Pre-clinical Evaluation of Hemoglobin Based Oxygen Carriers: Animal Models and Biomarkers

Buehler, Paul W.; D’Agnillo, Felice

doi:10.1007/978-3-642-40717-8_26

Cited by 1 publication

(7 citation statements)

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“…The present study shows that PolyHeme undergoes significant oxidation to methemoglobin in the circulation of guinea pigs. Uncontrolled oxidation of Hb in the circulation can be detrimental to the effectiveness of HBOCs because methemoglobin and other oxidized species no longer carry oxygen and have a greater propensity to release toxic heme or free iron into the circulation ( 14 , 25 ). Plasma and tissue antioxidant systems play a critical role in controlling the oxidation and breakdown of HBOCs; and thus, the selection of animal species with similar antioxidant profiles to humans is important to accurately assess methemoglobin formation in preclinical studies.…”

Section: Discussionmentioning

confidence: 99%

“…The reductive capacity of ascorbate has also been used to mitigate methemoglobin formation in clinical settings with HBOCs such as Hemopure ® (HbO 2 Therapeutics, Souderton, PA, USA) ( 13 ). Studying animal species that can accurately recapitulate the redox activity of HBOCs in vivo may also be important for the proper assessment of Hb-mediated nitric oxide (NO) scavenging reactions thought to underlie the reported hypertensive effects of HBOCs ( 14 , 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies from our laboratory indicate that the guinea pig may be a relevant small animal species to evaluate the unique pro-oxidative profiles of HBOCs (17,(19)(20)(21)(22)(23). This is based on the noted similarities between guinea pigs and humans in terms of their overall plasma and tissue antioxidant capabilities (14). Importantly, both species are unable to produce ascorbic acid (AA) due to an evolutionary loss of L-gluconolactoneoxidase, which is the rate limiting enzyme in AA synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…Hemoglobin-based oxygen carrier-associated safety concerns have been difficult to resolve, partly because preclinical testing has not always been predictive of clinical safety outcomes for some HBOCs ( 7 , 14 ). Moreover, there are important limitations related to the extrapolation of safety assessments in normal healthy animals to a heterogenous population of subjects with underlying comorbidities, endothelial dysfunction, and predisposition to various disease states ( 7 , 14 – 16 ). This has prompted the search for preclinical approaches that may better predict HBOC safety in humans.…”

Section: Introductionmentioning

confidence: 99%

“…This has prompted the search for preclinical approaches that may better predict HBOC safety in humans. Two areas of preclinical testing that have garnered some attention include the selection of relevant animal species and the use of sensitive biomarkers to help detect subtle safety signals ( 14 , 17 , 18 ). Previous studies from our laboratory indicate that the guinea pig may be a relevant small animal species to evaluate the unique pro-oxidative profiles of HBOCs ( 17 , 19 – 23 ).…”

Section: Introductionmentioning

confidence: 99%

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Renal glomerular and tubular responses to glutaraldehyde- polymerized human hemoglobin

et al. 2023

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Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and volume replacement therapeutics, however, their molecular and cellular effects on the vasculature and different organ systems are not fully defined. Using a guinea pig transfusion model, we examined the renal glomerular and tubular responses to PolyHeme, a highly characterized glutaraldehyde-polymerized human hemoglobin with low tetrameric hemoglobin content. PolyHeme-infused animals showed no major changes in glomerular histology or loss of specific markers of glomerular podocytes (Wilms tumor 1 protein, podocin, and podocalyxin) or endothelial cells (ETS-related gene and claudin-5) after 4, 24, and 72 h. Relative to sham controls, PolyHeme-infused animals also showed similar expression and subcellular distribution of N-cadherin and E-cadherin, two key epithelial junctional proteins of proximal and distal tubules, respectively. In terms of heme catabolism and iron-handling responses, PolyHeme induced a moderate but transient expression of heme oxygenase-1 in proximal tubular epithelium and tubulointerstitial macrophages that was accompanied by increased iron deposition in tubular epithelium. Contrary to previous findings with other modified or acellular hemoglobins, the present data show that PolyHeme does not disrupt the junctional integrity of the renal glomerulus and tubular epithelium, and triggers moderate activation of heme catabolic and iron sequestration systems likely as part of a renal adaptive response.

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Section: Discussionmentioning

confidence: 99%