Wang Jun, Shi Yanrong, Cao Suyi, Liu Xiuyun, Martin Lee J, Simoni Jan, Soltys Bohdan J, Hsia Carleton J C, Koehler Raymond C
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States.
Department of Pathology, Johns Hopkins University, Baltimore, MD, United States.
Front Med Technol. 2023 Feb 21;5:1074643. doi: 10.3389/fmedt.2023.1074643. eCollection 2023.
Polynitroxylated PEGylated hemoglobin (PNPH, aka SanFlow) possesses superoxide dismutase/catalase mimetic activities that may directly protect the brain from oxidative stress. Stabilization of PNPH with bound carbon monoxide prevents methemoglobin formation during storage and permits it to serve as an anti-inflammatory carbon monoxide donor. We determined whether small volume transfusion of hyperoncotic PNPH is neuroprotective in a porcine model of traumatic brain injury (TBI) with and without accompanying hemorrhagic shock (HS). TBI was produced by controlled cortical impact over the frontal lobe of anesthetized juvenile pigs. Hemorrhagic shock was induced starting 5 min after TBI by 30 ml/kg blood withdrawal. At 120 min after TBI, pigs were resuscitated with 60 ml/kg lactated Ringer's (LR) or 10 or 20 ml/kg PNPH. Mean arterial pressure recovered to approximately 100 mmHg in all groups. A significant amount of PNPH was retained in the plasma over the first day of recovery. At 4 days of recovery in the LR-resuscitated group, the volume of frontal lobe subcortical white matter ipsilateral to the injury was 26.2 ± 7.6% smaller than homotypic contralateral volume, whereas this white matter loss was only 8.6 ± 12.0% with 20-ml/kg PNPH resuscitation. Amyloid precursor protein punctate accumulation, a marker of axonopathy, increased in ipsilateral subcortical white matter by 132 ± 71% after LR resuscitation, whereas the changes after 10 ml/kg (36 ± 41%) and 20 ml/kg (26 ± 15%) PNPH resuscitation were not significantly different from controls. The number of cortical neuron long dendrites enriched in microtubules (length >50 microns) decreased in neocortex by 41 ± 24% after LR resuscitation but was not significantly changed after PNPH resuscitation. The perilesion microglia density increased by 45 ± 24% after LR resuscitation but was unchanged after 20 ml/kg PNPH resuscitation (4 ± 18%). Furthermore, the number with an activated morphology was attenuated by 30 ± 10%. In TBI pigs without HS followed 2 h later by infusion of 10 ml/kg LR or PNPH, PNPH remained neuroprotective. These results in a gyrencephalic brain show that resuscitation from TBI + HS with PNPH protects neocortical gray matter, including dendritic microstructure, and white matter axons and myelin. This neuroprotective effect persists with TBI alone, indicating brain-targeting benefits independent of blood pressure restoration.
多硝基化聚乙二醇化血红蛋白（PNPH，又名SanFlow）具有超氧化物歧化酶/过氧化氢酶模拟活性，可能直接保护大脑免受氧化应激。用结合的一氧化碳稳定PNPH可防止储存期间高铁血红蛋白的形成，并使其能够作为抗炎一氧化碳供体。我们确定了在伴有或不伴有失血性休克（HS）的创伤性脑损伤（TBI）猪模型中，小剂量输注高渗PNPH是否具有神经保护作用。通过对麻醉的幼猪额叶进行控制性皮质撞击来制造TBI。在TBI后5分钟开始通过抽取30 ml/kg血液诱导失血性休克。在TBI后120分钟，用60 ml/kg乳酸林格氏液（LR）或10或20 ml/kg PNPH对猪进行复苏。所有组的平均动脉压均恢复至约100 mmHg。在恢复的第一天，大量PNPH保留在血浆中。在LR复苏组恢复4天时，损伤同侧额叶皮质下白质的体积比同型对侧体积小26.2±7.6%，而用20 ml/kg PNPH复苏时，这种白质损失仅为8.6±12.0%。淀粉样前体蛋白点状积聚是轴突病的标志物，在LR复苏后同侧皮质下白质中增加了132±71%，而在10 ml/kg（36±41%）和20 ml/kg（26±15%）PNPH复苏后的变化与对照组无显著差异。富含微管（长度>50微米）的皮质神经元长树突数量在LR复苏后新皮质中减少了41±24%，但在PNPH复苏后无显著变化。损伤周围小胶质细胞密度在LR复苏后增加了45±24%，但在20 ml/kg PNPH复苏后无变化（4±18%）。此外，具有活化形态的数量减少了30±10%。在TBI猪且无HS，2小时后输注10 ml/kg LR或PNPH的情况下，PNPH仍然具有神经保护作用。这些在脑回脑的结果表明，用PNPH对TBI + HS进行复苏可保护新皮质灰质，包括树突微结构、白质轴突和髓鞘。这种神经保护作用在单独的TBI中持续存在，表明其脑靶向益处独立于血压恢复。
