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.
Similar content being viewed by others
References
Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA (2003) Liver regeneration. J Am Coll Surg 197(4):634–659
Court FG, Wemyss-Holden SA, Dennison AR, Maddern GJ (2002) The mystery of liver regeneration. Br J Surg 89(9):1089–1095
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
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
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
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
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
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
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
Gao X, Xing D (2009) Molecular mechanisms of cell proliferation induced by low power laser irradiation. J Biomed Sci 16:4
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
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
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
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
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
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
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
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
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
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
Oron U (2006) Photoengineering of tissue repair in skeletal and cardiac muscles. Photomed Laser Surg 24(2):111–120
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
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
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
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
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
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
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
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
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
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
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
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
Martins PN, Theruvath TP, Neuhaus P (2008) Rodent models of partial hepatectomies. Liver Int 28(1):3–11
Michalopoulos GK (1990) Liver regeneration: molecular mechanisms of growth control. FASEB J 4(2):176–187
Michalopoulos GK (2010) Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 176(1):2–13
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
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
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
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
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
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
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
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
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
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10103-013-1264-y