.L., Tokairin, T., Omori, Y., Su, M., Yoshioka, T., Enomoto, K., (2005) Transdifferentiation of mature rat hepatocytes into bile duct-like cells in vitro. Amer. J. Pathol 166, 1077–1088.Google Scholar
  28. 28.
    Priester, S., Wise, C., Glaser, S. S. (2010) Involvement of cholangiocyte proliferation in biliary fibrosis. World J. Gastrointest. P athophysiol. 1, 30–37.Google Scholar
  29. 29.
    Racanelli, V., Rehermann, B. (2006) The liver as an immunological organ. Hepatology 43, S54–S62.PubMedGoogle Scholar
  30. 30.
    Roskams, T., Desmet, V (1998) Ductular reaction and its diagnostic significance. Seminars in Diagnostic Pathology 15, 259–269.PubMedGoogle Scholar
  31. 31.
    Roskams, T., van den Oord, J. J., De Vos, R., Desmet, V. J. (1990) Neuroendocrine features of reactive bile ductules in cholestatic liver disease. Amer J. Pathol. 137, 1019–1025.Google Scholar
  32. 32.
    Roskams, T. A., Libbrecht, L., Desmet, V. J. (2003) Progenitor cells in diseased human liver. Semin Liver Dis. 23, 385–396.PubMedGoogle Scholar
  33. 33.
    Roskams, T. A., Theise, N. D., Balabaud, C., Bhagat, G., Bhathal, P. S., Bioulac-Sage, P., Brunt, E. M., Crawford, J. M., Crosby, H. A., Desmet, V., Finegold, M. J., Geller, S.A., Gouw, A. S., Hytiroglou, P., Knisely, A. S., Kojiro, M., Lefkowitch, J. F.L., Nakanuma, Y., Olynyk, J. K., Park, Y. N., Portmann, B., Saxena, R., Scheuer, P. J., Strain, A. L., Thung, S. N., Wanless, I. R., West, A. B. (2004) Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 39, 1739–1745.PubMedGoogle Scholar
  34. 34.
    Saxena, R., Theise, N. (2004) Canals of Hering: recent insights and current knowledge. Semin Liver Dis. 24, 43–48.PubMedGoogle Scholar
  35. 35.
    Shibayama, Y. (1990) Factors producing bile infarction and bile duct proliferation in biliary obstruction. J. Pathol. 160, 57–62.PubMedGoogle Scholar
  36. 36.
    Sirica, A. E., Gainey, T. W., Harrell, M. B., Caran, N. (1997) Cholangiocarcinogenesis and biliary adaptation responses in hepatic injury. In: Sirica, A. E., Longnecker, D. S. (eds), Biliary and Pancreatic Ductal Epithelia: Pathobiology and Pathophysiology. Marcel Dekker, New York, pp. 229–290.Google Scholar
  37. 37.
    Slott, P. A., Liu, M. H., Tavoloni, N. (1990) Origin, pattern, and mechanism of bile duct proliferation following biliary obstruction in the rat. Gastroenterology 99, 466–477.PubMedGoogle Scholar
  38. 38.
    Solomonia, R. O., Apkhazava, D., Nozadze, M., Jackson, A. P., McCabe, B. J., Horn, G. (2008) Different forms of MARCKS protein are involved in memory formation in the learning process of imprinting. Exp. Brain Res. 188, 323–330.PubMedGoogle Scholar
  39. 39.
    Wright, J. E., Braithwaite, J. L. (1964) The effects of interruption of a lobar bile duct in the rat. J.Anat. 98, 219–225.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Yamamoto, K., Fisher, M. M., Phillips, M. J. (1985) Hilar biliary plexus in human liver. A comparative study of the intrahepatic bile ducts in man and animals. Lab. Invest. J. Tech. Meth. Pathol. 52, 103–106.Google Scholar
  41. 41.
    Yoshida, K., Yasuda, M., Nasu, T., Murakami, T. (2010) Scanning electron microscopic study of vascular and biliary casts in chicken and duck liver. J. Vet. Med. Sci./Jap. Soc. Vet. Sci. 72, 925–928.Google Scholar

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© Akadémiai Kiadó, Budapest 2012

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Authors and Affiliations

  • Elza Azmaiparashvili
    • 1
  • Ekaterine Berishvili
    • 2
  • Z. Kakabadze
    • 2
  • O. Pilishvili
    • 1
  • Ekaterine Mikautadze
    • 3
  • R. Solomonia
    • 3
  • M. Jangavadze
    • 4
  • D. Kordzaia
    • 4
    Email author
  1. 1.Faculty of MedicineIv. Javakhishvili Tbilisi State UniversityTbilisiGeorgia
  2. 2.Department of Clinical AnatomyTbilisi State Medical UniversityTbilisiGeorgia
  3. 3.Institute of Chemical BiologyIlia Tbilisi State UniversityTbilisiGeorgia
  4. 4.Al. Natishvili Institute of Morphology, Faculty of MedicineIv. Javakhishvili Tbilisi State UniversityTbilisiGeorgia

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