GBT1118, a compound that increases the oxygen affinity of hemoglobin, improves survival in murine hypoxic acute lung injury.
GBT1118, a compound that increases the oxygen affinity of hemoglobin, improves survival in murine hypoxic acute lung injury.
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GBT1118 是一种增加血红蛋白氧亲和力的化合物，可提高小鼠缺氧急性肺损伤的存活率。
DOI：
10.1152/japplphysiol.00079.2017
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Bastarache,JulieA
中科院分区：
文献类型：
--
作者：
Putz,NathanD;Shaver,CiaraM;Dufu,Kobina;Li,Chien-Ming;Xu,Qing;Hutchaleelaha,Athiwat;Lehrer-Graiwer,Josh;Majka,SusanM;Ware,LorraineB;Bastarache,JulieA
急性呼吸窘迫综合征（ARDS）以肺部炎症和肺水肿为特征，严重时可导致动脉低氧血症和死亡。纠正低氧血症的策略有可能改善ARDS的临床结局。本研究的目的是评估血红蛋白修饰作为治疗ARDS引起的低氧血症的新疗法的潜力。在暴露于5%或10%缺氧前24小时通过气管内滴注LPS诱导的急性肺损伤小鼠模型中评价了两种不同剂量的GBT 1118（一种增加血红蛋白氧亲和力的化合物）的治疗效果（每组n= 8-15）。正如预期的那样，给予小鼠GBT 1118显著增加了血红蛋白的氧亲和力。与接受溶媒对照的小鼠相比，接受GBT 1118处理的小鼠在LPS + 5%缺氧后的死亡率显著降低（溶媒组为47%，低剂量GBT 1118组为22%，高剂量GBT 1118组为13%，对数秩检验P= 0.032），并且疾病严重程度降低。接受GBT 1118治疗的小鼠在缺氧暴露4小时内显示SpO 2持续显着增加。GBT 1118给药未改变肺泡毛细血管通透性、支气管肺泡灌洗（BAL）炎性细胞计数或IL-1β、TNF-α或巨噬细胞炎性蛋白-1 α的BAL浓度。高剂量GBT 1118不影响组织学肺损伤，但确实降低了组织缺氧，如肝脏（P= 0.043）和肾脏（P= 0.043）中哌莫硝唑（Hypoxyprobe）染色的测量强度。我们的结论是，使用GBT 1118增加血红蛋白的氧亲和力可能是治疗急性肺损伤相关的低氧血症的一种新疗法。新的和值得注意的是在这项研究中，我们表明，GBT 1118，一种增加血红蛋白对氧的亲和力的化合物，在两次撞击的肺损伤模型中，在不引起组织缺氧的情况下，改善了存活率和氧饱和度。血红蛋白氧亲和力的调节代表了治疗急性肺损伤和急性呼吸窘迫综合征（以低氧血症为特征的病症）的新治疗方法。
Acute respiratory distress syndrome (ARDS) is characterized by lung inflammation and pulmonary edema, leading to arterial hypoxemia and death if the hypoxemia is severe. Strategies to correct hypoxemia have the potential to improve clinical outcomes in ARDS. The goal of this study was to evaluate the potential of hemoglobin modification as a novel therapy for ARDS-induced hypoxemia. The therapeutic effect of two different doses of GBT1118, a compound that increases the oxygen affinity of hemoglobin, was evaluated in a murine model of acute lung injury induced by intratracheal LPS instillation 24 h before exposure to 5% or 10% hypoxia (n= 8–15 per group). As expected, administration of GBT1118 to mice significantly increased the oxygen affinity of hemoglobin. Compared with mice receiving vehicle control, mice treated with GBT1118 had significantly lower mortality after LPS + 5% hypoxia (47% with vehicle vs. 22% with low-dose GBT1118, 13% with high-dose GBT1118,P= 0.032 by log rank) and had reduced severity of illness. Mice treated with GBT1118 showed a sustained significant increase in SpO2over 4 h of hypoxia exposure. Treatment with GBT1118 did not alter alveolar-capillary permeability, bronchoalveolar lavage (BAL) inflammatory cell counts, or BAL concentrations of IL-1β, TNF-α, or macrophage inflammatory protein-1α. High-dose GBT1118 did not affect histological lung injury but did decrease tissue hypoxia as measured intensity of pimonidazole (Hypoxyprobe) staining in liver (P= 0.043) and kidney (P= 0.043). We concluded that increasing the oxygen affinity of hemoglobin using GBT1118 may be a novel therapy for treating hypoxemia associated with acute lung injury.NEW & NOTEWORTHYIn this study, we show that GBT1118, a compound that increases hemoglobin affinity for oxygen, improves survival and oxygen saturation in a two-hit lung injury model of intratracheal LPS without causing tissue hypoxia. Modulation of hemoglobin oxygen affinity represents a novel therapeutic approach to treatment of acute lung injury and acute respiratory distress syndrome, conditions characterized by hypoxemia.
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影响因子：
64.8
作者：
SUNSHINE, HR;HOFRICHTER, J;EATON, WA
通讯作者：
EATON, WA
急性呼吸窘迫综合征患者呼气末正压较高与较低。
DOI：
10.1056/nejmoa032193
发表时间：
2004
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brower,RoyG;Lanken,PaulN;MacIntyre,Neil;Matthay,MichaelA;Morris,Alan;Ancukiewicz,Marek;Schoenfeld,David;Thompson,BTaylor;NationalHeart,Lung,andBloodInstituteARDSClinicalTrialsNetwork
通讯作者：
NationalHeart,Lung,andBloodInstituteARDSClinicalTrialsNetwork
镰状细胞性贫血中胎儿血红蛋白的调节
影响因子：
1
作者：
M. Steinberg
通讯作者：
M. Steinberg
影响因子：
0.9
作者：
Dufu K;Lehrer-Graiwer J;Ramos E;Oksenberg D
通讯作者：
Oksenberg D
影响因子：
9.6
作者：
Rice, Todd W.;Wheeler, Arthur P.;Ware, Lorraine B.
通讯作者：
Ware, Lorraine B.