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Unfortunately, during pathological conditions resulting in chronic hemolysis cell-free hemoglobin (Hb) is released into the circulation which releases free heme, resulting in several complications. One approach to prevent these toxicities is administration of supplemental scavenger proteins, haptoglobin (Hp) and hemopexin (Hpx). The goal of this body of work is to objectively measure levels of vascular reactivity and inflammatory profiles after an infusion of acellular hemoglobin in animals that were given a co-administration of PEGylated human apohemoglobin (PEG-apoHb), a hemopexin (Hpx)-mimetic that can scavenge free heme from hemoglobin, together with human plasma-derived Hp that can scavenge dimerized Hb. Utilizing intravital microscopy, Golden Syrian hamsters instrumented with a dorsal window chamber were used to evaluate the in vivo effects of 4 experimental groups that were then challenged with a hypovolemic injection (10% of the animal's blood volume) of human Hb (hHb, 5 g/dL). The four experimental groups consisted of: 1) lactated Ringer's (control), 2) PEG-apoHb only, 3) Hp only, and 4) PEG-apoHb + Hp. The microvascular hemodynamics (diameter and flow) in arterioles and venules were recorded at baseline, 20 minutes after treatment, and 20 minutes after hHb challenge. Systemic parameters (blood pressure and heart rate), blood gases (pH, pCO 2 , and pO 2 ), blood parameters (Hb concentration and hematocrit), and multiorgan functionality/ inflammation were also measured. Our results suggest that co-administration of PEG-apoHb + Hp as a booster prior to the infusion of acellular hemoglobin significantly prevented vasoconstriction in the microcirculation, significantly increased the number of functional capillaries, and significantly reduced inflammation.

Therapeutic agents that increase the Hb affinity for oxygen (O 2 ) could, in theory, lead to decreased O 2 release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O 2 , was used to assess the impact of increasing Hb affinity for O 2 on brain tissue oxygenation, blood pressure, heart rate, O 2 delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O 2 delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O 2 , reducing the Po 2 for 50% HbO 2 saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O 2 delivery and extraction. Chronically increasing Hb affinity for O 2 with GBT1118 preserved cortical O 2 tension during normoxia, improved cortical O 2 tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O 2 and consequently reducing sickling of RBCs in blood during hypoxia in SCD. NEW & NOTEWORTHY Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.

This study sought to determine the role of physical training (PT) on body weight (BW), energy balance, histological markers of nonalcoholic fatty liver disease (NAFLD) and metabolic gene expression in the liver of ob/ob mice. Adult male ob/ob mice were assigned into groups sedentary (S; n = 8) and trained (T; n = 9). PT consisted in running sessions of 60 min at 60% of maximal speed conducted five days per week for eight weeks. BW of S group was higher from the 4(th) to 8(th) week of PT compared to their own BW at the beginning of the experiment. PT decreased daily food intake and increased resting oxygen consumption and energy expenditure in T group. No difference was observed in respiratory exchange ratio, but the rates of carbohydrate and lipids oxidation, and maximal running capacity were greater in T than S group. Both groups showed liver steatosis but not inflammation. PT increased CPT1a and SREBP1c mRNA expression in T group, but did not change MTP, PPAR-α, PPAR-γ, and NFKB mRNA expression. In conclusion, PT prevented body weight gain in ob/ob mice by inducing negative energy balance and increased physical exercise tolerance. However, PT did not change inflammatory gene expression and failed to prevent liver steatosis possible due to an upregulation in the expression of SREBP1c transcription factor. These findings reveal that PT has positive effect on body weight control but not in the liver steatosis in a leptin deficiency condition.