Search

The present study aimed to compare the ability of tense (T) and relaxed (R) quaternary state polymerized human hemoglobin (PolyhHb) to restore hemodynamics after severe trauma in a rat model, and to assess their relative toxicity in a guinea pigs (GPs). To assess the efficacy of these PolyhHbs in restoring hemodynamics, Wistar rats were subjected to traumatic brain injury (TBI) followed by hemorrhagic shock (HS). Animals were separated into 3 groups based on the resuscitation solution: Whole blood, T-state or R-state PolyhHb, and followed for 2 hours after resuscitation. For toxicity evaluation, GPs were subjected to HS and the hypovolemic state was maintained for 50 minutes. Then, the GPs were divided randomly into 2 groups, and reperfused with T- or R-state PolyhHb. Rats resuscitated with blood and T-state PolyhHb had a higher recovery of MAP at 30 min after resuscitation when compared to R-state PolyhHb, demonstrating the greater ability of T-state PolyhHb to restore hemodynamics compared to R-state PolyhHb. Resuscitation with R-state PolyhHb in GPs increased markers of liver damage and inflammation, kidney injury and systemic inflammation compared to the T-state PolyhHb group. Finally, increased levels of cardiac damage markers, such as troponin were observed, indicating greater cardiac injury in GPs resuscitated with R-state PolyhHb. Therefore, our results showed that T-state PolyhHb exhibited superior efficacy in a model of TBI followed by HS in rats, and presented reduced vital organ toxicity in GPs, when compared to R-state PolyhHb. [ABSTRACT FROM AUTHOR]

The widespread adoption of high-calorie, high-fat, high-sucrose diets (HFHSD) has become a global health concern, particularly due to their association with cardiovascular diseases and metabolic disorders. These comorbidities increase susceptibility to severe outcomes from viral infections and trauma, with trauma-related incidents significantly contributing to global mortality rates. This context underscores the critical need for a reliable blood supply. Recent research has focused on high molecular weight (MW) polymerized human hemoglobin (PolyhHb) as a promising alternative to red blood cells (RBCs), showing encouraging outcomes in previous studies. Given the overlap of metabolic disorders and trauma-related health issues, it is crucial to assess the potential toxicity of PolyhHb transfusions, particularly in models that represent these vulnerable populations. This study evaluated the effects of PolyhHb exchange transfusion in guinea pigs that had developed metabolic disorders due to a 12-week HFHSD regimen. The guinea pigs, underwent a 20 % blood volume exchange transfusion with either PolyhHb or the lower molecular weight polymerized bovine hemoglobin, Oxyglobin. Results revealed that both PolyhHb and Oxyglobin transfusions led to liver damage, with a more pronounced effect observed in HFHSD-fed animals. Additionally, markers of cardiac dysfunction indicated signs of cardiac injury in both the HFHSD and normal diet groups following the Oxyglobin transfusion. This study highlights how pre-existing metabolic disorders can exacerbate the potential side effects of hemoglobin-based oxygen carriers (HBOCs). Importantly, the newer generation of high MW PolyhHb showed lower cardiac toxicity compared to the earlier generation low MW PolyhHb, known as Oxyglobin, even in models with pre-existing endothelial and metabolic challenges. [Display omitted] • High fat and high sucrose diet exacerbates liver damage from PolyhHb and Oxyglobin transfusions. • Cardiac dysfunction is observed post-Oxyglobin transfusion in both high fat and high sucrose diet and normal diet. • High MW PolyhHb demonstrates reduced cardiac toxicity compared to Oxyglobin. [ABSTRACT FROM AUTHOR]

This study aims to investigate the effects of hypoxically stored Red Blood Cells (RBCs) in a rat model of traumatic brain injury followed by severe hemorrhagic shock (HS) and resuscitation. RBCs were made hypoxic using an O 2 depletion system (Hemanext Inc. Lexington, MA) and stored for 3 weeks. Experimental animals underwent craniotomy and blunt brain injury followed by severe HS. Rats were resuscitated with either fresh RBCs (FRBCs), 3-week-old hypoxically stored RBCs (HRBCs), or 3-week-old conventionally stored RBCs (CRBCs). Resuscitation was provided via RBCs transfusion equivalent to 70 % of the shed blood and animals were followed for 2 h. The control group was comprised of healthy animals that were not instrumented or injured. Post-resuscitation hemodynamics and lactate levels were improved with FRBCs and HRBCs, and markers of organ injury in the liver (Aspartate aminotransferase [AST]), lung (chemokine ligand 1 [CXCL-1] and Leukocytes count), and heart (cardiac troponin, Interleukin- 6 [IL-6] and Tumor Necrosis Factor Alpha[TNF-α]) were lower with FRBCs and HRBCs resuscitation compared to CRBCs. Following reperfusion, biomarkers for oxidative stress, lipid peroxidation, and RNA/DNA injury were assessed. Superoxide dismutase [SOD] levels in the HRBCs group were similar to the FRBCs group and levels in both groups were significantly higher than CRBCs. Catalase levels were not different than control values in the FRBCs and HRBCs groups but significantly lower with CRBCs. Thiobarbituric acid reactive substances [Tbars] levels were higher for both CRBCs and HRBCs. Hypoxically stored RBCs show few differences from fresh RBCs in resuscitation from TBI + HS and decreased organ injury and oxidative stress compared to conventionally stored RBCs. [ABSTRACT FROM AUTHOR]

Amelioration of immune overactivity during sepsis is key to restoring hemodynamics, microvascular blood flow, and tissue oxygenation, and in preventing multi-organ dysfunction syndrome. The systemic inflammatory response syndrome that results from sepsis ultimately leads to degradation of the endothelial glycocalyx and subsequently increased vascular leakage. Current fluid resuscitation techniques only transiently improve outcomes in sepsis, and can cause edema. Nitric oxide (NO) treatment for sepsis has shown promise in the past, but implementation is difficult due to the challenges associated with delivery and the transient nature of NO. To address this, we tested the anti-inflammatory efficacy of sustained delivery of exogenous NO using i.v. infused NO releasing nanoparticles (NO-np). The impact of NO-np on microhemodynamics and immune response in a lipopolysaccharide (LPS) induced endotoxemia mouse model was evaluated. NO-np treatment significantly attenuated the pro-inflammatory response by promoting M2 macrophage repolarization, which reduced the presence of pro-inflammatory cytokines in the serum and slowed vascular extravasation. Combined, this resulted in significantly improved microvascular blood flow and 72-h survival of animals treated with NO-np. The results from this study suggest that sustained supplementation of endogenous NO ameliorates and may prevent the morbidities of acute systemic inflammatory conditions. Given that endothelial dysfunction is a common denominator in many acute inflammatory conditions, it is likely that NO enhancement strategies may be useful for the treatment of sepsis and other acute inflammatory insults that trigger severe systemic pro-inflammatory responses and often result in a cytokine storm, as seen in COVID-19. Image 1 • Inflammatory response was reduced with nitric oxide releasing nanoparticles (NO-nps). • Endotoxemia-induced microvascular deficits were alleviated by NO-nps. • NO-nps promoted M2 macrophage repolarization, and reduced M1 macrophage population. • NO-nps could improve outcomes of insults that cause a cytokine storm, like COVID-19. [ABSTRACT FROM AUTHOR]