Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter April 4, 2017

The role of thromboxane A2 in complement activation-related pseudoallergy

  • Tamás Gyula Fülöp

    Tamás Gyula Fülöp, BS, PhD Student, Nanomedicine Research and Education Center, Semmelweis University, Budapest 1089 Nagyvárad tér 4, Budapest, Hungary fulopgyulatamas@gmail.com, and MIRA Institute, Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands. Gyula Tamás Fülöp is a PhD student at the Nanomedicine Research and Education Center at Semmelweis Medical University of Budapest, Hungary. He got his bachelor and master’s degree in Medical and Pharmaceutical Biotechnology at the University of Applied Sciences in Krems, Austria.

    EMAIL logo
    , Josbert M. Metselaar

    Josbert M. Metselaar, Pharm D, MIRA Institute, Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands. Josbert M. Metselaar (Rotterdam, July 6th 1971) obtained an MSc degree in Pharmaceutical Sciences in 1995 and a Pharm D (Doctor of Pharmacy) degree in 1998, both at Utrecht University. During his study, he completed a research internship in pharmacology and PK/PD modeling at the Department of Pharmaceutics, University of Florida, USA. In 1999, he started his PhD at the Department of Pharmaceutics and the Department of Immunology Veterinary Medicine in Utrecht within the scope of a large academic research collaboration funded by the Japanese pharmaceutical company Yamanouchi (nowadays Astellas). He studied novel targeted formulations of anti-inflammatory compounds in autoimmune diseases. After completing his PhD in 2003 and a postdoctoral fellowship in the same field of research in 2005, he decided to focus on translating his academic accomplishments into novel clinical and industrial investigational products. To this end, he founded his own university spin off company Enceladus Pharmaceuticals, with which he raised significant funding over the years.

    , Gert Storm

    Gert Storm, PhD, Professor, MIRA Institute, Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands, and Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands. Gert Storm is a (bio)pharmaceutical scientist at Utrecht University. He studied biology and obtained his PhD at the Department of Pharmaceutics of the same university. His research interests are in the fields of biopharmaceutics and drug targeting. In his early career, he worked at Liposome Technology Inc. (USA), at the San Francisco (UCSF) School of Pharmacy and at Pharma Bio-Research Consultancy B.V. (The Netherlands). In September 1991, he took up his position at Utrecht University. In 1999, he was appointed adjunct professor at the Royal School of Pharmacy, University of Copenhagen, and since 2009, he is Honorary Professor in Biomacromolecular Drug Delivery at that same university. In 2000, he was appointed as a professor (Targeted Drug Delivery) at Utrecht University. Since 2012, he is also professor (Targeted Therapeutics) at the MIRA institute of the University of Twente (Netherlands). Besides, he keeps a position at the University Medical Center Utrecht (UMCU) within the Centre for Image-Guided Oncological Interventions.

    and János Szebeni

    Janos Szebeni, MD, PhD, DSc, Med. Habil., immunologist, director of the Nanomedicine Research and Education Center at Semmelweis University, Budapest, Hungary. He is also a professor of immunology and biology at the University of Miskolc and founder and CEO of an immune toxicology contract research biotech company, SeroScience Ltd., Hungary. During his 40-year professional career, he has held various junior, senior scientific and (guest) professor positions in Hungary and abroad, mainly in the United States, where he lived for 21 years. His research on various themes in hematology, membrane biology and immunology has resulted in over 120 papers and many book chapters, patents and a book titled The Complement System: Novel Roles in Health and Disease (Kluwer, 2004). Three fields stand out where he has been most active: artificial blood, liposomes and the complement system. His original works from the late 1990s led to the “CARPA” concept, i.e. that complement activation underlies numerous (nano)drug-induced hypersensitivity (infusion) reactions.

Abstract

Complement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction occurring upon intravenous administration of numerous liposomal therapeutics, other nonbiological complex drugs and biologicals. It has a complex molecular and cellular mechanism that involves the production, actions and interactions of numerous vasoactive mediators in blood, including thromboxane A2 (TXA2). This short review focuses on the latter eicosanoid: its role in CARPA, effects underlying some of the symptoms and experimental evidence for its rate-limiting role in pulmonary hypertension in pigs. Animal experiments and recent clinical observations suggest that the cyclooxygenase blocker indomethacin may represent an effective new approach to prevent liposome-induced CARPA, lending clinical relevance to better understand the involvement of TXA2 and other eicosanoids in this adverse immune effect.

About the authors

Tamás Gyula Fülöp

Tamás Gyula Fülöp, BS, PhD Student, Nanomedicine Research and Education Center, Semmelweis University, Budapest 1089 Nagyvárad tér 4, Budapest, Hungary fulopgyulatamas@gmail.com, and MIRA Institute, Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands. Gyula Tamás Fülöp is a PhD student at the Nanomedicine Research and Education Center at Semmelweis Medical University of Budapest, Hungary. He got his bachelor and master’s degree in Medical and Pharmaceutical Biotechnology at the University of Applied Sciences in Krems, Austria.

Josbert M. Metselaar

Josbert M. Metselaar, Pharm D, MIRA Institute, Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands. Josbert M. Metselaar (Rotterdam, July 6th 1971) obtained an MSc degree in Pharmaceutical Sciences in 1995 and a Pharm D (Doctor of Pharmacy) degree in 1998, both at Utrecht University. During his study, he completed a research internship in pharmacology and PK/PD modeling at the Department of Pharmaceutics, University of Florida, USA. In 1999, he started his PhD at the Department of Pharmaceutics and the Department of Immunology Veterinary Medicine in Utrecht within the scope of a large academic research collaboration funded by the Japanese pharmaceutical company Yamanouchi (nowadays Astellas). He studied novel targeted formulations of anti-inflammatory compounds in autoimmune diseases. After completing his PhD in 2003 and a postdoctoral fellowship in the same field of research in 2005, he decided to focus on translating his academic accomplishments into novel clinical and industrial investigational products. To this end, he founded his own university spin off company Enceladus Pharmaceuticals, with which he raised significant funding over the years.

Gert Storm

Gert Storm, PhD, Professor, MIRA Institute, Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands, and Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands. Gert Storm is a (bio)pharmaceutical scientist at Utrecht University. He studied biology and obtained his PhD at the Department of Pharmaceutics of the same university. His research interests are in the fields of biopharmaceutics and drug targeting. In his early career, he worked at Liposome Technology Inc. (USA), at the San Francisco (UCSF) School of Pharmacy and at Pharma Bio-Research Consultancy B.V. (The Netherlands). In September 1991, he took up his position at Utrecht University. In 1999, he was appointed adjunct professor at the Royal School of Pharmacy, University of Copenhagen, and since 2009, he is Honorary Professor in Biomacromolecular Drug Delivery at that same university. In 2000, he was appointed as a professor (Targeted Drug Delivery) at Utrecht University. Since 2012, he is also professor (Targeted Therapeutics) at the MIRA institute of the University of Twente (Netherlands). Besides, he keeps a position at the University Medical Center Utrecht (UMCU) within the Centre for Image-Guided Oncological Interventions.

János Szebeni

Janos Szebeni, MD, PhD, DSc, Med. Habil., immunologist, director of the Nanomedicine Research and Education Center at Semmelweis University, Budapest, Hungary. He is also a professor of immunology and biology at the University of Miskolc and founder and CEO of an immune toxicology contract research biotech company, SeroScience Ltd., Hungary. During his 40-year professional career, he has held various junior, senior scientific and (guest) professor positions in Hungary and abroad, mainly in the United States, where he lived for 21 years. His research on various themes in hematology, membrane biology and immunology has resulted in over 120 papers and many book chapters, patents and a book titled The Complement System: Novel Roles in Health and Disease (Kluwer, 2004). Three fields stand out where he has been most active: artificial blood, liposomes and the complement system. His original works from the late 1990s led to the “CARPA” concept, i.e. that complement activation underlies numerous (nano)drug-induced hypersensitivity (infusion) reactions.

  1. Conflict of interest statement: Authors state no conflict of interest. All authors have read the journal’s publication ethics and publication malpractice statement available at the journal’s website and hereby confirm that they comply with all its parts applicable to the present scientific work.

References

1. Szebeni J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol Immunol 2014;61:163–73.10.1016/j.molimm.2014.06.038Search in Google Scholar PubMed

2. Urbanics R, Szebeni J. Lessons learned from the porcine CARPA model: constant and variable responses to different nanomedicines and administration protocols. Eur J Nanomed 2015;7:219–31.10.1201/b22372-11Search in Google Scholar

3. Szebeni J, Storm G. Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs. Biochem Biophys Res Commun 2015;468:490–7.10.1016/j.bbrc.2015.06.177Search in Google Scholar PubMed

4. Dézsi L, Fülöp T, Mészáros T, Szénási G, Urbanics R, Vázsonyi C, et al. Features of complement activation-related pseudoallergy to liposomes with different surface charge and pegylation: comparison of the porcine and rat responses. J Contr Release 2014:pii: S0168-3659(14)00591-4.10.1016/j.jconrel.2014.08.009Search in Google Scholar PubMed

5. Romberg B, Metselaar JM, Baranyi L, Snel CJ, Bunger R, Hennink WE, et al. Poly(amino acid)s: promising enzymatically degradable stealth coatings for liposomes. Int J Pharm 2007;331:186–9.10.1016/j.ijpharm.2006.11.018Search in Google Scholar PubMed

6. Szebeni J, Baranyi L, Savay S, Milosevits J, Bunger R, Laverman P, et al. Role of complement activation in hypersensitivity reactions to Doxil and hynic PEG liposomes: experimental and clinical studies. J Liposome Res 2002;12:165–72.10.1081/LPR-120004790Search in Google Scholar

7. van den Hoven JM, Nemes R, Metselaar JM, Nuijen B, Beijnen JH, Storm G, et al. Complement activation by PEGylated liposomes containing prednisolone. Eur J Pharm Sci 2013;49:265–71.10.1016/j.ejps.2013.03.007Search in Google Scholar PubMed

8. Moghimi SM. Complement propriety and conspiracy in nanomedicine: perspective and a hypothesis. Nucleic Acid Ther 2016;26:67–72.10.1089/nat.2015.0587Search in Google Scholar PubMed

9. Wibroe PP, Ahmadvand D, Oghabian MA, Yaghmur A, Moghimi SM. An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil(R), Caelyx(R), DOXOrubicin, and SinaDoxosome. J Control Release 2016;221:1–8.10.1016/j.jconrel.2015.11.021Search in Google Scholar PubMed

10. Szebeni J, Barenholz Y. Complement activation, immunogenicity, and immune suppression as potential side effects of liposomes. In: Peer D, editor. Handbook of Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications. Singapore: Pan Standford Publishing Pte.Ltd., 2012:309–34.Search in Google Scholar

11. Palmer MA, Piper PJ, Vane JR. Release of rabbit aorta contracting substance (RCS) and prostaglandins induced by chemical or mechanical stimulation of guinea-pig lungs. Br J Pharmacol 1973;49:226–42.10.1111/j.1476-5381.1973.tb08368.xSearch in Google Scholar PubMed PubMed Central

12. Piper PJ, Samhoun MN. Stimulation of arachidonic acid metabolism and generation of thromboxane A2 by leukotrienes B4, C4 and D4 in guinea-pig lung in vitro. Br J Pharmacol 1982;77:267–75.10.1111/j.1476-5381.1982.tb09295.xSearch in Google Scholar

13. Piper PJ, Yaacob HB. Interactions of platelet activating factor, thromboxane A2 and leukotrienes in guinea-pig heart. Prog Clin Biol Res 1989;301:493–8.Search in Google Scholar

14. Baranyi L, Szebeni J, Savay S, Bodo M, Basta M, Bentley TB, et al. Complement-dependent shock and tissue damage induced by intravenous injection of cholesterol-enriched liposomes in rats. J Appl Res 2003;3:221–31.Search in Google Scholar

15. Szebeni J, Baranyi L, Savay S, Bodo M, Milosevits J, Alving CR, et al. Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function. Am J Physiol Heart Circ Physiol 2006;290:H1050–8.10.1152/ajpheart.00622.2005Search in Google Scholar

16. Nicolaou A, Mauro C, Urquhart P, Marelli-Berg F. Polyunsaturated fatty acid-derived lipid mediators and T cell function. Front Immunol 2014;5:75.10.3389/fimmu.2014.00075Search in Google Scholar

17. Sakariassen KS, Alberts P, Fontana P, Mann J, Bounameaux H, Sorensen AS. Effect of pharmaceutical interventions targeting thromboxane receptors and thromboxane synthase in cardiovascular and renal diseases. Future Cardiol 2009;5:479–93.10.2217/fca.09.33Search in Google Scholar

18. Wang LH, Kulmacz RJ. Thromboxane synthase: structure and function of protein and gene. Prostaglandins Other Lipid Mediat 2002;68–69:409–22.10.1016/S0090-6980(02)00045-XSearch in Google Scholar

19. Vermylen J, Deckmyn H. Thromboxane synthase inhibitors and receptor antagonists. Cardiovasc Drugs Ther 1992;6:29–33.10.1007/BF00050914Search in Google Scholar PubMed

20. Fiddler GI, Lumley P. Preliminary clinical studies with thromboxane synthase inhibitors and thromboxane receptor blockers. A review. Circulation 1990;81(Suppl 1):I69–78;discussion I9–80.Search in Google Scholar

21. FitzGerald GA, Reilly IA, Pedersen AK. The biochemical pharmacology of thromboxane synthase inhibition in man. Circulation 1985;72:1194–201.10.1161/01.CIR.72.6.1194Search in Google Scholar PubMed

22. Duke-Novakovski T, Singh-Suri S, Kajikawa O, Caldwell S, Charavaryamath C, Singh B. Immuno-phenotypic and functional characterization of rabbit pulmonary intravascular macrophages. Cell Tissue Res 2013;351:149–60.10.1007/s00441-012-1509-2Search in Google Scholar PubMed

23. Csukas D, Urbanics R, Weber G, Rosivall L, Szebeni J. Pulmonary intravascular macrophages: prime suspects as cellular mediators of porcine CARPA. Eur J Nanomed 2015;7:27–36.10.1515/ejnm-2015-0008Search in Google Scholar

24. Bertram TA, Overby LH, Danilowicz R, Eling TE, Brody AR. Pulmonary intravascular macrophages produce prostaglandins and leukotrienes in vitro. Chest 1988;93:82S–4S.10.1378/chest.93.3_Supplement.82SSearch in Google Scholar

25. Radomski M. The biological role of thromboxane A2 in the process of hemostasis and thrombosis; pharmacology and perspectives of therapeutical use of thromboxane synthetase inhibitors and receptor PGH2/TXA2 antagonists. Acta physiologica Polonica 1985;36:153–64.Search in Google Scholar

26. Bauer J, Ripperger A, Frantz S, Ergun S, Schwedhelm E, Benndorf RA. Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane-mediated thromboxane A2 receptor activation. Br J Pharmacol 2014;171:3115–31.10.1111/bph.12677Search in Google Scholar

27. Ting HJ, Murad JP, Espinosa EV, Khasawneh FT. Thromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targeting. J Cardiovasc Pharmacol Ther 2012;17:248–59.10.1177/1074248411424145Search in Google Scholar

28. Kontogiorgis C, Hadjipavlou-Litina D. Thromboxane synthase inhibitors and thromboxane A2 receptor antagonists: a quantitative structure activity relationships (QSARs) analysis. Curr Med Chem 2010;17:3162–214.10.2174/092986710792231978Search in Google Scholar

29. Feletou M, Vanhoutte PM, Verbeuren TJ. The thromboxane/endoperoxide receptor (TP): the common villain. J Cardiovasc Pharmacol 2010;55:317–32.10.1097/FJC.0b013e3181d8bc8aSearch in Google Scholar

30. Armstrong RA, Wilson NH. Aspects of the thromboxane receptor system. Gen Pharmacol 1995;26:463–72.10.1016/0306-3623(94)00183-NSearch in Google Scholar

31. Hall SE. Thromboxane A2 receptor antagonists. Med Res Rev 1991;11:503–79.10.1002/med.2610110504Search in Google Scholar

32. Patscheke H. Thromboxane A2/prostaglandin H2 receptor antagonists. A new therapeutic principle. Stroke 1990;21:IV139–42.Search in Google Scholar

33. Patrono C. Thromboxane synthesis inhibitors and receptor antagonists. Thromb Res Suppl 1990;11:15–23.10.1016/0049-3848(90)90387-RSearch in Google Scholar

34. Quinton TM, Murugappan S, Kim S, Jin J, Kunapuli SP. Different G protein-coupled signaling pathways are involved in alpha granule release from human platelets. J Thromb Haemost 2004;2:978–84.10.1111/j.1538-7836.2004.00741.xSearch in Google Scholar PubMed

35. Murugappan S, Shankar H, Kunapuli SP. Platelet receptors for adenine nucleotides and thromboxane A2. Semin Thromb Hemost 2004;30:411–8.10.1055/s-2004-833476Search in Google Scholar PubMed

36. Shankar H, Murugappan S, Kim S, Jin J, Ding Z, Wickman K, et al. Role of G protein-gated inwardly rectifying potassium channels in P2Y12 receptor-mediated platelet functional responses. Blood 2004;104:1335–43.10.1182/blood-2004-01-0069Search in Google Scholar PubMed

37. Davi G, Santilli F, Vazzana N. Thromboxane receptors antagonists and/or synthase inhibitors. Handb Exp Pharmacol 2012:261–86.10.1007/978-3-642-29423-5_11Search in Google Scholar

38. Jackman JA, Meszaros T, Fulop T, Urbanics R, Szebeni J, Cho NJ. Comparison of complement activation-related pseudoallergy in miniature and domestic pigs: foundation of a validatable immune toxicity model. Nanomedicine 2016;12:933–43.10.1016/j.nano.2015.12.377Search in Google Scholar

39. Al-Naamani N, Sagliani KD, Dolnikowski GG, Warburton RR, Toksoz D, Kayyali U, et al. Plasma 12- and 15-hydroxyeicosanoids are predictors of survival in pulmonary arterial hypertension. Pulm Circ 2016;6:224–33.10.1086/686311Search in Google Scholar

40. Al-Naamani N, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Roberts KE, et al. Prognostic significance of biomarkers in pulmonary arterial hypertension. Ann Am Thorac Soc 2016;13:25–30.10.1513/AnnalsATS.201508-543OCSearch in Google Scholar

41. Patkó Z, Szebeni J. Blood cell changes in complement activation-related pseudoallergy. Eur J Nanomed 2015;7:233–44.10.1515/ejnm-2015-0021Search in Google Scholar

42. Geng L, Wu J, So SP, Huang G, Ruan KH. Structural and functional characterization of the first intracellular loop of human thromboxane A2 receptor. Arch Biochem Biophys 2004;423:253–65.10.1016/j.abb.2004.01.001Search in Google Scholar

43. Huang JS, Ramamurthy SK, Lin X, Le Breton GC. Cell signalling through thromboxane A2 receptors. Cell Signal 2004;16:521–33.10.1016/j.cellsig.2003.10.008Search in Google Scholar

44. Halushka PV, Allan CJ, Davis-Bruno KL. Thromboxane A2 receptors. J Lipid Mediat Cell Signal 1995;12:361–78.10.1016/0929-7855(95)00023-JSearch in Google Scholar

45. Halushka PV, Matsuda K, Masuda A, Ruff A, Morinelli TA, Mathur RS. Testosterone regulation of platelet and vascular thromboxane A2 receptors. Agents Actions Suppl 1995;45:19–26.10.1007/978-3-0348-7346-8_3Search in Google Scholar PubMed

46. Kinsella BT, O’Mahony D, Lawson JA, Pratico D, Fitzgerald GA. Cellular activation of thromboxane receptors. Ann N Y Acad Sci 1994;714:270–8.10.1111/j.1749-6632.1994.tb12054.xSearch in Google Scholar PubMed

47. Kinsella BT, O’Mahony DJ, FitzGerald GA. Phosphorylation and regulated expression of the human thromboxane A2 receptor. J Biol Chem 1994;269:29914–9.10.1016/S0021-9258(18)43968-3Search in Google Scholar

48. Szebeni J, Muggia F, Barenholz Y. Case study: complement activation related hypersensitivity reactions to PEGylated liposomal doxorubicin: experimental and clinical evidence, mechanisms and approaches to Inhibition. In: Dobrovolskaia MA, McNeil SE, editors. Handbook of Immunological Properties of Engineered Nanomaterials, 2nd ed. World Scientific Publishing Company; 2015:331–61.10.1142/9789813140455_0010Search in Google Scholar

49. Hart FD, Boardman PL. Indomethacin: a new non-steroid anti-inflammatory agent. Br Med J 1963;2:965–70.10.1136/bmj.2.5363.965Search in Google Scholar

50. Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin abolish prostaglandin release from the spleen. Nat New Biol 1971;231:237–9.10.1038/newbio231237a0Search in Google Scholar

51. Hastings KL, Center for Drug Evaluation and Research, US Food and Drug Administration. Implications of the new FDA/CDER immunotoxicology guidance for drugs. Int Immunopharmacol 2002;11:1613–8.10.1016/S1567-5769(02)00061-9Search in Google Scholar

52. Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product, 2013.Search in Google Scholar

53. Szebeni J, Bedocs P, Csukas D, Rosivall L, Bunger R, Urbanics R. A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines. Adv Drug Deliv Rev 2012;64:1706–16.10.1016/j.addr.2012.07.005Search in Google Scholar PubMed

Received: 2016-12-19
Accepted: 2017-2-28
Published Online: 2017-4-4
Published in Print: 2017-4-1

©2017 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 28.3.2024 from https://www.degruyter.com/document/doi/10.1515/ejnm-2016-0039/html
Scroll to top button