Acellular haemoglobin attenuates hypoxia-inducible factor-1alpha (HIF-1alpha) and its target genes in haemodiluted rats.
ABSTRACT Hb (haemoglobin)-based blood substitutes represent a class of therapeutics designed to correct oxygen deficit under conditions of anaemia and traumatic blood loss. The influences of these agents on HIF-1alpha (hypoxia-inducible factor-1alpha) target genes involved in adaptation to hypoxia have so far not been studied. In the study presented here, rats underwent 80% ET (exchange transfusion) with either HS (hetastarch) or a polymerized Hb OG (Oxyglobin). HS induced dramatic EPO (erythropoietin) gene transcription, reaching a maximum at 4 h post-ET. In contrast, OG suppressed EPO transcription until approx. 24 h post-ET. Large plasma EPO levels that were observed post-ET with HS were significantly blunted in animals transfused with OG. OG, unlike HS, induced a sharp increase in HO-1 (haem oxygenase-1) transcription at 4 h, which declined rapidly within 24 h, whereas modest increases in iNOS [inducible (nitric oxide synthase)] and constitutive NOS [eNOS (endothelial NOS)] were detected over the control. Our results demonstrate for the first time that severe haemodilution-induced erythropoietic responses in kidneys were attenuated by a low-oxygen-affinity cell-free Hb and suggest that tissue-specific oxygen-sensing pathways can be influenced by allosterically modified Hbs.
Conference Paper: Edge Dislocation of FWM Dynamic Grating in Photo-Refractive MediumLasers and Electro-optics Europe, 1996. CLEO/Europe., Conference on; 10/1996
- [Show abstract] [Hide abstract]
ABSTRACT: Release of hemoglobin (Hb) into the circulation is a central pathophysiologic event that contributes to morbidity and mortality in chronic hemolytic anemias and severe malaria. These toxicities arise from Hb-mediated vasoactivity, possibly due to NO scavenging and localized tissue oxidative processes. Currently, there is no established treatment that targets circulating extracellular Hb. Here, we assessed the role of haptoglobin (Hp), the primary scavenger of Hb in the circulation, in limiting the toxicity of cell-free Hb infusion. Using a canine model, we found that glucocorticoid stimulation of endogenous Hp synthesis prevented Hb-induced hemodynamic responses. Furthermore, guinea pigs administered exogenous Hp displayed decreased Hb-induced hypertension and oxidative toxicity to extravascular environments, such as the proximal tubules of the kidney. The ability of Hp to both attenuate hypertensive responses during Hb exposure and prevent peroxidative toxicity in extravascular compartments was dependent on Hb-Hp complex formation, which likely acts through sequestration of Hb rather than modulation of its NO- and O2-binding characteristics. Our data therefore suggest that therapies involving supplementation of endogenous Hb scavengers may be able to treat complications of acute and chronic hemolysis, as well as counter the adverse effects associated with Hb-based oxygen therapeutics.The Journal of clinical investigation 09/2009; 119(8):2271-80. DOI:10.1172/JCI39115 · 13.77 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Recent setbacks in using Hb-based technology to develop oxygen carriers or blood substitutes may spur new and fundamentally different approaches for the development of a new generation of hemoglobin-based oxygen carriers (HBOCs). This article briefly details some underlying mechanisms that may have been responsible for the adverse-event profile associated with HBOCs, with a focus on the contribution of the author's laboratory toward identifying some of these biochemical pathways and some ways and means to control them. It is hoped that this will aid in the development of a safe and effective second generation of HBOCs.Clinics in laboratory medicine 06/2010; 30(2):381-9. DOI:10.1016/j.cll.2010.02.009 · 1.35 Impact Factor