Skip to main content

Advertisement

SpringerLink
Log in

Role of podoplanin and Kupffer cells in liver injury after ischemia–reperfusion in mice

  • Original Article
  • Published:
Surgery Today Aims and scope Submit manuscript

Abstract

Aim

To investigate the relationship between the intrahepatic expression of podoplanin (PDPN) and Kupffer cells (KCs) in ischemia–reperfusion (I/R) liver damage.

Methods

C57Bl/6 mice were injected with 200 µl of clodronate liposomes (macrophage depletion; MDP group) to deplete KCs or control liposomes (control group) via the ophthalmic vein plexus 24 h prior to ischemia. Animals were subjected to 90 min of partial hepatic ischemia (70%), followed by reperfusion, and were then killed at designated time points. Serum and liver tissues were harvested for further analyses.

Results

Serum ALT levels, mortality rates, and the percentage of necrotic area in liver sections were significantly higher in the MDP group than in the control group. PDPN was expressed in the lymphatic epithelium, interlobular bile duct epithelium, and in some hepatocytes in each group. Its expression in hepatocytes was down-regulated in the MDP group. The accumulation of platelets in the sinusoid was reduced 6 h after I/R in the MDP group. Tissue HGF and IGF-1 levels decreased in the MDP group.

Conclusions

These results suggest that KCs play a key role in the activation of platelets through direct contact with PDPN-positive hepatocytes in I/R livers.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

Abbreviations

ALT:

Alanine aminotransferase

CLEC-2:

C-type lectin-like receptor2

PDPN:

Podoplanin

SEM:

Standard error of mean

TNF:

Tumor necrosis factor

MPD:

Clodronate liposome

KC:

Kupffer cells

I/R:

Ischemia/reperfusion

References

  1. Vedder NB, Fouty BW, Winn RK, Harlan JM, Rice CL. Role of neutrophils in generalized reperfusion injury associated with resuscitation from shock. Surgery. 1989;106(3):509–16.

    CAS  PubMed  Google Scholar 

  2. Huguet C, Gavelli A, Bona S. Hepatic resection with ischemia of the liver exceeding one hour. J Am Coll Surg. 1994;178(5):454–8.

    CAS  PubMed  Google Scholar 

  3. Lemasters JJ, Thurman RG. Reperfusion injury after liver preservation for transplantation. Annu Rev Pharmacol Toxicol. 1997;37:327–38.

    Article  CAS  Google Scholar 

  4. Colletti LM, Cortis A, Lukacs N, Kunkel SL, Green M, Strieter RM. Tumor necrosis factor up-regulates intercellular adhesion molecule 1, which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat. Shock. 1998;10(3):182–91.

    Article  CAS  Google Scholar 

  5. Colletti LM, Kunkel SL, Walz A, Burdick MD, Kunkel RG, Wilke CA, et al. Chemokine expression during hepatic ischemia/reperfusion-induced lung injury in the rat. The role of epithelial neutrophil activating protein. J Clin Invest. 1995;95(1):134–41.

    Article  CAS  Google Scholar 

  6. Jaeschke H, Farhood A, Bautista AP, Spolarics Z, Spitzer JJ, Smith CW. Functional inactivation of neutrophils with a Mac-1 (CD11b/CD18) monoclonal antibody protects against ischemia-reperfusion injury in rat liver. Hepatology. 1993;17(5):915–23.

    Article  CAS  Google Scholar 

  7. Ellett JD, Atkinson C, Evans ZP, Amani Z, Balish E, Schmidt MG, et al. Murine Kupffer cells are protective in total hepatic ischemia/reperfusion injury with bowel congestion through IL-10. J Immunol. 2010;184(10):5849–58.

    Article  CAS  Google Scholar 

  8. Sutter AG, Palanisamy AP, Ellet JD, Schmidt MG, Schnellmann RG, Chavin KD. Intereukin-10 and Kupffer cells protect steatotic mice livers from ischemia-reperfusion injury. Eur Cytokine Netw. 2014;25(4):69–76.

    Article  CAS  Google Scholar 

  9. Devey L, Ferenbach D, Mohr E, Sangster K, Bellamy CO, Hughes J, et al. Tissue-resident macrophages protect the liver from ischemia reperfusion injury via a heme oxygenase-1-dependent mechanism. Mol Ther. 2009;17(1):65–72.

    Article  CAS  Google Scholar 

  10. Anitua E, Andia I, Ardanza B, Nurden P, Nurden AT. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost. 2004;91(1):4–15.

    Article  CAS  Google Scholar 

  11. Matsuo R, Ohkohchi N, Murata S, Ikeda O, Nakano Y, Watanabe M, et al. Platelets strongly induce hepatocyte proliferation with IGF-1 and HGF In Vitro. J Surg Res. 2008;145(2):279–86.

    Article  CAS  Google Scholar 

  12. Takagi S, Sato S, Oh-hara T, Takami M, Koike S, Mishima Y, et al. Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2. PLoS One. 2013;8(8): e73609.

    Article  CAS  Google Scholar 

  13. Pollitt AY, Poulter NS, Gitz E, Navarro-Nunez L, Wang YJ, Hughes CE, et al. Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells. J Biol Chem. 2014;289(52):35695–710.

    Article  CAS  Google Scholar 

  14. Bertozzi CC, Schmaier AA, Mericko P, Hess PR, Zou Z, Chen M, et al. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood. 2010;116(4):661–70.

    Article  CAS  Google Scholar 

  15. Ramirez MI, Millien G, Hinds A, Cao Y, Seldin DC, Williams MC. T1alpha, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth. Dev Biol. 2003;256(1):61–72.

    Article  CAS  Google Scholar 

  16. Rishi AK, Joyce-Brady M, Fisher J, Dobbs LG, Floros J, VanderSpek J, et al. Cloning, characterization, and development expression of a rat lung alveolar type I cell gene in embryonic endodermal and neural derivatives. Dev Biol. 1995;167(1):294–306.

    Article  CAS  Google Scholar 

  17. Breiteneder-Geleff S, Matsui K, Soleiman A, Meraner P, Poczewski H, Kalt R, et al. Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis. Am J Pathol. 1997;151(4):1141–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kaji C, Tomooka M, Kato Y, Kojima H, Sawa Y. The expression of podoplanin and classic cadherins in the mouse brain. J Anat. 2012;220(5):435–46.

    Article  CAS  Google Scholar 

  19. Peterziel H, Muller J, Danner A, Barbus S, Liu HK, Radlwimmer B, et al. Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation. Neuro Oncol. 2012;14(4):426–39.

    Article  CAS  Google Scholar 

  20. Farr A, Nelson A, Hosier S. Characterization of an antigenic determinant preferentially expressed by type I epithelial cells in the murine thymus. J Histochem Cytochem. 1992;40(5):651–64.

    Article  CAS  Google Scholar 

  21. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz B, et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity. 2011;35(6):986–96.

    Article  CAS  Google Scholar 

  22. Hou TZ, Bystrom J, Sherlock JP, Qureshi O, Parnell SM, Anderson G, et al. A distinct subset of podoplanin (gp38) expressing F4/80+ macrophages mediate phagocytosis and are induced following zymosan peritonitis. FEBS Lett. 2010;584(18):3955–61.

    Article  CAS  Google Scholar 

  23. Kerrigan AM, Navarro-Nunez L, Pyz E, Finney BA, Willment JA, Watson SP, et al. Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2. J Thromb Haemost. 2012;10(3):484–6.

    Article  CAS  Google Scholar 

  24. Kato Y, Kaneko M, Sata M, Fujita N, Tsuruo T, Osawa M. Enhanced expression of Aggrus (T1alpha/podoplanin), a platelet-aggregation-inducing factor in lung squamous cell carcinoma. Tumour Biol. 2005;26(4):195–200.

    Article  CAS  Google Scholar 

  25. Mishima K, Kato Y, Kaneko MK, Nishikawa R, Hirose T, Matsutani M. Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression. Acta Neuropathol. 2006;111(5):483–8.

    Article  CAS  Google Scholar 

  26. Kono H, Fujii H, Ogiku M, Hara M, Tsuchiya M, Ishii K, et al. The Kupffer cell inhibition exacerbates but splenectomy prevents mortality in a rat septic peritonitis model. J Surg Res. 2012;175(1):101–12.

    Article  CAS  Google Scholar 

  27. Lentsch AB, Yoshidome H, Cheadle WG, Miller FN, Edwards MJ. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells. Hepatology. 1998;27(2):507–12.

    Article  CAS  Google Scholar 

  28. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5.

    Article  CAS  Google Scholar 

  29. Li J, Li RJ, Lv GY, Liu HQ. The mechanisms and strategies to protect from hepatic ischemia-reperfusion injury. Eur Rev Med Pharmacol Sci. 2015;19(11):2036–47.

    CAS  PubMed  Google Scholar 

  30. Kono H, Fujii H, Ogiku M, Hosomura N, Amemiya H, Tsuchiya M, et al. Role of IL-17A in neutrophil recruitment and hepatic injury after warm ischemia-reperfusion mice. J Immunol. 2011;187(9):4818–25.

    Article  CAS  Google Scholar 

  31. Meyer J, Lejmi E, Fontana P, Morel P, Gonelle-Gispert C, Bühler L. A focus on the role of platelets in liver regeneration: Do platelet-endothelial cell interactions initiate the regenerative process? J Hepatol. 2015;63(5):1263–71.

    Article  CAS  Google Scholar 

  32. Freeman CM, Quillin RC, Wilson GC, Nojima H, Johnson BL, Sutton JM, et al. Characterization of Microparticles after Hepatic Ischemia-Reperfusion Injury. PLoS One. 2014;9(5): e97945.

    Article  Google Scholar 

  33. Abu Rmilah AA, Zhou W, Nyberg SL. Hormonal contribution to liver regeneration. Mayo Clin Proc Innov Qual Outcomes. 2020;4(3):315–38.

    Article  Google Scholar 

  34. Lisman T, Porte RJ. The role of platelets in liver inflammation and regeneration. Semin Thromb Hemost. 2010;36(2):170–4.

    Article  Google Scholar 

  35. Suzuki-Inoue K, Inoue O, Ozaki Y. Novel platelet activation receptor CLEC-2: from discovery to prospects. J Thromb Haemost. 2011;9(Suppl 1):44–55.

    Article  CAS  Google Scholar 

  36. Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, et al. Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem. 2007;282(36):25993–6001.

    Article  CAS  Google Scholar 

  37. Kono H, Fujii H, Suzuki-Inoue K, Inoue O, Furuya S, Hirayama K, et al. The platelet-activating receptor C-type lectin receptor-2 plays an essential role in liver regeneration after partial hepatectomy in mice. J Thromb Haemost. 2017;15(5):998–1008.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan

    Yuuki Nakata, Hiroshi Kono, Yoshihiro Akazawa, Kazuyoshi Hirayama, Hiroyuki Wakana, Hisataka Fukushima, Chao Sun & Hideki Fujii

  2. Department of Orthopedic Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, China

    Chao Sun

Authors
  1. Yuuki Nakata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Kono
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshihiro Akazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuyoshi Hirayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroyuki Wakana
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hisataka Fukushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hideki Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Yuuki Nakata contributed to data collection and writing the manuscript. Hiroshi Kono contributed to the conception and design of the study. Yoshihiro Akazawa contributed to the analysis and interpretation of the study. Michio Hara contributed to critical revisions to the manuscript. Kazuyoshi Hirayama contributed to critical revisions to the manuscript. Yoshihiro Akazawa contributed to data collection. Hisataka Fukushima contributed to data collection. Chao Sun contributed to data collection and writing the manuscript. Hideki Fujii contributed to the conception and design of this study, and obtained funding.

Corresponding author

Correspondence to Hiroshi Kono.

Ethics declarations

Conflict of interest

No author has any financial conflicts to disclose about this manuscript, and there were no personal relationships with other individuals or organizations that may have potentially and inappropriately influenced the work performed or its conclusions. We have no conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakata, Y., Kono, H., Akazawa, Y. et al. Role of podoplanin and Kupffer cells in liver injury after ischemia–reperfusion in mice. Surg Today 52, 344–353 (2022). https://doi.org/10.1007/s00595-021-02378-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00595-021-02378-3

Keyword

Search

Navigation