Abstract
Hemoglobin vesicles (HbV), cellular-type artificial oxygen carriers, are human hemoglobin encapsulated within a phospholipid bilayer membrane. Because HbV are injected intravenously, the biocompatibility of the HbV with blood components is extremely important to ensure their safety for clinical use. We evaluated this biocompatibility by particularly examining the influence of HbV on human blood cells and on plasma proteins in vitro. (1) Regarding influences to platelets that are involved not only in hemostasis but also in inflammation, HbV themselves neither activate platelets nor show aberrant effect on agonist-induced platelet activation. (2) HbV do not affect the agonist-induced activation of neutrophil functions that play important roles in innate immunity. (3) HbV do not affect hematopoietic progenitor activity. (4) The HbV examined herein (containing DHSG) do not activate the complement system, but old-type HbV (containing DPPG, no PEG modification) do so to a marked degree. (5) Neither coagulation nor the kallikrein–kinin cascade was affected by the current type of HbV. (6) Multiple HbV infusions in rats cause a transiently slight decrease in the complement titer only after first infusion, with no allergic reaction. No anaphylactic shock was observed in rats administered multiple empty vesicles without hemoglobin. (7) Infusion of HbV can “transiently” render HbV phagocytized-splenic cells immunosuppressive in ex vivo culture condition. Results of our in vitro and in vivo investigations show that HbV are highly biocompatible with human blood cells, human plasma proteins and rat immune systems.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abe H, Azuma H, Yamaguchi M, Fujihara M, Ikeda H, Sakai H, Takeoka S, Tsuchida E (2007) Effects of hemoglobin vesicles, a liposomal artificial oxygen carrier, on hematological responses, complement and anaphylactic reactions in rats. Artif Cells Blood Substit Biotechnol 35:157–172
al-Ramadi BK, Brodikin MA, Mosser DM, Einstein TK (1991) Immunosuppression induced by attenuated Salmonella: evidence for mediation by macrophage precursors. J Immunol 146:2737–2746
Baggiolini M, Dahinden CA (1994) CC chemokines in allergic inflammation. Immunol Today 15:127–133
Bellemare F, Israel-Assayag E, Cormier Y (1995) PC: PS liposomes induce a recruitment of neutrophils and the release of TNF alpha in the lungs of mice sensitized with Saccaropolyspora rectivirgula. Eur J Clin Invest 25:340–345
Bradley AJ, Devine DV, Ansell SM, Janzen J, Brooks DE (1998) Inhibition of liposome-induced complement activation by incorporated poly(ethylene glycol)-lipids. Arch Biochem Biophys 357:185–194
Chanan-Khan A, Szebeni J, Savay S, Liebes L, Rafique NM, Alving CR, Muggia FM (2003) Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions. Ann Oncol 14:1430–1437
Chonn A, Cullis PR, Devine DV (1991) The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes. J Immunol 146:4234–4241
Cunningham CM, Kingzette M, Richards RL, Alving CR, Lint TF, Gewurz H (1979) Activation of human complement by liposomes: a model for membrane activation of the alternative pathway. J Immunol 122:1237–1242
Dasgupta SA, Mookerjee SK, Chowdhury SK, Ghose AC (1999) Immunosuppression in hamsters with progressive visceral leishmaniasis: an evaluation of the role of nitric oxide toward impairment of the lymphoproliferative response. Parasitol Res 85:594–596
Devine DV, Wong K, Serrano K, Chonn A, Cullis PR (1994) Liposome-complement interactions in rat serum: implications for liposome survival studies. Biochim Biophys Acta 1191:43–51
Fujihara M, Azuma H, Ikeda H (2008) Biocompatibility of hemoglobin vesicles, a cellular-type artificial oxygen carrier, on human blood cells and plasma proteins in vitro. Artif Blood 16:212–220
Fujihara M, Takahashi D, Abe H, Sakai H, Horinouchi H, Kobayashi K, Ikeda H, Azuma H. Primary and secondary immune responses to keyhole limpet hemocyanin in rats after infusion of hemoglobin vesicle, an artificial oxygen carrier. Artif Organs (in press)
Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115:3378–3384
Griep MA, Fujikawa K, Nelsestuen GL (1985) Binding and activation properties of human factor XII, prekallikrein and derived peptides with acidic lipid vesicles. Biochemistry 24:4124–4130
Hatipoglu U, Gao XP, Verral S, Sejourne F, Pitrak D, Alkan-Onyuksel H, Rubinstein I (1998) Sterically stabilized phospholipids attenuate human neutrophils chemotaxis in vitro. Life Sci 63:693–699
Ito T, Fujihara M, Abe H, Yamaguchi M, Wakamoto S, Takeoka S, Sakai H, Tsuchida E, Ikeda H, Ikebuchi K (2001) Effects of poly(ethyleneglycol)-modified hemoglobin vesicles on N-formyl-methionyl-leucyl-phenylalanine-induced responses of polymorphonuclear neutrophils in vitro. Artif Cells Blood Substit Immobil Biotechnol 29:427–437
Klibanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268:235–237
Laing RB, Milne LJ, Leen CL, Malcolm GP, Steers AJ (1994) Anaphylactic reactions to liposomal amphotericin. Lancet 344:682
Laverman P, Boerman OC, Oyen WJG, Corstens FHM, Storm G (2001) In vivo applications of PEG liposomes: unexpected observations. Crit Rev Ther Drug Carrier Syst 18:551–566
Mitropoulos KA, Martin JC, Reeves BE, Esnouf MP (1989) The activation of the contact phase of coagulation by physiologic surfaces in plasma: the effect of large negatively charged liposomal vesicles. Blood 73:1525–1533
Rand ML, Leung R, Packham MA (2003) Platelet function assays. Transfus Apheresis Sci 28:307–317
Sakai H, Suzuki Y, Sou K, Kano M (2012) Cardiopulmonary responses to the small injection of hemoglobin vesicles (artificial oxygen carriers) in miniature pig. J Biomed Mater Res Part A 100:2668--2677
Sakai H, Takeoka S, Park SI, Kose T, Nishide H, Izumi Y, Yoshizu A, Kobayashi K, Tsuchida E (1997) Surface modification of haemoglobin vesicles with poly(ethylene glycol) and effects on aggregation, viscosity and blood flow during 90 % exchange transfusion in anesthetized rats. Bioconjug Chem 8:23–30
Sakai H, Horinouchi H, Tomiyama K, Ikeda E, Takeoka S, Kobayashi K, Tsuchida E (2001) Hemoglobin-vesicle as oxygen carriers: influence on phagocytic activity and histopathological changes in reticuloendothelial system. Am J Pathol 159:1079–1088
Sakai H, Horinouchi H, Yamamoto M, Ikeda E, Takeoka S, Takaori M, Tsuchida E, Kobayashi K (2006) Acute 40 % exchange-transfusion with hemoglobin-vesicles (HbV) suspended in recombinant human serum albumin solution: degradation of HbV and erythropoiesis in a rat spleen for 2 weeks. Transfusion 46:339–347
Sakai H, Sou K, Horinouchi H, Kobayashi K, Tsuchida E (2008) Haemoglobin-vesicles as artificial oxygen carriers: present situation and future visions. J Intern Med 263:4–15
Schleifer KW, Mansfield JM (1993) Suppressor macrophages in african trypanosomiasis inhibit T cell proliferative responses by nitric oxide and prostaglandins. J Immunol 151:5492–5503
Sou K, Klipper R, Goins B, Tsuchida E, Phillips WT (2005) Circulation kinetics and organ distribution of Hb-vesicles developed as a red blood cell substitute. J Pharmacol Exp Ther 312:702–709
Szebeni J (2005) Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology 216:106–121
Szebeni J, Fontana JL, Wassef NM, Mongan PD, Morse DS, Dobbins DE, Stahl GL, Bünger R, Alving CR (1999) Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs: a model for pseudoallergic cardiopulmonary reactions to liposomes, role of complement and inhibition by soluble CR1 and anti-C5a antibody. Circulation 99:2302–2309
Szebeni J, Baranyi L, Savay S, Bodo M, Morse DS, Basta M, Stahl GL, Bünger R, Alving CR (2000) Liposome-induced pulmonary hypertension: properties and mechanism of a complement-mediated pseudoallergic reaction. Am J Physiol Heart Circ Physiol 279:H1319–H1328
Szebeni J, Muggia F, Gabizon A, Barenholz Y (2011) Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev 63:1020–1030
Takahashi D, Azuma H, Sakai H, Sou K, Wakita D, Abe H, Fujihara M, Horinouchi H, Nishimura T, Kobayashi K, Ikeda H (2011) Phagocytosis of liposome particles by rat splenic immature monocytes makes them transiently and highly immunosuppressive. J Pharmacol Exp Ther 337:42–49
Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 4:145–160
Wakamoto S, Fujihara M, Abe H, Sakai H, Takeoka S, Tsuchida E, Ikeda H, Ikebuchi K (2001) Effects of poly(ethyleneglycol)-modified hemoglobin vesicles on agonist-induced platelet aggregation and RANTES release in vitro. Artif Cells Blood Substit Immobil Biotechnol 29:191–201
Wakamoto S, Fujihara M, Abe H, Yamaguchi M, Azuma H, Ikeda H, Takeoka S, Tsuchida E (2005) Effects of hemoglobin vesicles on resting and agonist-stimulated human platelets in vitro. Artif Cells Blood Substit Biotechnol 33:101–111
Woodle MC, Lasic DD (1992) Sterically stabilized liposomes. Biochim Biophys Acta 1113:171–199
Yamaguchi M, Fujihara M, Wakamoto S, Sakai H, Takeoka S, Tsuchida E, Azuma H, Ikeda H (2009a) Influence of hemoglobin vesicles, cellular-type artificial oxygen carriers, on human umbilical cord blood hematopoietic progenitor cells in vitro. J Biomed Mater Res A 88:34–42
Yamaguchi M, Fujihara M, Wakamoto S, Sakai H, Takeoka S, Tsuchida E, Hamada H, Azuma H, Ikeda H (2009b) Biocompatibility study of hemoglobin vesicles, cellular-type artificial oxygen carriers, with human umbilical cord hematopoietic stem/progenitor cells using an in vitro expansion system. ASAIO J 55:200–205
Zu YL, Qi J, Gilchrist A, Fernandez GA, Vazquez-Abad D, Kreutzer DL, Huang CK, Sha’afi RI (1998) p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-α or FMLP stimulation. J Immunol 160:1982–1989
Acknowledgments
The work presented here in was supported in part by Health and Labour Sciences Research Grants (Health Science Research Including Drug Innovation) from the Ministry of Health, Labour and Welfare, Japan).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Azuma, H., Fujihara, M., Sakai, H. (2013). Biocompatibility of Hemoglobin Vesicles, a Cellular-Type Artificial Oxygen Carrier, on Blood Cells and Plasma Proteins In Vitro and In Vivo. In: Kim, H., Greenburg, A. (eds) Hemoglobin-Based Oxygen Carriers as Red Cell Substitutes and Oxygen Therapeutics. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40717-8_22
Download citation
DOI: https://doi.org/10.1007/978-3-642-40717-8_22
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-40716-1
Online ISBN: 978-3-642-40717-8
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)