Suppressing NF-κB and NKRF Pathways by Induced Pluripotent Stem Cell Therapy in Mice with Ventilator-Induced Lung Injury.
Suppressing NF-κB and NKRF Pathways by Induced Pluripotent Stem Cell Therapy in Mice with Ventilator-Induced Lung Injury.
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通过呼吸机诱导的肺损伤在小鼠中诱导多能干细胞疗法抑制NF-κB和NKRF途径。
DOI：
10.1371/journal.pone.0066760
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chiou SH
中科院分区：
文献类型：
--
作者：
Liu YY;Li LF;Yang CT;Lu KH;Huang CC;Kao KC;Chiou SH
在急性肺损伤（ALI）患者中使用大潮气量机械通气可诱导炎性细胞因子（如巨噬细胞炎性蛋白-2（MIP-2））的释放、中性粒细胞的募集以及肺泡上皮和内皮屏障的破坏。诱导多能干细胞（iPSC）已被证明可以改善小鼠的ALI，但调节机械通气和iPSC之间相互作用的机制尚未完全阐明。核因子-κ B（NF-κB）和NF-κB抑制因子（NKRF）被认为参与了ALI中性粒细胞活化的调节。因此，我们假设静脉注射iPSC或iPSC衍生的条件培养基（iPSC-CM）将减少潮气量通气诱导的中性粒细胞浸润、氧化应激和通过NF-κB/NKRF途径产生的MIP-2。雄性C57 BL/6小鼠，年龄在6至8周之间，体重在20至25 g之间，在5×107个细胞/kg小鼠iPSC或iPSC-CM施用后，暴露于具有室内空气的高潮气量（30 ml/kg）机械通气1至4 h。未通气的小鼠用作对照组。高潮气量机械通气诱导iPSCs向小鼠损伤肺的整合、微血管通透性、中性粒细胞浸润、丙二醛、MIP-2产生以及NF-κB和NKRF活化增加。给予iPSC或iPSC-CM可减轻机械通气诱导的肺损伤指标，包括炎症、肺水肿、超微结构病理改变和功能性气体交换障碍，这通过用SN 50药理学抑制NF-κB活性或用NKRF短干扰RNA药理学抑制NKRF表达来模拟。我们的数据表明，基于iPSC的治疗至少部分地通过抑制NF-κB/NKRF通路来减轻大潮气量机械通气诱导的肺损伤。值得注意的是，iPSC的条件培养基显示出与iPSC相同的有益效果。
High-tidal-volume mechanical ventilation used in patients with acute lung injury (ALI) can induce the release of inflammatory cytokines, as macrophage inflammatory protein-2 (MIP-2), recruitment of neutrophils, and disruption of alveolar epithelial and endothelial barriers. Induced pluripotent stem cells (iPSCs) have been shown to improve ALI in mice, but the mechanisms regulating the interactions between mechanical ventilation and iPSCs are not fully elucidated. Nuclear factor kappa B (NF-κB) and NF-κB repressing factor (NKRF) have been proposed to modulate the neutrophil activation involved in ALI. Thus, we hypothesized intravenous injection of iPSCs or iPSC-derived conditioned medium (iPSC-CM) would decrease high-tidal-volume ventilation-induced neutrophil infiltration, oxidative stress, and MIP-2 production through NF-κB/NKRF pathways. Male C57BL/6 mice, aged between 6 and 8 weeks, weighing between 20 and 25 g, were exposed to high-tidal-volume (30 ml/kg) mechanical ventilation with room air for 1 to 4 h after 5×107 cells/kg mouse iPSCs or iPSC-CM administration. Nonventilated mice were used as control groups. High-tidal-volume mechanical ventilation induced the increases of integration of iPSCs into the injured lungs of mice, microvascular permeability, neutrophil infiltration, malondialdehyde, MIP-2 production, and NF-κB and NKRF activation. Lung injury indices including inflammation, lung edema, ultrastructure pathologic changes and functional gas exchange impairment induced by mechanical ventilation were attenuated with administration of iPSCs or iPSC-CM, which was mimicked by pharmacological inhibition of NF-κB activity with SN50 or NKRF expression with NKRF short interfering RNA. Our data suggest that iPSC-based therapy attenuates high-tidal-volume mechanical ventilation-induced lung injury, at least partly, through inhibition of NF-κB/NKRF pathways. Notably, the conditioned medium of iPSCs revealed beneficial effects equal to those of iPSCs.
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影响因子：
5.3
作者：
Froese, N;Schwarzer, M;Hauser, H
通讯作者：
Hauser, H
影响因子：
14
作者：
Li, Hsin-Yang;Chien, Yueh;Chiou, Shih-Hwa
通讯作者：
Chiou, Shih-Hwa
影响因子：
7.8
作者：
Liu, Yung-Yang;Liao, Shuen-Kuei;Li, Li-Fu
通讯作者：
Li, Li-Fu
DOI：
10.1152/ajplung.00031.2003
发表时间：
2003-08-01
影响因子：
4.9
作者：
Li, LF;Ouyang, B;Quinn, DA
通讯作者：
Quinn, DA
DOI：
10.1164/ajrccm.163.3.2003001
发表时间：
2001-03-01
影响因子：
24.7
作者：
Held, HD;Boettcher, S;Uhlig, S
通讯作者：
Uhlig, S