Immune Safety Evaluation of Polymerized Porcine Hemoglobin (pPolyHb): A Potential Red Blood Cell Substitute

Zhu, Hongli; Yan, Kunping; Dang, Xiaodong; Huang, He; Chen, Erfang; Chen, Bang; Luo, Chao; Chang, Thomas Ming Swi; Dai, Peng; Chen, Chao

doi:10.3109/10731199.2011.631499

Cited by 16 publications

(8 citation statements)

References 26 publications

(28 reference statements)

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“…Glutaraldehyde-polymerized porcine hemoglobin (pPolyHb) was prepared as previously described (Zhu et al 2011a, Zhu et al 2011b). pPolyHb (10.5 Ϯ 0.5 g/dL polymerized porcine hemoglobin, methemoglobin Ͻ 5%, endotoxin Ͻ 1.0 EU/mL, osmolality 300 -330 mOsm, pH 7.4 Ϯ 0.05, average molecular weight of pPolyHb 600 Ϯ 50 kD, 64 kD tetramer Ͻ 2%) was formulated and stored at 4 ° C under nitrogen gas until use.…”

Section: Ppolyhb Solutionsmentioning

confidence: 99%

Pretreatment with pPolyHb attenuates H₂O₂-induced endothelial cell injury through inhibition of JNK/p38 MAPK pathway by upregulation of heme oxygenase-1

Hou

Yan

Zhao

et al. 2015

Artificial Cells, Nanomedicine, and Biotechnology

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Polymerized porcine hemoglobin (pPolyHb) exhibits a protective effect on ischemia/reperfusion of organ grafts. A series of experiments were performed to explore the underlying cytoprotective mechanisms of pPolyHb pretreatment on H2O2-induced cell death and apoptosis. The results showed that the pretreatment augmented heme oxygenase-1 (HO-1) expression, and at the same time, decreased the phosphorylation of JNK/p38 mitogen-activated protein kinase (MAPK) and intracellular ROS generation in H2O2-treated HUVECs. Moreover, the inhibition of HO-1 expression by tin porphyrin (SnPP) abolished the protective effects of pPolyHb, which suggested that the cytoprotective effect of pPolyHb involves upregulating HO-1 and subsequently decreasing the phosphorylation of the JNK and p38 MAPK and ROS generation.

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Section: Ppolyhb Solutionsmentioning

confidence: 99%

Pretreatment with pPolyHb attenuates H₂O₂-induced endothelial cell injury through inhibition of JNK/p38 MAPK pathway by upregulation of heme oxygenase-1

Hou

Yan

Zhao

et al. 2015

Artificial Cells, Nanomedicine, and Biotechnology

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“…Inflammatory responses are expected from blood transfusions, and are exacerbated by transfusion of stored blood and, potentially by PolyhHb 20 , 23 , 24 . Plasma and spleen inflammatory markers are presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

Safety and efficacy of human polymerized hemoglobin on guinea pig resuscitation from hemorrhagic shock

Muller

Williams

Walser

et al. 2022

Sci Rep

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For the past thirty years, hemoglobin-based oxygen carriers (HBOCs) have been under development as a red blood cell substitute. Side-effects such as vasoconstriction, oxidative injury, and cardiac toxicity have prevented clinical approval of HBOCs. Recently, high molecular weight (MW) polymerized human hemoglobin (PolyhHb) has shown positive results in rats. Studies have demonstrated that high MW PolyhHb increased O2 delivery, with minimal effects on blood pressure, without vasoconstriction, and devoid of toxicity. In this study, we used guinea pigs to evaluate the efficacy and safety of high MW PolyhHb, since like humans guinea pigs cannot produce endogenous ascorbic acid, which limits the capacity of both species to deal with oxidative stress. Hence, this study evaluated the efficacy and safety of resuscitation from severe hemorrhagic shock with high MW PolyhHb, fresh blood, and blood stored for 2 weeks. Animals were randomly assigned to each experimental group, and hemorrhage was induced by the withdrawal of 40% of the blood volume (BV, estimated as 7.5% of body weight) from the carotid artery catheter. Hypovolemic shock was maintained for 50 min. Resuscitation was implemented by infusing 25% of the animal’s BV with the different treatments. Hemodynamics, blood gases, total hemoglobin, and lactate were not different before hemorrhage and during shock between groups. The hematocrit was lower for the PolyhHb group compared to the fresh and stored blood groups after resuscitation. Resuscitation with stored blood had lower blood pressure compared to fresh blood at 2 h. There was no difference in mean arterial pressure between groups at 24 h. Resuscitation with PolyhHb was not different from fresh blood for most parameters. Resuscitation with PolyhHb did not show any remarkable change in liver injury, inflammation, or cardiac damage. Resuscitation with stored blood showed changes in liver function and inflammation, but no kidney injury or systemic inflammation. Resuscitation with stored blood after 24 h displayed sympathetic hyper-activation and signs of cardiac injury. These results suggest that PolyhHb is an effective resuscitation alternative to blood. The decreased toxicities in terms of cardiac injury markers, vital organ function, and inflammation following PolyhHb resuscitation in guinea pigs indicate a favorable safety profile. These results are promising and support future studies with this new generation of PolyhHb as alternative to blood when blood is unavailable.

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“…Hb and mannan both functioned as the adjuvants. As an oxygen carrier, Hb was a potential immunomodulatory protein without a significant adverse immune effect, which could regulate inflammation, cytokine secretion, and activation of macrophage in the plasma. , Mannan was a ligand of TLR-4 or TLR-2 and could be recognized via mannose receptor, dectin-2, and DC-SIGN, which induce Th1-type and Th2-type immune response. − Hb and mannan could play the immunomodulatory activities in a synergistic manner. Consistently, physical administration of HM with EDIII was demonstrated to increase the immunogenicity of EDIII in the present study.…”

Section: Discussionmentioning

confidence: 99%

Conjugation of Hemoglobin and Mannan Markedly Improves the Immunogenicity of Domain III of the Zika Virus E Protein: Structural and Immunological Study

Shen

et al. 2021

Bioconjugate Chem.

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Zika virus (ZIKV) leads to congenital microcephaly and anomalies and severe neurological diseases such as Guillain-Barre syndrome. Safe and effective vaccines are necessitated to deal with these severe health threats. As an ideal antigen, the domain III of the envelope protein (EDIII) of ZIKV can evoke potent neutralizing antibodies without any antibody-dependent enhancement (ADE) effect. However, EDIII necessitates to be formulated with an antigen delivery system or adjuvants to improve its immunogenicity. Hemoglobin (Hb) regulates inflammation, cytokine levels, and activate macrophage. Mannan is a polysaccharide of the fungal cell wall with an immunomodulatory activity. In this study, EDIII was conjugated with Hb and mannan, using the disulfide bond as the linker. Hb and mannan both functioned as the adjuvants. Conjugation of Hb and mannan acted as the delivery system for EDIII. The structure of EDIII was essentially maintained upon conjugation of Hb and mannan. The intracellular release of EDIII from the conjugate (HM−EDIII-2) was achieved by reduction of the glutathione-sensitive disulfide bond. As compared with EDIII, HM− EDIII-2 elicited high EDIII-specific IgG titers and high levels of Th1-type cytokines (IFN-γ and IL-2) and Th2-type cytokines (IL-5 and IL-10), along with no apparent toxicity to the organs. Moreover, the pharmacokinetic study revealed a prolonged serum exposure of HM−EDIII-2 to the immune cells. Thus, HM−EDIII-2 could boost a strong humoral and cellular immune response to EDIII. Our study was expected to provide the feasibility necessary to develop a robust and potentially safe ZIKV vaccine.

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Immune Safety Evaluation of Polymerized Porcine Hemoglobin (pPolyHb): A Potential Red Blood Cell Substitute

Cited by 16 publications

References 26 publications

Pretreatment with pPolyHb attenuates H₂O₂-induced endothelial cell injury through inhibition of JNK/p38 MAPK pathway by upregulation of heme oxygenase-1

Pretreatment with pPolyHb attenuates H₂O₂-induced endothelial cell injury through inhibition of JNK/p38 MAPK pathway by upregulation of heme oxygenase-1

Safety and efficacy of human polymerized hemoglobin on guinea pig resuscitation from hemorrhagic shock

Conjugation of Hemoglobin and Mannan Markedly Improves the Immunogenicity of Domain III of the Zika Virus E Protein: Structural and Immunological Study

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Immune Safety Evaluation of Polymerized Porcine Hemoglobin (pPolyHb): A Potential Red Blood Cell Substitute

Cited by 16 publications

References 26 publications

Pretreatment with pPolyHb attenuates H2O2-induced endothelial cell injury through inhibition of JNK/p38 MAPK pathway by upregulation of heme oxygenase-1

Pretreatment with pPolyHb attenuates H2O2-induced endothelial cell injury through inhibition of JNK/p38 MAPK pathway by upregulation of heme oxygenase-1

Safety and efficacy of human polymerized hemoglobin on guinea pig resuscitation from hemorrhagic shock

Conjugation of Hemoglobin and Mannan Markedly Improves the Immunogenicity of Domain III of the Zika Virus E Protein: Structural and Immunological Study

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Pretreatment with pPolyHb attenuates H₂O₂-induced endothelial cell injury through inhibition of JNK/p38 MAPK pathway by upregulation of heme oxygenase-1

Pretreatment with pPolyHb attenuates H₂O₂-induced endothelial cell injury through inhibition of JNK/p38 MAPK pathway by upregulation of heme oxygenase-1