Biochemistry, Pathophysiology and Clinical Significance of Lactoferrin: A Review Article

Abstract

Lactoferrin is a multi-iron binding functional glycoprotein with significant clinical applications in the treatment of infectious diseases, inflammatory disorders, cancer, neonatology, and metabolic conditions. Its normal function involves high affinity iron sequestration complementary direct microbial membrane interactions making it an important part of the innate immune system. Clinically proven effective in lactoferrin supplementation to reduce neonatal infections on sepsis as well as necrotizing enterocolitis; this will be a promising prophylactic approach for preterm infants. Its antiviral activity broadens even more its therapeutic potency regarding emerging viral infections including some preliminary applications on COVID-19. It is reported that the immunomodulatory lactoferrin regulates both processes by controlling cytokine production and cell function. Fecal lactoferrin is an easy-to-apply inflammation marker within the intestines for inflammatory bowel disease besides being helpful in monitoring how well treatment is working. Apart from these functions, lactoferrin can exert anticancer activity via antiproliferative, pro-apoptotic as well as anti-angiogenic mechanisms. Newer evidences also support its application as an adjuvant in cancer therapy. Additionally, lactoferrin has a role in neonate development through gut maturation plus immune system education. Disorder management, especially metabolic, cardiovascular, and diabetic related disorders, seems to be where lactoferrin aces it by modulating iron homeostasis plus reducing oxidative stress. The challenges of the bioavailability and standardized preparations of lactoferrin limit the therapeutic promise it holds. Further advances in delivery technologies, together with expanded clinical trials, are needed to optimize its use.

Keywords:

Lactoferrin, immunomodulatory, cancer, neonatal infections

References

Actor, J. K., Hwang, S. A., & Kruzel, M. L. (2009). Lactoferrin as a natural immune modulator. Current Pharmaceutical Design, 15(17), 1956–1973. https://doi.org/10.2174/138161209788682325

Baker, E. N., & Baker, H. M. (2009). Molecular structure, binding properties and dynamics of lactoferrin. Cellular and Molecular Life Sciences, 66(1), 253–275. https://doi.org/10.1007/s00018-008-8412-1

Brock, J. H. (2012). Lactoferrin—50 years on. Biochemistry and Cell Biology, 90(3), 245–251. https://doi.org/10.1139/o2012-014

Brock, J. H. (2012). Lactoferrin—50 years on. Biochemistry and Cell Biology, 90(3), 245–251. https://doi.org/10.1139/o2012-014

Chang, R., Ng, T. B., & Sun, W. Z. (2020). Lactoferrin as potential preventive and adjunct treatment for COVID-19. International Journal of Antimicrobial Agents, 56(3), 106164. https://doi.org/10.1016/j.ijantimicag.2020.106164

Gibbons, J. A., Kozlowski, H., Hirschman, J., & Zimecki, M. (2015). Lactoferrin: The molecular balancing act of an immune modulator. Nutrients, 7(4), 2820–2838. https://doi.org/10.3390/nu7042820

Gifford, J. L., Hunter, H. N., & Vogel, H. J. (2005). Lactoferricin: a lactoferrin-derived peptide with antimicrobial, antiviral, antitumor and immunological properties. Cellular and Molecular Life Sciences, 62(22), 2588–2598. https://doi.org/10.1007/s00018-005-5414-2

Gisbert, J. P., & McNicholl, A. G. (2009). Questions and answers on the role of fecal biomarkers in inflammatory bowel disease. Digestive Diseases and Sciences, 54(6), 1177–1185. https://doi.org/10.1007/s10620-008-0456-4

González-Chávez, S. A., Arévalo-Gallegos, S., & Rascón-Cruz, Q. (2009). Lactoferrin: structure, function and applications. International Journal of Antimicrobial Agents, 33(4), 301.e1–301.e8. https://doi.org/10.1016/j.ijantimicag.2008.08.005

Huang, Y., et al. (2020). Antiviral properties of lactoferrin: A natural immune modulator. Frontiers in Immunology, 11, 2196. https://doi.org/10.3389/fimmu.2020.02196

Kao, D. W., Hsieh, Y. C., & Lin, Y. T. (2015). Clinical effects of lactoferrin on periodontal health: a systematic review. Clinical Oral Investigations, 19(7), 1645–1653. https://doi.org/10.1007/s00784-015-1450-1

Kruzel, M. L., Zimecki, M., & Actor, J. K. (2017). Lactoferrin in a context of inflammation-induced pathology. Frontiers in Immunology, 8, 1438. https://doi.org/10.3389/fimmu.2017.01438

Laursen, I., & Moestrup, S. K. (2009). Interactions of the transferrin family: receptors and ligands. Cellular and Molecular Life Sciences, 66(1), 103–116. https://doi.org/10.1007/s00018-008-8390-9

Legrand, D. (2016). Overview of lactoferrin as a natural immune modulator. Journal of Pediatrics, 173(Suppl), S10–S15. https://doi.org/10.1016/j.jpeds.2016.02.047

Legrand, D., Elass, E., Carpentier, M., & Mazurier, J. (2020). Lactoferrin: A modulator of immune and inflammatory responses. Cellular and Molecular Life Sciences, 77(2), 377–385. https://doi.org/10.1007/s00018-019-03329-4

Lönnerdal, B. (2009). Nutritional roles of lactoferrin. Current Opinion in Clinical Nutrition and Metabolic Care, 12(3), 293–297. https://doi.org/10.1097/MCO.0b013e32832929fc

Mäkitalo, L., Rautiainen, M., & Kolho, K.-L. (2016). Fecal lactoferrin: a noninvasive biomarker in inflammatory bowel disease. World Journal of Gastroenterology, 22(10), 2845–2851. https://doi.org/10.3748/wjg.v22.i10.2845

Manzoni, P., Rinaldi, M., Cattani, S., & Pugni, L. (2009). Oral supplementation with lactoferrin reduces the incidence of late-onset sepsis in very low birth weight neonates: a randomized trial. The Journal of Pediatrics, 155(5), 736–741. https://doi.org/10.1016/j.jpeds.2009.05.026

Nibbering, P. H. (2006). Lactoferrin and the innate mucosal immune defense. Advances in Experimental Medicine and Biology, 606, 53–63. https://doi.org/10.1007/978-0-387-34812-2_6

Ochoa, T. J., & Cleary, T. G. (2009). Effect of lactoferrin on enteric pathogens. Biochimie, 91(1), 30–34. https://doi.org/10.1016/j.biochi.2008.05.011

Pammi, M., & Suresh, G. (2017). Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database of Systematic Reviews, (6), CD007137. https://doi.org/10.1002/14651858.CD007137.pub4

Sánchez, L., Calvo, M., & Brock, J. H. (1992). Biological role of lactoferrin. Archives of Disease in Childhood, 67(5), 657–661. https://doi.org/10.1136/adc.67.5.657

Tian, Y., Zhang, Y., & Liu, H. (2015). Effects of lactoferrin on glycemic control and insulin resistance in diabetic rats. Journal of Diabetes Research, 2015, 1–9. https://doi.org/10.1155/2015/960892

Wakabayashi, H., Oda, H., & Yamauchi, K. (2014). Lactoferrin for prevention of common viral infections. Journal of Infection and Chemotherapy, 20(11), 666–671. https://doi.org/10.1016/j.jiac.2014.07.003

Ward, P. P., Paz, E., & Conneely, O. M. (2005). Multifunctional roles of lactoferrin: A critical overview. Cellular and Molecular Life Sciences, 62(22), 2540–2548. https://doi.org/10.1007/s00018-005-5372-1

Zhao, M., Liu, L., Chen, J., Zhang, C., & Wang, J. (2019). Advances in the delivery of lactoferrin for cancer therapy. International Journal of Nanomedicine, 14, 1183–1193. https://doi.org/10.2147/IJN.S190706