Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2019, vol. 28, nr 11, November, p. 1561–1567

doi: 10.17219/acem/104531

Publication type: review article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Fibronectin and its soluble EDA-FN isoform as biomarkers for inflammation and sepsis

Anna Lemańska-Perek1,A,B,C,D,F, Barbara Adamik2,D,E,F

1 Department of Chemistry and Immunochemistry, Wroclaw Medical University, Poland

2 Department and Clinic of Anesthesiology and Intensive Therapy, Wroclaw Medical University, Poland


Fibronectin (FN) is a widely distributed glycoprotein which is present in different bodily fluids, on the surface of cells and in the extracellular matrix (ECM). It plays roles in various processes, including cell adhesion, migration, growth, proliferation, and tissue repair. Fibronectin exists in 2 forms: a soluble, inactive molecule, called plasma FN (pFN), which is synthesized by hepatocytes in the liver, and an insoluble cellular form (cFN), which is produced locally by different types of cells and is a key component of the ECM. Fibrinogen fibrils ensure structural support for cell adhesion and promote cell migration, proliferation and apoptosis. Additionally, FN controls the availability of growth factors. The plasma form of FN is a crucial component of the fibrin clot in the early wound-healing response, while the cellular form of FN supports efficient platelet adhesion, activation, aggregation, and procoagulant activity. Alternative splicing of the FN gene results in the generation of protein variants which contain the additional isoforms – extra domain A of FN (EDA) and extra domain A of FN (EDB); these are associated with, e.g., tissue remodeling, fibroblast differentiation, inflammation, and tumor progression. Fibronectin also serves as a target for a large number of bacterial proteins, and as part of a 3-component bridge (FN, integrin and FN-binding proteins – FnBPs) it contributes to bacterial colonization of endothelial and epithelial cells. Fibronectin has been identified in sepsis in humans as a negative acute-phase protein, and a low level of FN seems to be a marker of a poor prognosis for a patient. Here, the role of FN in inflammatory processes and sepsis is presented.

Key words

extra domain A of fibronectin (EDA), fibronectin-binding proteins (FnBPs), inflammation, sepsis, fibronectin

References (59)

  1. To WS, Midwood KS. Plasma and cellular fibronectin: Distinct and independent functions during tissue repair. Fibrogenesis Tissue Repair. 2011:4:21.
  2. Lemańska-Perek A, Pupek M, Polańska B, Leszek J, Kątnik-Prastowska I. Alterations in molecular status of plasma fibronectin associated with aging of normal human individuals. Clin Bioch. 2013;46(9):787–794.
  3. White ES, Baralle FE, Muro AF. New insights into form and function of fibronectin splice variants. J Pathol. 2008;216(1):1–14.
  4. Tajiri M, Yoshida S, Wada Y. Differential analysis of site-specific glycans on plasma and cellular fibronectin: Application of a hydrophilic affinity method for glycopeptide enrichment. Glycobiology. 2005;15(12):1332–1340.
  5. Wang Y, Reheman A, Spring CM, et al. Plasma fibronectin supports hemostasis and regulates thrombosis. J Clin Invest. 2014;124(10):4281–4293.
  6. White ES, Muro AF. Fibronectin splice variants: Understanding their multiple roles in health and disease using engineered mouse models. IUBMB Life. 2011;63(7):538–546.
  7. Lemańska-Perek A, Krzyżanowska-Gołąb D, Pupek M, Klimeczek P, Witkiewicz W, Kątnik-Prastowska I. Analysis of soluble molecular fibronectin-fibrin complexes and EDA-fibronectin concentration in plasma of patients with atherosclerosis. Inflammation. 2016;39(3):1059–1068.
  8. Muro AF, Moretti FA, Moore BB, et al. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med. 2008;177(6):638–645.
  9. Jarnagin WR, Rockey DC, Koteliansky VE, Wang SS, Bissell DM. Expression of variant fibronectin in wound healing: Cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol. 1994;127(6 Pt 2):2037–2048.
  10. Cappellari GG, Barazzoni R, Cattin L, Muro AF, Zanetti M. Lack of fibronectin extra domain A alternative splicing exacerbates endothelial dysfunction in diabetes. Sci Rep. 2016;6:37965.
  11. Rybak JN, Roesli C, Kaspar M, Villa A, Neri D. The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases. Cancer Res. 2007;67(22):10948–10957.
  12. Kraft S, Klemis V, Sens C, et al. Identification and characterization of a unique role for EDB fibronectin in phagocytosis. J Mol Med (Berl). 2016;94(5):567–581.
  13. Wierzbicka-Patynowski I, Schwarzbauer JE. The ins and outs of fibronectin matrix assembly. J Cell Sci. 2003;116(Pt 16):3269–3276.
  14. Johansson S, Svineng G, Wennerberg K, Armulikn A, Lohikangas L. Fibronectin-integrin interactions. Front Biosci. 1997;2:d126–146.
  15. Leiss M, Beckmann K, Girós A, Costell M, Fässier R. The role of integrin binding sites in fibronectin matrix assembly in vivo. Curr Opin Cell Biol. 2008;20(5):502–507.
  16. Lowrie AG, Salter DM, Ross JA. Latent effects of fibronectin, α5β1 integrin, αVβ5 integrin and the cytoskeleton regulate pancreatic carcinoma cell IL-8 secretion. Br J Cancer. 2004;91(7):1327–1334.
  17. Kelsh-Lasher RM, Ambesi A, Bertram C, McKeown-Longo PJ. Integrin α4β1 and TLR4 cooperate to induce fibrotic gene expression in response to fibronectin’s EDA domain. J Invest Dermatol. 2017;137(12):2505–2512.
  18. Bazigou E, Xie S, Chen C, et al. Integrin-α9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell. 2009;17(2):175–186.
  19. Kelsh R, You R, Horzempa C, Zheng M, McKeown-Long PJ. Regulation of the innate immune response by fibronectin: Synergism between the III-1 and EDA domains. PLoS One. 2014;9(7):e102974.
  20. Midwood KS, Valenick LV, Hsia H, Schwarzbauer JE. Coregulation of fibronectin signaling and matrix contraction by tenascin-C and syndecan-4. Mol Biol Cell. 2004;15(12):5670–5677.
  21. Shi F, Harman J, Fujiwara K, Sottile J. Collagen I matrix turnover is regulated by fibronectin polymerization. Am J Physiol. 2010;298(5):1265–1275.
  22. Martino MM, Hubbell JA. The 12th–14th type III repeats of fibronectin function as a highly promiscuous growth factor-binding domain. FASEB J. 2010;24(12):4711–4721.
  23. Wijelath ES, Rahman S, Namekata M, et al. Heparin-II domain of fibronectin is a vascular endothelial growth factor-binding domain: Enhancement of VEGF biological activity by a singular growth factor/matrix protein synergism. Circ Res. 2006;99(8):853–860.
  24. Serini G, Bochaton-Piallat ML, Ropraz P, et al. The fibronectin domain ED-A is crucial for myofibroblastic phenothype induction by transforming growth factor-beta 1. J Cell Biol. 1998;142(3):873–881.
  25. Bhattacharyya S, Tamaki Z, Wang W, et al. Fibronectin EDA promotes chronic cutaneous fibrosis through toll-like receptor signaling. Sci Transl Med. 2014;6(232):232ra50.
  26. Cardoso I, Østerlund EK, Stamnaes J, et al. Dissecting the interaction between transglutaminase 2 and fibronectin. Amino Acids. 2017;49(3):489–500.
  27. Telci D, Griffin M. Tissue transglutaminase (TG2) – a wound response enzyme. Front Biosci. 2006;11:867–882.
  28. Stine JM, Ahl GJH, Schlenker C, Rushac DV, Briknarowá K. The interaction between the third type III domain from fibronectin and anastellin involves β-strand exchange. Biochemistry. 2017;56(35):4667–4675.
  29. Hart J. Inflammation. 1: Its role in the healing of chronic wounds. J Wound Care. 2002;11(6):245–249.
  30. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–810.
  31. Hagiwara T, Kono I, Nemoto K, Kashiwaqi H, Onozaki K. Recombinant interleukin-1 triggers the increase of circulating fibronectin level in rats. Int Arch Allergy Appl Immunol. 1989;89(4):376–380.
  32. Peters JH, Trevithick JE, Johnson P, Hynes RO. Expression of the alternatively spliced EIIIB segment of fibronectin. Cell Adhes Commun. 1995;3(1):67–89.
  33. Aznavoorian S, Stracke ML, Krutzsch H, Schiffman E, Liotta LA. Signal transduction for chemotaxis and haptotaxis by matrix molecules in tumour cells. J Cell Biol. 1990;110(4):1427–1438.
  34. Rossen RD, Rubio JA, Porter WJ, et al. Monocyte CD49e and 110–120 kDa fibronectin fragments: HIV prognostic indicators independent of viral load and CD4 T-cell counts. AIDS. 2009;23(17):2247–2253.
  35. Nyberg P, Sakai T, Cho KH, Caparon MG, Fässler R, Björck L. Interactions with fibronectin attenuate the virulence of Streptococcus pyogenes. EMBO J. 2004;23(10):2166–2174.
  36. Astrof S, Hynes RO. Fibronectins in vascular morphogenesis. Angiogenesis. 2009;12(2):165–175.
  37. van Keulen JK, de Kleijn DP, Nijhuis MM, et al. Levels of extra domain A containing fibronectin in human atherosclerotic plaques are associated with a stable plaque phenotype. Atherosclerosis. 2007;195(1):83–91.
  38. Matsumoto E, Yoshida T, Kwarada Y, Sakakura T. Expression of fibronectin isoforms in human breast tissue: Production of extra A+/extra domain B+ by cancer cells and extra A+ by stroma cells. Jpn J Cancer Res. 1999;90(3):320–325.
  39. Sun X, Fa Z, Cui Z, et al. The EDA-containing cellular fibronectin induces epithelial-mesenchymal transition in lung cancer cells thought integrin α9β1-mediated activation of P13-K/AKT and Erk 1/2. Carcinogenesis. 2014;35(1):184–191.
  40. Ou J, Peng Y, Deng J, et al. Endothelial cell-derived fibronectin extra domain A promotes colorectal cancer metastasis via inducing epithelial-mesenchymal transition. Carcinogenesis. 2014;35(7):1661–1670.
  41. Arnold SA, Loomans HA, Ketova T, Arnold CD, Clark PE, Zijlstra A. Urinary oncofetal ED-A fibronectin correlates with poor prognosis in patients with bladder cancer. Clin Exp Metastasis. 2016;33(1):29–44.
  42. von Au A, Vasel M, Kraft S, et al. Circulating fibronectin controls tumor growth. Neoplasia. 2013;15(8):925–938.
  43. Attieh Y, Clark AG, Grass C, et al. Cancer-associated fibroblasts lead tumor invasion through integrin-β3-dependent fibronectin assembly. J Cell Biol. 2017;216(11):3509.
  44. Dhyani A, Pulakazhi Venu VK, Uboldi P, Muro AF, Catapano AL, Noraya DG. Absence of fibronectin-EDA contributes to sepsis outcomes in a murine model. Atherosclerosis. 2016;252:e179.
  45. Pierrakos C, Vincent JL. Sepsis biomarkers: A review. Crit Care. 2010;14(1):R15.
  46. Prieto Prieto J, Veiga de Cabo J, et al. Plasma fibronectin as a marker of sepsis. Int J Infect Dis. 2004;8(4):236–243.
  47. Reichsoellner M, Raggam RB, Wagner J, Krause R, Hoeing M. Clinical evaluation of multiple inflammation biomarkers for diagnosis and prognosis for patients with systemic inflammatory response syndrome. J Clin Microbiol. 2014;52(11):4063–4066.
  48. Mamani M, Hashemi SH, Hajilooi M, Saedi F, Niayesh A, Fallh M. Evaluation of fibronectin and C-reactive protein levels in patients with sepsis: A case-control study. Acta Med Iran. 2012;50(6):404–410.
  49. Cheslyn-Curtis S, Aldridge MC, Dudley HAF. Effect of acute starvation on plasma fibronectin response to sepsis. Br J Surg. 1990;77(2):199–203.
  50. Satoi S, Kitade H, Hiramatsu Y, et al. Increased extra domain-A containing fibronectin and hepatic dysfunction during septic response: An in vivo and in vitro study. Shock. 2000;13(6):492–496.
  51. Shinji H, Yosizawa Y, Tajima A, et al. Role of fibronectin-binding proteins A and B in vitro cellular infections and in vivo septic infections by Staphylococcus aureus. Infect Immun. 2011;79(6):2215–2223.
  52. Hauck CR, Ohlsen K. Sticky connections: Extracellular matrix protein recognition and integrin-mediated cellular invasion by Staphylococcus aureus. Curr Opin Microbiol. 2006;9(1):5–11.
  53. Katayama S, Tagomori M, Morita N, et al. Determination of the Clostridium perfringens-binding site on fibronectin. Anaerobe. 2015;34:174–181.
  54. Schroder A, Schroder B, Roppenser B, et al. Staphylococcus aureus fibronectin binding protein-A induces motile attachment sites and complex actin remodeling in living endothelial cells. Mol Biol Cell. 2006;17(12):5198–5210.
  55. Glancey G, Cameron JS, Ogg C, Poston S. Adherence of Staphylococcus aureus to cultures of human peritoneal mesothelial cells. Nephrol Dial Transplant. 1993;8(2):157–162.
  56. Fowler T, Wann ER, Joh D, Johansson S, Foster TJ, Höök M. Cellular invasion by Staphylococcus aureus involves a fibronectin bridge between the bacterial fibronectin-binding MSCRAMMs and host cell beta1 integrins. Eur J Cell Biol. 2000;79(10):672–679.
  57. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. 2017;149:38–44.
  58. Lemańska-Perek A, Polańska B, Krzyżanowska-Gołąb D, Kątnik-Prastowska I. Occurrence of soluble supra-molecular FN-fibrin complexes in the plasma of children with recurrent respiratory infection. Ann Clin Biochem. 2015;52(Pt 4):441–447.
  59. Prakash P, Kulkarni PP, Lentz SR, Chauhan AK. Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet toll-like receptor 4. Blood. 2015;125(20):3164–3172.