SERPINB1 ameliorates acute lung injury in liver transplantation through ERK1/2-mediated STAT3-dependent HO-1 induction
SERPINB1 ameliorates acute lung injury in liver transplantation through ERK1/2-mediated STAT3-dependent HO-1 induction
复制标题
SERPINB1 通过 ERK1/2 介导的 STAT3 依赖性 HO-1 诱导改善肝移植中的急性肺损伤
DOI：
10.1016/j.freeradbiomed.2017.04.011
复制
发表时间：
2017-07-01
影响因子：
7.4
通讯作者：
Hei, Ziqing
中科院分区：
文献类型：
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作者：
Yao, Weifeng;Li, Haobo;Hei, Ziqing
背景：术后急性肺损伤(ALI)是肝移植术后的严重并发症，严重影响术后患者的生存。其潜在机制在很大程度上是未知的，有效的治疗也是有限的。探讨中性粒细胞丝氨酸蛋白酶抑制因子B1(SerpinB1)在肝移植急性肺损伤(ALI)中的作用及其与信号转导和转录激活因子3(STAT3)、血红素加氧酶-1(HO-1)的相互作用。方法：SD大鼠原位自体肝移植(OALT)后，给予重组SB1(RSB1)，同时加入STAT3特异性抑制剂WP1066。然后用SB1-siRNA敲除内源性serpinB1。同时，将肺泡上皮细胞RLE-6TN和BEAS-2B暴露于单独或与SerpinB1共同作用的肿瘤坏死因子-α，并通过基因敲除的方法检测STAT3和HO-1的作用。最后在rSB1预处理后给予ERK1/2抑制剂U0126、p38 MAPK抑制剂SB20358或JNK抑制剂SP600125处理，然后进行OALT。结果：OALT导致大鼠肺部炎症和氧化应激增加，并伴有严重的肺损伤，与肺血清B1、HO-1和STAT3的升高相一致。SerpinB1基因敲除增加了OALT后的肺损伤和肺部炎症。RSB1剂量依赖性地减轻OALT后肺损伤，减轻肺部炎症和氧化应激，并伴随HO-1和STAT3蛋白表达的增强。SerpinB1的这些保护作用可被STAT3抑制而取消。同样，在RLE-6TN细胞和BEAS-2B细胞中，肿瘤坏死因子-α诱导细胞损伤，并增加HO-1和STAT3。SerpinB1进一步增加HO-1和STAT3蛋白的表达，减轻肿瘤坏死因子-α诱导的细胞氧化应激、细胞凋亡和线粒体损伤，这些作用可被STAT3或HO-1基因敲除。结论：serpinB1通过激活HO-1来减轻OALT大鼠的炎症反应，减轻肺组织的氧化应激，减轻ALI，这种作用是通过STAT3和ERK1/2来实现的。
Background: Postoperative acute lung injury (ALI) is a severe complication after liver transplantation, which severely affects postoperative patients' survival. The underlying mechanism is largely unknown and effective treatment limited. We explored the role of serpin protease inhibitor B1 (SERPINB1), a potent inhibitor of neutrophil serine proteases, in ALI in liver transplantation and its interplay with signal transducer and activator of transcription 3 (STAT3) and heme oxygenase-1 (HO-1).Methods: Sprague-Dawley rats underwent orthotopic autologous liver transplantation (OALT) were treated with recombinant SB1 (rSB1) in the absence or presence of STAT3 specific inhibitor, WP1066. Then SB1-siRNA was used to knockdown endogenous SERPINB1. Also, alveolar epithelial cells RLE-6TN and BEAS-2B were exposed to TNF-alpha without or with SERPINB1 and the roles of STAT3 and HO-1 were examined by respective gene knockdown. Finally, rats were treated with ERK1/2 inhibitor U0126, p38 MAPK inhibitor SB20358, or JNK inhibitor SP600125 after rSB1 pretreatment and then subjected to OALT.Results: OALT resulted in increased pulmonary inflammation and oxidative stress, accompanied by severe lung injury that was coincident with increased pulmonary SERPINB1, HO-1, and STAT3. SERPINB1 gene knockdown increased post-OALT lung injury and pulmonary inflammation. rSB1 administration dose-dependently reduced post-OALT lung injury and decreased pulmonary inflammation and oxidative stress with concomitant enhanced HO-1 and STAT3 protein expression. These protective effects of SERPINB1 were abolished by STAT3 inhibition. Similarly, in RLE-6TN cells and BEAS-2B cells, TNF-alpha induced cell injury and increased HO-1 and STAT3. SERPINB1 further increased HO-1 and STAT3 protein expression and attenuated TNF-alpha-induced cellular oxidative stress, apoptotic cells, and mitochondria damage, which were cancelled by STAT3 or HO-1 gene knockdown. Furthermore, these SERPINB1-mediated STAT3/HO-1 activation and pulmonary protective effects were abolished by inhibition of ERK1/2 but not p38 MAPK or JNK.Conclusions: SERPINB1 decreased inflammation, ameliorated oxidative stress in the lung, and attenuated ALI in rats with OALT by activating HO-1 and it does so through STAT3 and it does so by activating ERK1/2.