Skip to main content

Advertisement

Log in

Liver regeneration following partial hepatectomy is improved by enhancing the HGF/Met axis and Akt and Erk pathways after low-power laser irradiation in rats

  • Original Article
  • Published:
Lasers in Medical Science Aims and scope Submit manuscript

Abstract

A simple, easy, and safe procedure aiming to improve liver regeneration could be of great clinical benefit in critical situations such as major hepatectomy, trauma, or hemorrhage. Low-power laser irradiation (LPLI) has come into a wide range of use in clinical practice by inducing regeneration in healthy and injured tissues. However, the effect of LPLI on the process of liver regeneration, especially those related to the molecular mechanisms, is not fully understood. Thus, the aim of the present study was to investigate the main molecular mechanisms involved in liver regeneration of partially hepatectomized rats exposed to LPLI. We used Wistar male rats, which had their remaining liver irradiated or not with LPLI (wavelength of 632.8 nm and fluence of 65 mW/cm2) for 15 min after a 70 % hepatectomy. We subsequently investigated hepatocyte growth factor (HGF), Met, Akt, and Erk 1/2 signaling pathways through protein expression and phosphorylation analyses along with cell proliferation (proliferating cell nuclear antigen (PCNA) and Ki-67) using immunoblotting and histological studies. Our results show that LPLI can improve liver regeneration as shown by increased HGF protein expression and the phosphorylation levels of Met, Akt, and Erk 1/2 accompanied by higher levels of the PCNA and Ki-67 protein in the remnant livers. In summary, our results suggest that LPLI may play a clinical role as a simple, fast, and easy-to-perform strategy in order to enhance the liver regenerative capacity of a small liver remnant after hepatectomy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA (2003) Liver regeneration. J Am Coll Surg 197(4):634–659

    Article  PubMed  Google Scholar 

  2. Court FG, Wemyss-Holden SA, Dennison AR, Maddern GJ (2002) The mystery of liver regeneration. Br J Surg 89(9):1089–1095

    Article  PubMed  CAS  Google Scholar 

  3. Di Domenico S, Santori G, Traverso N, Balbis E, Furfaro A, Grillo F, Gentile R, Bocca B, Gelli M, Andorno E, Dahame A, Cottalasso D, Valente U (2011) Early effects of portal flow modulation after extended liver resection in rat. Dig Liver Dis 43(10):814–822

    Article  PubMed  Google Scholar 

  4. Yigitler C, Farges O, Kianmanesh R, Regimbeau JM, Abdalla EK, Belghiti J (2003) The small remnant liver after major liver resection: how common and how relevant? Liver Transpl 9(9):S18–25

    Article  PubMed  Google Scholar 

  5. Teixeira AR, Molan NT, Kubrusly MS, Bellodi-Privato M, Coelho AM, Leite KR, Machado MA, Bacchella T, Machado MC (2009) Postconditioning ameliorates lipid peroxidation in liver ischemia-reperfusion injury in rats. Acta Cirurgica Brasileira/Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia 24(1):52–56

    PubMed  Google Scholar 

  6. Seyama Y, Imamura H, Inagaki Y, Matsuyama Y, Tang W, Makuuchi M, Kokudo N (2012) Intermittent clamping is superior to ischemic preconditioning and its effect is more marked with shorter clamping cycles in the rat liver. J Gastroenterol. doi:10.1007/s00535-012-0613-0

  7. Teixeira AR, Molan NT, Bellodi-Privato M, Coelho AM, Leite KR, Seguro AC, Bacchella T, Machado MC (2008) Rosiglitazone-enriched diet did not protect liver ischemia-reperfusion injury in a rat model. Acta Cirurgica Brasileira/Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia 23(4):378–383

    Article  PubMed  Google Scholar 

  8. Lee EJ, Silva SM, Simoes Mde J, Montero EF (2012) Effect of N-acetylcysteine in liver ischemia-reperfusion injury after 30 % hepatectomy in mice. Acta Cirurgica Brasileira/Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia 27(4):346–349

    Article  PubMed  Google Scholar 

  9. Wang KX, Hu SY, Jiang XS, Zhu M, Jin B, Zhang GY, Chen B (2008) Protective effects of ischaemic postconditioning on warm/cold ischaemic reperfusion injury in rat liver: a comparative study with ischaemic preconditioning. Chin Med J (Engl) 121(20):2004–2009

    Google Scholar 

  10. Gao X, Xing D (2009) Molecular mechanisms of cell proliferation induced by low power laser irradiation. J Biomed Sci 16:4

    Article  PubMed  Google Scholar 

  11. Oron U, Maltz L, Tuby H, Sorin V, Czerniak A (2010) Enhanced liver regeneration following acute hepatectomy by low-level laser therapy. Photomed Laser Surg 28(5):675–678

    Article  PubMed  CAS  Google Scholar 

  12. Grossman N, Schneid N, Reuveni H, Halevy S, Lubart R (1998) 780 nm low power diode laser irradiation stimulates proliferation of keratinocyte cultures: involvement of reactive oxygen species. Lasers Surg Med 22(4):212–218

    Article  PubMed  CAS  Google Scholar 

  13. Kreisler M, Christoffers AB, Al-Haj H, Willershausen B, d’Hoedt B (2002) Low level 809-nm diode laser-induced in vitro stimulation of the proliferation of human gingival fibroblasts. Lasers Surg Med 30(5):365–369

    Article  PubMed  Google Scholar 

  14. Pereira AN, Eduardo Cde P, Matson E, Marques MM (2002) Effect of low-power laser irradiation on cell growth and procollagen synthesis of cultured fibroblasts. Lasers Surg Med 31(4):263–267

    Article  PubMed  Google Scholar 

  15. Vinck EM, Cagnie BJ, Cornelissen MJ, Declercq HA, Cambier DC (2003) Increased fibroblast proliferation induced by light emitting diode and low power laser irradiation. Lasers Med Sci 18(2):95–99

    Article  PubMed  Google Scholar 

  16. Stein A, Benayahu D, Maltz L, Oron U (2005) Low-level laser irradiation promotes proliferation and differentiation of human osteoblasts in vitro. Photomed Laser Surg 23(2):161–166

    Article  PubMed  CAS  Google Scholar 

  17. Stadler I, Evans R, Kolb B, Naim JO, Narayan V, Buehner N, Lanzafame RJ (2000) In vitro effects of low-level laser irradiation at 660 nm on peripheral blood lymphocytes. Lasers Surg Med 27(3):255–261

    Article  PubMed  CAS  Google Scholar 

  18. Tuby H, Maltz L, Oron U (2007) Low-level laser irradiation (LLLI) promotes proliferation of mesenchymal and cardiac stem cells in culture. Lasers Surg Med 39(4):373–378

    Article  PubMed  Google Scholar 

  19. Gavish L, Perez L, Gertz SD (2006) Low-level laser irradiation modulates matrix metalloproteinase activity and gene expression in porcine aortic smooth muscle cells. Lasers Surg Med 38(8):779–786

    Article  PubMed  Google Scholar 

  20. Schindl A, Merwald H, Schindl L, Kaun C, Wojta J (2003) Direct stimulatory effect of low-intensity 670 nm laser irradiation on human endothelial cell proliferation. Br J Dermatol 148(2):334–336

    Article  PubMed  CAS  Google Scholar 

  21. Oron U (2006) Photoengineering of tissue repair in skeletal and cardiac muscles. Photomed Laser Surg 24(2):111–120

    Article  PubMed  Google Scholar 

  22. Oron A, Oron U, Chen J, Eilam A, Zhang C, Sadeh M, Lampl Y, Streeter J, DeTaboada L, Chopp M (2006) Low-level laser therapy applied transcranially to rats after induction of stroke significantly reduces long-term neurological deficits. Stroke 37(10):2620–2624

    Article  PubMed  Google Scholar 

  23. Castro-e-Silva O Jr, Zucoloto S, Marcassa LG, Marcassa J, Kurachi C, Melo CA, Ramalho FS, Ramalho LN, Bagnato VS (2003) Spectral response for laser enhancement in hepatic regeneration for hepatectomized rats. Lasers Surg Med 32(1):50–53

    Article  PubMed  Google Scholar 

  24. de Castro E Silva O Jr, Zucoloto S, Menegazzo LA, Granato RG, Marcassa LG, Bagnato VS (2001) Laser enhancement in hepatic regeneration for partially hepatectomized rats. Lasers Surg Med 29(1):73–77

    Article  Google Scholar 

  25. Oliveira AF, Silva TC, Sankarankutty AK, Pacheco EG, Ferreira J, Bagnato VS, Zucoloto S, Silva Ode C (2006) The effect of laser on remanescent liver tissue after 90 % hepatectomy in rats. Acta Cirurgica Brasileira/Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia 21(Suppl 1):29–32

    PubMed  Google Scholar 

  26. Barbosa AJ, Santana AC, Castro e Silva T, Kurachi C, Inada N, Bagnato VS, Silva Ode C Jr (2011) Effect of laser on the remnant liver after the first 24 hours following 70 % hepatectomy in rats. Acta Cirurgica Brasileira/Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia 26(6):470–474

    Article  PubMed  Google Scholar 

  27. Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR (2001) Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci U S A 98(1):247–252

    Article  PubMed  CAS  Google Scholar 

  28. Higgins GM, Anderson RM (1931) Experimental pathology of the liver I. Restoration of the liver of the white rat following surgical removal. Arch Pathol 12(4):186–206

    Google Scholar 

  29. Emond J, Capron-Laudereau M, Meriggi F, Bernuau J, Reynes M, Houssin D (1989) Extent of hepatectomy in the rat. Evaluation of basal conditions and effect of therapy. Eur Surg Res 21(5):251–259

    Article  PubMed  CAS  Google Scholar 

  30. Caricilli AM, Picardi PK, de Abreu LL, Ueno M, Prada PO, Ropelle ER, Hirabara SM, Castoldi A, Vieira P, Camara NO, Curi R, Carvalheira JB, Saad MJ (2011) Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol 9(12):e1001212

    Article  PubMed  CAS  Google Scholar 

  31. Tobar N, Oliveira AG, Guadagnini D, Bagarolli RA, Rocha GZ, Araujo TG, Santos-Silva JC, Zollner RL, Boechat LH, Carvalheira JB, Prada PO, Saad MJ (2011) Diacerhein improves glucose tolerance and insulin sensitivity in mice on a high-fat diet. Endocrinology 152(11):4080–4093

    Article  PubMed  CAS  Google Scholar 

  32. Araujo TG, Oliveira AG, Carvalho BM, Guadagnini D, Protzek AO, Carvalheira JB, Boschero AC, Saad MJ (2012) Hepatocyte growth factor plays a key role in insulin resistance-associated compensatory mechanisms. Endocrinology 153(12):5760–5769

    Article  PubMed  CAS  Google Scholar 

  33. Rocha GZ, Dias MM, Ropelle ER, Osorio-Costa F, Rossato FA, Vercesi AE, Saad MJ, Carvalheira JB (2011) Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res 17(12):3993–4005

    Article  PubMed  CAS  Google Scholar 

  34. Martins PN, Theruvath TP, Neuhaus P (2008) Rodent models of partial hepatectomies. Liver Int 28(1):3–11

    Article  PubMed  Google Scholar 

  35. Michalopoulos GK (1990) Liver regeneration: molecular mechanisms of growth control. FASEB J 4(2):176–187

    PubMed  CAS  Google Scholar 

  36. Michalopoulos GK (2010) Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 176(1):2–13

    Article  PubMed  CAS  Google Scholar 

  37. Okano J, Shiota G, Matsumoto K, Yasui S, Kurimasa A, Hisatome I, Steinberg P, Murawaki Y (2003) Hepatocyte growth factor exerts a proliferative effect on oval cells through the PI3K/AKT signaling pathway. Biochem Biophys Res Commun 309(2):298–304

    Article  PubMed  CAS  Google Scholar 

  38. Webster CR, Anwer MS (2001) Phosphoinositide 3-kinase, but not mitogen-activated protein kinase, pathway is involved in hepatocyte growth factor-mediated protection against bile acid-induced apoptosis in cultured rat hepatocytes. Hepatology 33(3):608–615

    Article  PubMed  CAS  Google Scholar 

  39. Nakagami H, Morishita R, Yamamoto K, Taniyama Y, Aoki M, Matsumoto K, Nakamura T, Kaneda Y, Horiuchi M, Ogihara T (2001) Mitogenic and antiapoptotic actions of hepatocyte growth factor through ERK, STAT3, and AKT in endothelial cells. Hypertension 37(2 Part 2):581–586

    Article  PubMed  CAS  Google Scholar 

  40. Karu T (1999) Primary and secondary mechanisms of action of visible to near-IR radiation on cells. J Photochem Photobiol B 49(1):1–17

    Article  PubMed  CAS  Google Scholar 

  41. Shefer G, Oron U, Irintchev A, Wernig A, Halevy O (2001) Skeletal muscle cell activation by low-energy laser irradiation: a role for the MAPK/ERK pathway. J Cell Physiol 187(1):73–80

    Article  PubMed  CAS  Google Scholar 

  42. Shefer G, Barash I, Oron U, Halevy O (2003) Low-energy laser irradiation enhances de novo protein synthesis via its effects on translation-regulatory proteins in skeletal muscle myoblasts. Biochim Biophys Acta 1593(2–3):131–139

    Article  PubMed  CAS  Google Scholar 

  43. Nguyen VN, Mirejovsky P, Mirejovsky T, Melinova L, Mandys V (2000) Expression of cyclin D1, Ki-67 and PCNA in non-small cell lung cancer: prognostic significance and comparison with p53 and bcl-2. Acta Histochem 102(3):323–338

    Article  PubMed  CAS  Google Scholar 

  44. Ben-Dov N, Shefer G, Irintchev A, Wernig A, Oron U, Halevy O (1999) Corrigendum to: ‘Low-energy laser irradiation affects satellite cell proliferation and differentiation in vitro’. Biochim Biophys Acta 1450(1):108

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo and Conselho Nacional de Pesquisa. The authors thank L. Janeri, J. Pinheiro, and P. Latuf-Filho (Department of Internal Medicine, UNICAMP, Campinas, São Paulo) for technical assistance.

Conflict of interest

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Antonio R. Franchi Teixeira.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Araújo, T.G., de Oliveira, A.G., Tobar, N. et al. Liver regeneration following partial hepatectomy is improved by enhancing the HGF/Met axis and Akt and Erk pathways after low-power laser irradiation in rats. Lasers Med Sci 28, 1511–1517 (2013). https://doi.org/10.1007/s10103-013-1264-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10103-013-1264-y

Keywords

Navigation