Surgery Today

, Volume 29, Issue 1, pp 1–9 | Cite as

Role of shear stress and immune responses in liver regeneration after a partial hepatectomy

  • Yoshinobu Sato
  • Kazuhiro Tsukada
  • Katsuyoshi Hatakeyama


This report reviews studies addressing the new concepts in liver regeneration after a partial hepatectomy (PHx). The review begins with an overview of the immunologic mechanisms of liver regeneration after PHx, especially regarding Kupffer cells and extrathymic T cells of the regenerative liver in the cell-mediated immunity, based on major histocompatibility complex I and II antigens. Attention is then devoted to “on and off” studies in liver regeneration after PHx, by hypothesizing the shear stress based on the fact that the portal flow against hepatocytes or sinusoidal endothelial cells triggers their regeneration after a partial hepatectomy and controls the volume of the regenerating liver by the stimulating the cell surface modulator (CSM) of hepatocytes and sinusoidal endothelial cells (SEC). We propose that the acute elevation of shear stress after PHx influences the adhesion between SEC and intrahepatic leukocytes. These concepts are expected to positively contribute to the future research on liver regeneration after PHx.

Key Words

Liver regeneration shear stress immunity major histocompatibility complex sieve plates space of Disse 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Minoru O, Noriaki T, Kunzo O (1984) Activation of NK activity and auto-reactive cytotoxicity after hepatectomy. Acta Med Okayama 38:207–213Google Scholar
  2. 2.
    Flye MW, Yu S (1990) Augmentation of cell-mediated cytotoxicity following 50% partial hepatectomy. Transplantation 49:581–587CrossRefPubMedGoogle Scholar
  3. 3.
    Miyahara S, Yokomuro K, Takahashi H, Kimura Y (1983) Regeneration and the immune system I. In vitro and in vivo activation of lymphocytes by liver regeneration and the role of Kupffer cells in stimulation. Eur J Immunol 13:878–883CrossRefPubMedGoogle Scholar
  4. 4.
    Pinto M, Herzberg H, Barnea A, Shenberg E (1987) Effects of partial hepatectomy on the immune response in mice. Clin Immunol Immunopathol 142:123–132CrossRefGoogle Scholar
  5. 5.
    Sato Y, Inoue S, Nagao T, Yoshida K, Akiyama N, Muto T (1991) Cyclosporine suppresses class II antigen expression in regenerating liver of rats after partial hepatectomy. Jpn Gastroenterol Surg 24:172Google Scholar
  6. 6.
    Sato Y, Tsukada K, Yoshida K, Muto T, Matsumoto Y (1992) FK506 suppresses class II antigen expression in regenerating livers following partial hepatectomy in the rat. Transplant Proc 24:1628–1630PubMedGoogle Scholar
  7. 7.
    Sato Y, Tsukada K, Matsumoto Y, Abo T (1993) Interferon-γ inhibits liver regeneration by stimulating major histocompatibility complex class II antigen expression by regenerating liver. Hepatology 18:340–346CrossRefPubMedGoogle Scholar
  8. 8.
    Sato Y, Farges O, Delphine B, Bismuth H (1995) Intrahepatic lymphocytes following 70% partial hepatectomy in the rats: extrathymic T cells in the rats. Int Hepatol Commun 3 suppl:S132CrossRefGoogle Scholar
  9. 9.
    Sato Y, Farges O, Delphine B, Bismuth H (1996) Mechanism of extrathymic and thymic T cells following 70% PHx in the rats. Hepatology 21(1):I-74Google Scholar
  10. 10.
    Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173CrossRefPubMedGoogle Scholar
  11. 11.
    Guy-Grand D, Cerf-Bensussan N, Briottet C (1991) Two gut intraepithelial CD8+ lymphocyte populations with different T-cell receptors: a role for the gut epithelium in T-cell differentiation. J Exp Med 173:471–481CrossRefPubMedGoogle Scholar
  12. 12.
    Abo T, Ohteki T, Seki S, Koyamada N, Yoshikai Y, Masuda T, Rikiishi H, Kumagai K (1991) The appearance of T cells bearing self-reactive T-cell receptors in the livers of mice injected with bacteria. J Exp Med 174:417–424CrossRefPubMedGoogle Scholar
  13. 13.
    Seki S, Abo T, Sugiura K, Kumagai K (1991) Unusual αβ T cells expanded in autoimmune lpr mice are probably a counterpart of normal T cells in the liver. J Immunol 147:1214–1221PubMedGoogle Scholar
  14. 14.
    Sato Y, Tsukada K, Iiai T, Ohmori K, Yoshida K, Muto T, Watanabe Y, Matsumoto Y, Abo T (1993) Activation of extrathymic T cells in the liver during liver regeneration following partial hepatectomy. Immunology 78:86–91PubMedGoogle Scholar
  15. 14a.
    Sato Y, Farges O, Delphine B, Bismuth H (1998) Detection of intermediate TcR cells, NK3.2.3-positive T cells, and CD5+ B cells in older rats. Acta Med Biol (in press)Google Scholar
  16. 15.
    Itoh H, Abo T, Sugawara S, Kanno A, Kumagai K (1988) Agerelated variation in the proportion and activity of murine liver natural killer cells and their cytotoxicity against regenerating hepatocytes. J Immunol 141:315–323PubMedGoogle Scholar
  17. 16.
    Abo T, Ohteki T, Seki S, Koyamada N, Yoshikai Y, Masuda T, Rikiishi H, Kumagai K (1991) The appearance of T cells bearing self-reactive T-cell receptors in the livers of mice injected with bacteria. J Exp Med 174:417–424CrossRefPubMedGoogle Scholar
  18. 17.
    Fausto N (1994) Liver stem cells In: Arias IM, Boyer JL, Fausto N, Jokoby WB, Schachter D, Shafritz DA (eds) The liver: biology and pathology, 3rd edn. Raven Press New York, pp 1501–1518Google Scholar
  19. 18.
    Sato Y, Koyama S, Tsukada K, Hatakeyama K (1997) Acute portal hypertension reflecting shear stress is a trigger of liver regeneration following partial hepatectomy. Surgery Today 27 (in press)Google Scholar
  20. 19.
    Kamiya A, Togawa T (1980) Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol 239:H14-H21PubMedGoogle Scholar
  21. 20.
    Ando J, Tsuboi H, Korenaga R, Takada Y, Toyama SN, Miyasaka M, Kamiya A (1994) Shear stress inhibits adhesion of cultured mouse endothelial cells to lymphocytes by downregulating VCAM-1 expression. Am J Physiol 267:C679-C687PubMedGoogle Scholar
  22. 21.
    Hsieh HJ, Li NQ (1993) Pulsatile and steady flow induces c-fos expression in human endothelial cells. J Cell Physiol 154:143–151CrossRefPubMedGoogle Scholar
  23. 22.
    Ohno M, Lopez F, Gibbons GH, Cooke JP, Dzau VJ (1992) Shear stress induced TGF-beta 1 gene expression of active TGF-beta 1 is mediated via a K+ channel (abstract). Circulation 86:I-87Google Scholar
  24. 23.
    Marsden PA, Heng HH, Scherer SW, Stewart RJ, Hall AV, Shi XM, Tsui LC, Schappert KT (1993) Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem 268:17478–17488PubMedGoogle Scholar
  25. 24.
    Morello D, FitzGerald MJ, Babinet C, Fausto N (1990) c-myc, c-fos, and c-jun regulation in the regenerating livers of normal and H2K/c-myc transgenic mice. Mol Cell Biol 10:3185–3193PubMedGoogle Scholar
  26. 25.
    Fausto N, Mead JE, Gruppuso PA, Braun L (1990) TGF-beta in the liver development, regulation and carcinogenesis. Ann NY Acad Sci 593:231–242CrossRefPubMedGoogle Scholar
  27. 26.
    Michalopoulos GK (1990) Liver regeneration: molecular mechanisms of growth control. FASEB J 4:176–187PubMedGoogle Scholar
  28. 27.
    Sonsoles H, Beatrice D, Ana MG, Maria JMD-G, Lisardo B (1995) Nitric oxide is released in regenerating liver after partial hepatectomy. Hepatology 21:776–786Google Scholar
  29. 28.
    Braet F, Zanger RD, Baekeland M, Crabbe E, Van Der Smissen P, Wisse E (1995) Structure and dynamics of the fenestrae-associated cytoskeleton of rat liver sinusoidal endothelial cells. Hepatology 21:180–189PubMedGoogle Scholar
  30. 29.
    Whitfield JF, Boynton AL, Rixon RH (1985) The control of cell proliferation by calcium, Ca2+ calmodulin, and cyclic AMP. In: Boynton AL, Leffert HN (eds) Control of animal cell proliferation. Academic, New York, pp 331–365Google Scholar
  31. 30.
    Koch KS, Leffert HN (1979) Increased sodium ion influx is necessary to initiate rat hepatocyte proliferation. Cell 18:153–163CrossRefPubMedGoogle Scholar
  32. 31.
    Yee AG, Revel JP (1978) Loss and reappearance of gap junctions in regenerating liver. J Cell Biol 78:554–564CrossRefPubMedGoogle Scholar
  33. 32.
    Schaffner F, Popper H (1963) Capillarization of hepatic sinusoid in man. Gastroenterology 44:239–242PubMedGoogle Scholar
  34. 33.
    Fraser R, Bowler LM, Day WA, Dobbs B, Johnson HD, Lee D (1980) High perfusion pressure damages the sieving ability of sinusoidal endothelium in rat livers. Br J Exp Pathol 61:222–228PubMedGoogle Scholar
  35. 34.
    Oda M, Nakamura M, Watanabe N, Ohya Y, Sekuzuka E, Tsukada N, Yonei Y (1983) Some dynamic aspects of the hepatic microcirculation: demonstration of sinusoidal endothelail fenestrae as a possible regulatory factor. In: Tsuchiya M, Wayland H, Oda M, Okazaki I (eds) Intravital observation of organ microcirculation. Excerpta Medica, Amsterdam, pp 105–138Google Scholar
  36. 35.
    Nakata K (1961) Direct measurement of blood pressures in minute vessels of the liver. Am J Physiol 199:1181–1188Google Scholar
  37. 36.
    Rous P, Larimore LD (1920) Relation of the portal blood to liver maintenance. J Exp Med 31:609–632CrossRefPubMedGoogle Scholar
  38. 37.
    Mann FC, Fishback FC, Gay JG, Green GF (1931) Experimental pathology of the liver; Studies III, IV, V. Arch Pathol (Chicago) 12:787–807Google Scholar
  39. 38.
    Bollman JL (1961) The animal with an Eck fistula. Physiol Rev 41:607–621Google Scholar
  40. 39.
    Fisher B, Russ C, Updegraff H, Fisher ER (1954) Effect of increased hepatic blood flow upon liver regeneration. Arch Surg 69:263–272Google Scholar
  41. 40.
    Clarke AM, Thomson RY, Fraenkel GJ (1968) Vascular factors in liver regeneration. SGO 126:45–52PubMedGoogle Scholar
  42. 40a.
    Bucher NLR, Swaffield MN (1964) The rate of incorporation of labeled thymidine into the deoxyribonucleic acid of regenerating rat liver in relation to the amount of liver excised. Cancer Res 24:1611–1625PubMedGoogle Scholar
  43. 41.
    Starzl TE, Porter KA, Putnam CW (1975) Intraportal insulin protects from the liver injury of portacaval shunt in dogs. Lancet 2:1241–1246CrossRefPubMedGoogle Scholar
  44. 42.
    Francavilla A, Ove P, Wu SK, DiLeo A, Van Thiel D, Starzl TE (1982) Extraction of hepatic stimulatory activity (HSA) from (adult) rat liver following T3 injection (abstract). Hepatology 2:704Google Scholar
  45. 43.
    Francavilla A, Barone M, Van Thiel DH, Mazzaferro V, Prelich J, Starzl TE (1991) Further steps of HSS (hepatic stimulatory substance) purification. Dig Dis Sci 36:674–680CrossRefPubMedGoogle Scholar
  46. 44.
    Kan M, Huang J, Mansson PE, Yasumitsu H, Carr B, McKeehan WL (1989) Heparin-binding growth factor type 1 (acidic fibroblast growth factor): a potential biphasic autocrine and paracrine regulator of hepatocyte regeneration. Proc Natl Acad Sci USA 86:7432–7436CrossRefPubMedGoogle Scholar
  47. 45.
    Marsden ER, Hu Z, Fujio K, Nakatsukasa H, Thorgeirsson SS, Evarts RP (1992) Expression of acidic fibroblast growth factor in regenerating liver and during hepatic differentiation. Lab Invest 67:427–433PubMedGoogle Scholar
  48. 46.
    Cruise JL, Houck KA, Michalopouls G (1985) Induction of DNA synthesis in cultured rat hepatocytes through stimulation of alpha-1 adrenoreceptor by norepinephrine. Science 227:749–751CrossRefPubMedGoogle Scholar
  49. 47.
    Russell WE, Bucher NLR (1983) Vasopressin modulates liver regeneration in the Brattleboro rat. Am J Physiol 245:G321-G324PubMedGoogle Scholar
  50. 48.
    MacManus JP, Braceland BM (1976) A connection between the production of prostaglandins during liver regeneration and the DNA synthesis responses. Prostaglandins 11:609–620CrossRefPubMedGoogle Scholar
  51. 49.
    McGowan JA, Strain AJ, Bucher NL (1981) DNA synthesis in primary cultures of adult rat hepatocytes in a defined medium: effects of epidermal growth factor, insulin, glucagon, and cyclic-AMP. J Cell Physiol 108:353–363CrossRefPubMedGoogle Scholar
  52. 50.
    Skov Olsen P, Boesby S, Kirkegaard P, Therkelsen AT, Poulsen SS, Nexo E (1988) Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats. Hepatology 8:922–996Google Scholar
  53. 51.
    Mead JE, Fausto N (1989) Transforming growth factor α may be a physiological regulator of liver regeneration by means of an autocrine mechanism. Proc Natl Acad Sci USA 86:1558–1562CrossRefPubMedGoogle Scholar
  54. 52.
    Russell WE, Dempsey PJ, Sitaric C, Peck AJ, Coffey RJ Jr (1993) Transforming growth factor-alpha (TGF-α) concentrations increase in regenerating rat liver: evidence for a delayed accumulation of mature TGF alpha. Endocrinology 133:1731–1738CrossRefPubMedGoogle Scholar
  55. 53.
    Russell WE, McGowan JA, Bucher NLR (1984) Biological properties of a hepatocyte growth factor from rat platelets. J Cell Physiol 119:193–197CrossRefPubMedGoogle Scholar
  56. 54.
    Webber EM, FitzGerald MJ, Brown PI, Bartlett MH, Fausto N (1993) TGF-α expression during liver regeneration after partial hepatectomy and toxic injury, and potential interactions between TGF-α and HGF. Hepatology 18:1422–1431CrossRefPubMedGoogle Scholar
  57. 55.
    Lindroos PM, Zarnegar R, Michalopoulos GK (1991) Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration. Hepatology 13:743–749CrossRefPubMedGoogle Scholar
  58. 56.
    Fausto N, Webber EM (1993) Control of liver growth. Crit Rev Eukaryot Gene Express 3:117–135Google Scholar
  59. 57.
    Fausto N, Webber EM (1993) Mechanisms of growth regulation in liver regeneration and hepatic carcinogenesis. In: Boyer JL, Ockner K (eds) Progress in liver disease XI. WB Saunders, PhiladelphiaGoogle Scholar
  60. 58.
    Akerman P, Cote P, Yang SQ, McClain C, Nelson S, Bagby GJ, Diehl AM (1992) Antibodies to tumor necrosis factor-α inhibit liver regeneration after partial hepatectomy. Am J Physiol 263:G579-G585PubMedGoogle Scholar
  61. 59.
    Schreck R, Rieber P, Baeuerie PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of NF-kB transcription factor and HIV-1. EMBO J 10:2247–2258PubMedGoogle Scholar
  62. 60.
    Banerjee R, Karpen S, Siekevitz M, Lengyel G, Bauer J, Acs G (1989) Tumor necrosis factor-α induces a kappa B sequence-specific DNA-binding protein in human hepatoblastoma HepG2 cells. Hepatology 10:1008–1013CrossRefPubMedGoogle Scholar
  63. 61.
    Mito M, Ackroyed FW, Covelli VH, Eyskens E, Katayama I, McDermott WV (1967) Partial heterotopic liver homograft in dogs utilizing portal arterialization. Ann Surg 165:20–32CrossRefPubMedGoogle Scholar
  64. 62.
    Child CG, Barr D, Holswade GR, Harrison CS (1953) Liver regeneration following portacaval transposition in dogs. Ann Surg 138:600–608CrossRefPubMedGoogle Scholar
  65. 63.
    Sigel B, Baldia LB, Brightman SA, Dunn MR (1968) Effect of blood flow reversal in liver autotransplants upon the site of hepatocyte regeneration. J Clin Invest 47:1231–1237PubMedGoogle Scholar
  66. 64.
    Isomura H, Sawada N, Nakajima Y, Sakamoto H, Ideda T, Kijima T, Enomoto K, Mori M (1993) Increase in portal flow induces c-myc expression in isolated perfused rat liver. J Cell Physiol 154:329–332CrossRefPubMedGoogle Scholar
  67. 64a.
    Resnick N, Collins T, Atkinson W, Bonthron DT, Dewey CFJ, Gimbrone MA (1993) Platelet-derived growth factor B chain promoter contains a cis-acting fluid shear-stress-responsive element. Proc Natl Acad Sci USA 90:4591–4595CrossRefPubMedGoogle Scholar
  68. 65.
    Bucher EC (1991) Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity. Cell 67:1033–1036CrossRefGoogle Scholar
  69. 66.
    Lawrence MB, Springer TA (1991) Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell 65:859–873CrossRefPubMedGoogle Scholar
  70. 67.
    Tanaka Y, Adams DH, Shaw S (1993) Proteoglycan on endothelial cells present adhesion-inducing cytokines to leukocytes. Immunol Today 14:111–115CrossRefPubMedGoogle Scholar
  71. 68.
    Nagel T, Resnick N, Atkinson WJ, Dewey CF, Gimbrone MA Jr (1994) Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest 94:885–891CrossRefPubMedGoogle Scholar
  72. 69.
    Lawrence MB, McIntire LV, Eskin SG (1994) Effect of flow on polymorphonuclear leukocyte/endothelial cell adhesion. Am J Physiol 267:1284–1290Google Scholar
  73. 70.
    Chen S, Alon R, Fuhlbrigge RC, Springer TA (1997) Rolling and transient tethering of leukocytes on antibodies reveal specializations of selections. Proc Natl Acad Sci USA 94:3172–3177CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1999

Authors and Affiliations

  • Yoshinobu Sato
    • 1
  • Kazuhiro Tsukada
    • 1
  • Katsuyoshi Hatakeyama
    • 1
  1. 1.First Department of SurgeryNiigata University School of MedicineNiigataJapan

Personalised recommendations