Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury
Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury
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抑制STAT3活性对lps诱导的急性肺损伤的保护作用
DOI：
10.1152/ajplung.00281.2016
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发表时间：
2016-11-01
影响因子：
4.9
通讯作者：
Qin, Hongwei
中科院分区：
文献类型：
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作者：
Zhao, Jiping;Yu, Hao;Qin, Hongwei
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是死亡率较高的疾病。巨噬细胞和中性粒细胞负责 ALI 和 ARDS 的炎症反应，其特征是支气管肺泡灌洗液 (BALF) 和血浆中促炎介质的过量产生。 JAK/STAT 通路的异常激活对于感染和自身免疫等许多情况下的持续炎症至关重要。鉴于 STAT3 转录因子在激活巨噬细胞和中性粒细胞以及增强炎症方面的重要性，我们研究了使用小分子 STAT3 抑制剂 LLL12 抑制 STAT3 活性的治疗潜力。我们的结果表明，LPS 在体外诱导巨噬细胞中的 STAT3 激活，在体内 LPS 诱导的 ALI 模型中，在来自 BALF 的 CD45(+)CD11b(+) 细胞中诱导 STAT3 激活。 LLL12 治疗可抑制 ALI 模型中 LPS 诱导的肺部炎症，同时抑制 LPS 诱导的 STAT3 激活，并抑制肺和 BALF 中的巨噬细胞和炎症细胞浸润。根据 ELISA 测定，LLL12 治疗还抑制 BALF 和血清中巨噬细胞和炎症细胞中促炎基因的表达，包括 IL-1 beta、IL-6、TNF-α、iNOS、CCL2 和 MHC II 类。此外，LysMCre-SOCS3(fl/fl) 小鼠中 STAT3 的过度激活会加速 ALI 模型中炎症的严重程度。 LLL12 在 LPS 治疗前和治疗后均可降低 ALI 小鼠中 LPS 诱导的炎症反应。重要的是，LLL12 治疗减弱了 ARDS 患者血浆诱导的人外周血单核细胞中 STAT3 磷酸化，这表明针对 ALI 和 ARDS 患者治疗 STAT3 通路的可行性。
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are diseases with high mortality. Macrophages and neutrophils are responsible for inflammatory responses in ALI and ARDS, which are characterized by excessive production of proinflammatory mediators in bronchoalveolar lavage fluid (BALF) and plasma. Aberrant activation of the JAK/STAT pathway is critical for persistent inflammation in many conditions such as infection and autoimmunity. Given the importance of the STAT3 transcription factor in activating macrophages and neutrophils and augmenting inflammation, we investigated the therapeutic potential of inhibiting STAT3 activity using the small-molecule STAT3 inhibitor, LLL12. Our results demonstrate that LPS induces STAT3 activation in macrophages in vitro and in CD45(+)CD11b(+) cells from BALF in the LPS-induced ALI model in vivo. LLL12 treatment inhibits LPS-induced lung inflammation in the ALI model, which is accompanied by suppression of LPS-induced STAT3 activation and an inhibition of macrophage and inflammatory cell infiltration in lung and BALF. LLL12 treatment also suppresses expression of proinflammatory genes including IL-1 beta, IL-6, TNF-alpha, iNOS, CCL2, and MHC class II in macrophages and inflammatory cells from BALF and serum as determined by ELISA. Furthermore, hyperactivation of STAT3 in LysMCre-SOCS3(fl/fl) mice accelerates the severity of inflammation in the ALI model. Both pre- and post-LPS treatment with LLL12 decrease LPS-induced inflammatory responses in mice with ALI. Importantly, LLL12 treatment attenuates STAT3 phosphorylation in human peripheral blood mononuclear cells induced by plasma from patients with ARDS, which suggests the feasibility of targeting the STAT3 pathway therapeutically for patients with ALI and ARDS.