1. bookVolume 29 (2021): Issue 4 (October 2021)
Journal Details
First Published
08 Aug 2013
Publication timeframe
4 times per year
access type Open Access

VEGF-C and podoplanin, as biomarkers of sepsis. An experimental study

Published Online: 22 Oct 2021
Page range: 403 - 412
Received: 01 Sep 2021
Accepted: 27 Sep 2021
Journal Details
First Published
08 Aug 2013
Publication timeframe
4 times per year

Background: Sepsis is the leading cause of morbidity and mortality in intensive care units. This study explored the possible role of vascular endothelial growth factor-C (VEGF-C) and podoplanin (PDPN) in sepsis.

Methods: 22 Wistar rats were divided into three groups: two experimental (Group A and B, n=8/8) and a control (Group C, n=6). Sepsis was induced with intraperitoneal injection of ESBL (extended-spectrum beta-lactamases)-producing E-coli live bacteria for group A and with lipopolysaccharide for group B. Sterile saline solution was injected for group C. Blood samples were collected after 24 hours to determine the serum level of VEGF-C, and PDPN expression was examined in liver, kidney, and lung tissues. Bacteremia was assessed for group A.

Results: Higher serum levels of VEGF-C were found in Group A vs C (p=0.05) and group B vs. C (p=0.004), respectively.VEGF-C was also increased in animals with negative- vs. positive blood cultures from group A (p=0.04) and from group B vs. those with positive blood cultures from group A (p=0.03). High intensity of PDPN tissue expression was observed in the pulmonary alveolocytes from Group A and epithelium of the proximal renal tubules in groups B and C, compared to group A.

Conclusions: Circulating VEGF-C can be succesfuly used as a biomarker of sepsis with negative blood cultures and high risk of renal failure, whereas PDPN seems to exert a protective role against lung injuries in live bacteria-induced sepsis.


1. Adhikari NKJ, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet. 2010 Oct 16;376(9749):1339-46. DOI: 10.1016/S0140-6736(10)60446-110.1016/S0140-6736(10)60446-1 Search in Google Scholar

2. Fleischmann C, Scherag A, Adhikari NKJ, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016 Feb 1;193(3):259-72. DOI: 10.1164/ rccm.201504-0781OC10.1164/rccm.201504-0781OC Search in Google Scholar

3. Minasyan H. Sepsis and septic shock: Pathogenesis and treatment perspectives. J Crit Care. 2017 Aug;40:229-42. DOI: 10.1016/j.jcrc.2017.04.01510.1016/j.jcrc.2017.04.015 Search in Google Scholar

4. Sherwin R, Winters ME, Vilke GM, Wardi G. Does Early and Appropriate Antibiotic Administration Improve Mortality in Emergency Department Patients with Severe Sepsis or Septic Shock? J Emerg Med. 2017 Oct;53(4):588-95. DOI: 10.1016/j. jemermed.2016.12.009 Search in Google Scholar

5. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017 Oct 3;318(13):1241-9. DOI: 10.1001/jama.2017.1383610.1001/jama.2017.13836 Search in Google Scholar

6. Giannakopoulos K, Hoffmann U, Ansari U, Bertsch T, Borggrefe M, Akin I, et al. The Use of Biomarkers in Sepsis: A Systematic Review. Curr Pharm Biotechnol. 2017;18(6):499-507. DOI: 10.2174/138920101866617 0601080111 Search in Google Scholar

7. Kovacs J, Gurzu S, Jung J, Szederjesi J, Copotoiu S-M, Copotoiu R, et al. Clinico-pathological particularities of the shock-related pancreatitis. Pathol Oncol Res. 2012 Oct;18(4):977-81. DOI: 10.1007/s12253-012-9528-610.1007/s12253-012-9528-6 Search in Google Scholar

8. Gauer R, Forbes D, Boyer N. Sepsis: Diagnosis and Management. AFP. 2020 Apr 1;101(7):409-18. Search in Google Scholar

9. Matthaiou DK, Ntani G, Kontogiorgi M, Poulakou G, Armaganidis A, Dimopoulos G. An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients. Intensive Care Med. 2012 Jun;38(6):940-9. DOI: 10.1007/s00134-012-2563-710.1007/s00134-012-2563-7 Search in Google Scholar

10. Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013 May;13(5):426-35. DOI: 10.1016/S1473-3099(12)70323-710.1016/S1473-3099(12)70323-7 Search in Google Scholar

11. Lam SW, Bauer SR, Fowler R, Duggal A. Systematic Review and Meta-Analysis of Procalcitonin-Guidance Versus Usual Care for Antimicrobial Management in Critically Ill Patients: Focus on Subgroups Based on Antibiotic Initiation, Cessation, or Mixed Strategies. Crit Care Med. 2018 May;46(5):684-90. DOI: 10.1097/ CCM.000000000000295310.1097/CCM.0000000000002953 Search in Google Scholar

12. Karaman S, Leppänen V-M, Alitalo K. Vascular endothelial growth factor signaling in development and disease. Development. 2018 Jul 20;145(14):dev151019. DOI: 10.1242/dev.15101910.1242/dev.151019 Search in Google Scholar

13. Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem. 1994 Oct 14;269(41):25646-54. DOI: 10.1016/S0021-9258(18)47298-510.1016/S0021-9258(18)47298-5 Search in Google Scholar

14. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 1997 Jul 1;16(13):3898-911. DOI: 10.1093/emboj/16.13.389810.1093/emboj/16.13.3898 Search in Google Scholar

15. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9267-71. DOI: 10.1073/pnas.88.20.926710.1073/pnas.88.20.9267 Search in Google Scholar

16. Azamfirei L, Gurzu S, Solomon R, Copotoiu R, Copotoiu S, Jung I, et al. Vascular endothelial growth factor: a possible mediator of endothelial activation in acute respiratory distress syndrome. Minerva Anestesiol. 2010 Aug;76(8):609-16.10.1378/chest.136.4_MeetingAbstracts.76S-a Search in Google Scholar

17. Astarita JL, Acton SE, Turley SJ. Podoplanin: emerging functions in development, the immune system, and cancer. Front Immunol. 2012;3:283. DOI: 10.3389/fimmu.2012.0028310.3389/fimmu.2012.00283 Search in Google Scholar

18. Wicki A, Christofori G. The potential role of podoplanin in tumour invasion. Br J Cancer. 2007 Jan 15;96(1):1-5. DOI: 10.1038/sj.bjc.660351810.1038/sj.bjc.6603518 Search in Google Scholar

19. Suzuki-Inoue K, Inoue O, Ozaki Y. Novel platelet activation receptor CLEC-2: from discovery to prospects. J Thromb Haemost. 2011 Jul;9 Suppl 1:44-55. DOI: 10.1111/j.1538-7836.2011.04335.x10.1111/j.1538-7836.2011.04335.x Search in Google Scholar

20. 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 Oct;151(4):1141-52. Search in Google Scholar

21. Maruyama Y, Maruyama K, Kato Y, Kajiya K, Moritoh S, Yamamoto K, et al. The effect of podoplanin inhibition on lymphangiogenesis under pathological conditions. Invest Ophthalmol Vis Sci. 2014 Jul 1;55(8):4813-22. DOI: 10.1167/iovs.13-1371110.1167/iovs.13-13711 Search in Google Scholar

22. Rayes J, Lax S, Wichaiyo S, Watson SK, Di Y, Lombard S, et al. The podoplanin-CLEC-2 axis inhibits inflammation in sepsis. Nat Commun. 2017 Dec 21;8(1):2239 DOI: 10.1038/s41467-017-02402-610.1038/s41467-017-02402-6 Search in Google Scholar

23. Kitano H, Kageyama S-I, Hewitt SM, Hayashi R, Doki Y, Ozaki Y, et al. Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival. Arch Pathol Lab Med. 2010 Oct;134(10):1520-7. DOI: 10.5858/2009-0114-OA.110.5858/2009-0114-OA.1 Search in Google Scholar

24. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. DOI: 10.1001/jama.2016.028710.1001/jama.2016.0287 Search in Google Scholar

25. Hahn RG. Endotoxin boosts the vascular endothelial growth factor (VEGF) in rabbits. J Endotoxin Res. 2003;9(2):97-100. DOI: 10.1177/0968051903009002040110.1177/09680519030090020401 Search in Google Scholar

26. Adamik B, Zielinski S, Smiechowicz J, Kübler A. Endotoxin Elimination in Patients with Septic Shock: An Observation Study. Arch Immunol Ther Exp (Warsz). 2015 Dec;63(6):475-83. DOI: 10.1007/s00005-015-0348-810.1007/s00005-015-0348-8 Search in Google Scholar

27. Ramachandran G. Gram-positive and gram-negative bacterial toxins in sepsis: a brief review. Virulence. 2014 Jan 1;5(1):213-8. DOI: 10.4161/viru.2702410.4161/viru.27024 Search in Google Scholar

28. Bertani B, Ruiz N. Function and Biogenesis of Lipopolysaccharides. EcoSal Plus. 2018 Aug;8(1):10.1128/ ecosalplus.ESP-0001-2018. DOI: 10.1128/ecosalplus. ESP-0001-201810.1128/ecosalplus Search in Google Scholar

29. Matsuura M. Structural Modifications of Bacterial Lipopolysaccharide that Facilitate Gram-Negative Bacteria Evasion of Host Innate Immunity. Front Immunol. 2013;4:109. DOI: 10.3389/fimmu.2013.0010910.3389/fimmu.2013.00109 Search in Google Scholar

30. Poli-de-Figueiredo LF, Garrido AG, Nakagawa N, Sannomiya P. Experimental models of sepsis and their clinical relevance. Shock. 2008 Oct;30 Suppl 1:53-9. DOI: 10.1097/SHK.0b013e318181a34310.1097/SHK.0b013e318181a343 Search in Google Scholar

31. Zhu G, Huang Q, Huang Y, Zheng W, Hua J, Yang S, et al. Lipopolysaccharide increases the release of VEGF-C that enhances cell motility and promotes lymphangio-genesis and lymphatic metastasis through the TLR4-NF-κB/JNK pathways in colorectal cancer. Oncotarget. 2016 Oct 4;7(45):73711-24. DOI: 10.18632/oncotarget.1244910.18632/oncotarget.12449 Search in Google Scholar

32. Zhang Y, Lu Y, Ma L, Cao X, Xiao J, Chen J, et al. Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock. Immunity. 2014 Apr 17;40(4):501-14. DOI: 10.1016/j.immuni.2014.01.01310.1016/j.immuni.2014.01.013 Search in Google Scholar

33. Pan P, Liu X, Wu L, Li X, Wang K, Wang X, et al. TREM-1 promoted apoptosis and inhibited autophagy in LPS-treated HK-2 cells through the NF-κB pathway. Int J Med Sci. 2021 Jan 1;18(1):8-17. DOI: 10.7150/ ijms.5089310.7150/ijms.50893 Search in Google Scholar

34. Foster RR, Satchell SC, Seckley J, Emmett MS, Joory K, Xing CY, et al. VEGF-C promotes survival in podocytes. Am J Physiol Renal Physiol. 2006 Jul;291(1):F196-207. DOI: 10.1152/ajprenal.00431.200510.1152/ajprenal.00431.2005 Search in Google Scholar

35. Quintanilla M, Montero-Montero L, Renart J, Martín-Villar E. Podoplanin in Inflammation and Cancer. Int J Mol Sci. 2019 Feb 6;20(3):707. DOI: 10.3390/ ijms2003070710.3390/ijms20030707 Search in Google Scholar

36. Ugorski M, Dziegiel P, Suchanski J. Podoplanin - a small glycoprotein with many faces. Am J Cancer Res. 2016;6(2):370-86. Search in Google Scholar

37. Winde CM de, Makris S, Millward L, Benjamin AC, Cazzagon G, Martinez VG, et al. Podoplanin function is switched by partner proteins on fibroblastic reticular cells. BioRxiv. 2019 Nov (cited 2021 Sep 21):793141. DOI: 10.1101/79314110.1101/793141 Search in Google Scholar

38. Hitchcock JR, Cook CN, Bobat S, Ross EA, Flores-Langarica A, Lowe KL, et al. Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets. J Clin Invest. 2015 Dec;125(12):4429-46. DOI: 10.1172/JCI7907010.1172/JCI79070 Search in Google Scholar

39. Kerrigan AM, Navarro-Nu-ez 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 Mar;10(3):484-6. DOI: 10.1111/j.1538-7836.2011.04614.x10.1111/j.1538-7836.2011.04614.x Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo