Polymerized Bovine Hemoglobin Infusion Does Not Induce Lung Damage in a Rat Model

ABSTRACT

Establishing a hemoglobin-based oxygen carrier (HBOC) has potential to improve transfusion medicine and provide a novel intervention to minimize tissue damage during hypoxic or ischemic insults. However, in vitro studies suggest that HBOCs have toxic effects on endothelial cell barrier function. The purpose of this study was to determine if the HBOC polymerized bovine hemoglobin (PBvHb) alters pulmonary endothelial barrier function in rats during normoxia or hypoxia. Conscious male Sprague-Dawley rats were treated with lactated Ringer’s (LR) or PBvHb (3 ml of 1.3 mg PBvHb/ml in lactated Ringer’s) and exposed to 4hr of normoxia (F_iO₂=21%) or hypoxia (F_iO₂=10%). Evans blue dye (EBD) extravasation (estimate of pulmonary vascular leak), pulmonary artery (Pa) pressure, inflammatory mediators, vascular endothelial growth factor (VEGF), fms-like tyrosine kinase-1 (sFlt-1), and hypoxia inducible factor-1 (HIF-1α) were measured in the lung and/or plasma. As expected with hypoxia, Pa pressure increased (p<0.05). PBvHb also resulted in a significant increase in Pa pressure independent of hypoxia. While a significant main effect of PBvHb on EBD extravasation was observed, no differences in inflammatory cytokines or pulmonary white blood cells existed among groups. No pulmonary edema was present upon assessment of wet:dry lung weights or histological examination. Hypoxia did not influence plasma VEGF, but resulted in a small but significant increase in sFlt-1. Irrespective of hypoxia, PBvHb was associated with increased unbound VEGF and its soluble receptor sFlt-1. However, no differences in lung VEGF or HIF-1􀀁 were observed. We conclude that in this model, acute administration of PBvHb does not have severe overall effects on pulmonary endothelial barrier function or inflammation.

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