Microvascular and systemic responses to novel PEGylated carboxyhaemoglobin-based oxygen carrier in a rat model of vaso-occlusive crisis

摘要

Hypoxia drives sickle cell disease (SCD) by inducing sickle cell haemoglobin to polymerize and deform red blood cells (RBC) into the sickle shape. A novel carboxyhaemoglobin-based oxygen carrier (PEG-COHb; PP-007) promotes unsickling in vitro by relieving RBC hypoxia. An in vivo rat model of vaso-occlusive crisis (VOC) capable of accommodating a suite of physiological and microcirculatory measurements was used to compare treatment with PEG-COHb to a non-oxygen carrying control solution (lactated ringer’s [LRS]). Male Sprague-Dawley rats were anesthetized and surgically prepared to monitor microvascular interstitial oxygenation (P ISF O 2 ), cardiovascular parameters and blood chemistry. Human homozygous SCD RBCs were isolated and exchange transfused into the rats until the distal microcirculation of the exteriorized spinotrapezius muscle was hypoxic and RBC aggregates were visualized. VOC was left untreated (Sham) or treated 15?min later with PEG-COHb or LRS and observed for up to 4?h. Treatment with PEG-COHb showed better improvement of P ISF O 2 , end-point lactate, mean arterial pressure and survival duration compared to Sham and LRS. Restoring P ISF O 2 was associated with relieving the RBC aggregates driving VOC, which then affected other study metrics. Compared to LRS, PEG-COHb’s oxygen-carrying properties were key to improved outcomes.