Prevention of trauma/hemorrhagic shock-induced lung apoptosis by IL-6-mediated activation of Stat3.
Prevention of trauma/hemorrhagic shock-induced lung apoptosis by IL-6-mediated activation of Stat3.
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通过 IL-6 介导的 Stat3 激活预防创伤/失血性休克诱导的肺细胞凋亡。
DOI：
10.1111/j.1752-8062.2008.00076.x
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Tweardy,DavidJ
中科院分区：
文献类型：
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作者：
Moran,Ana;Tsimelzon,AnnaI;Mastrangelo,Mary-AnnA;Wu,Yong;Yu,Bi;Hilsenbeck,SusanG;Poli,Valeria;Tweardy,DavidJ
高达 37% 的患者在创伤/失血性休克 (T/HS) 后发生急性肺损伤 (ALI)，在其他情况下，急性肺损伤 (ALI) 是由于肺泡上皮细胞 (AEC) 凋亡所致。为了确定 AEC 细胞凋亡是否是 T/HS 后 ALI 的关键因素，以及信号转导器和翻译激活剂 (Stat)3 激活是否可以预防它，用 Stat3 抑制剂或安慰剂预处理大鼠，并接受 T/HS 或假手术方案，并在不加或加白细胞介素 (IL)-6 的情况下进行复苏。 T/HS 诱导高达 15% 的肺细胞凋亡，其中 82% 为 AEC。细胞凋亡随着休克持续时间的增加而增加，并且需要复苏。 IL-6 治疗刺激肺 Stat3 激活并防止 AEC 凋亡。用 Stat3 抑制剂预处理大鼠可阻断 IL-6 的抗凋亡作用。 Stat3β（一种天然存在的 Stat3 显性失活亚型）缺陷的小鼠对 T/HS 诱导的肺细胞凋亡具有抵抗力。 T/HS 改变了 87% 的凋亡相关基因的表达。 IL-6 治疗使 T/HS 改变的 75% 基因的表达正常化； Stat3 抑制阻止了 65% 的基因正常化，而该基因的表达已通过 IL-6 正常化。因此，T/HS 诱导的 AEC 细胞凋亡取决于低血压的持续时间，需要复苏，并且可以通过 IL-6 介导的 Stat3 激活来阻止，Stat3 的作用是使细胞凋亡转录组正常化。
Acute lung injury (ALI) occurs in up to 37% of patients following trauma/hemorrhagic shock (T/HS) and, in other settings, is due to alveolar epithelial cell (AEC) apoptosis. To determine if AEC apoptosis is a key contributor to ALI following T/HS and whether or not signal transducer and activator of translation (Stat)3 activation can prevent it, rats were pretreated with a Stat3 inhibitor or placebo and subjected to T/HS or sham protocol and resuscitated without or with interleukin (IL)‐6. T/HS induced apoptosis in up to 15% of lung cells, 82% of which were AEC. Apoptosis increased with increasing duration of shock and required resuscitation. IL‐6 treatment stimulated lung Stat3 activation and prevented AEC apoptosis. Pretreatment of rats with a Stat3 inhibitor blocked the antiapoptotic effect of IL‐6. Mice deficient in Stat3β, a naturally occurring dominant negative isoform of Stat3, were resistant to T/HS‐induced lung apoptosis. T/HS altered the expression of 87% of apoptosis‐related genes. IL‐6 treatment normalized expression of 75% of the genes altered by T/HS; Stat3 inhibition prevented normalization of 65% of the gene whose expression was normalized by IL‐6. Thus, T/HS‐induced AEC apoptosis, which depended on the duration of hypotension, required resuscitation and was prevented by IL‐6‐mediated activation of Stat3, which acted to normalize the apoptosis transcriptome.