Polynitroxylated PEGylated hemoglobin protects pig brain neocortical gray and white matter after traumatic brain injury and hemorrhagic shock.
Polynitroxylated PEGylated hemoglobin protects pig brain neocortical gray and white matter after traumatic brain injury and hemorrhagic shock.
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DOI：
10.3389/fmedt.2023.1074643
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发表时间：
2023
影响因子：
--
通讯作者：
Koehler, Raymond C.
中科院分区：
文献类型：
--
作者：
Wang, Jun;Shi, Yanrong;Cao, Suyi;Liu, Xiuyun;Martin, Lee J.;Simoni, Jan;Soltys, Bohdan J.;Hsia, Carleton J. C.;Koehler, Raymond C.
关键词：
多硝基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，可直接保护大脑免受氧化应激。PNPH与结合的一氧化碳的稳定防止高铁血红蛋白在储存期间形成，并允许其充当抗炎一氧化碳供体。我们确定了小容量高渗PNPH的输血是否在伴有和不伴有出血性休克（HS）的创伤性脑损伤（TBI）的猪模型中具有神经保护作用。TBI是通过对麻醉幼猪额叶的控制性皮质撞击产生的。在TBI后5分钟开始通过30 ml/kg的抽血诱导出血性休克。 在TBI后120分钟，用60 ml/kg乳酸林格氏液（LR）或10或20 ml/kg PNPH复苏猪。 所有组的平均动脉压均恢复至约100 mmHg。在恢复期第一天，血浆中保留了大量PNPH。在LR复苏组恢复4天时，损伤同侧额叶皮质下白色物质的体积比同型对侧体积小26.2 ± 7.6%，而20 ml/kg PNPH复苏时，这种白色物质的损失仅为8.6 ± 12.0%。LR复苏后，同侧皮质下白色物质中淀粉样前体蛋白点状积聚（轴突病的标志物）增加132 ± 71%，而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。 LR复苏后，新皮质中富含微管（长度> 50微米）的皮质神经元长树突的数量减少了41 ± 24%，但PNPH复苏后无显著变化。LR复苏后病灶周围小胶质细胞密度增加45 ± 24%，但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猪无HS，随后2小时后，注入10 ml/kg LR或PNPH，PNPH仍然具有神经保护作用。 脑回的这些结果表明，从TBI + HS与PNPH复苏保护新皮质灰质，包括树突状微结构，和白色物质轴突和髓鞘。这种神经保护作用仅在TBI时持续存在，表明脑靶向益处独立于血压恢复。
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.
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影响因子：
6.3
作者：
Cipolla, Marilyn J.;Linfante, Italo;Chan, Siu-Lung
通讯作者：
Chan, Siu-Lung
DOI：
10.1152/ajpheart.1998.275.4.h1313
发表时间：
1998-10-01
影响因子：
4.8
作者：
Asano, Y;Koehler, RC;Bucci, E
通讯作者：
Bucci, E
影响因子：
4.1
作者：
Hlatky, R;Furuya, Y;Robertson, CS
通讯作者：
Robertson, CS
影响因子：
8
作者：
Brady, Ken M.;Shaffner, Donald H.;Guerguerian, Anne-Marie
通讯作者：
Guerguerian, Anne-Marie
影响因子：
2.9
作者：
Conrad MS;Dilger RN;Johnson RW
通讯作者：
Johnson RW