Type 2 diabetes mellitus (T2DM) is a risk factor for pulmonary tuberculosis (PTB) and increased mortality. This work focused on the functions of phosphorylated STAT3 in lung injury in mouse with T2DM‐associated PTB and the molecules involved. A mouse model with T2DM‐PTB was induced by administrations of streptozotocin, nicotinamide and mycobacterium tuberculosis (Mtb). A pSTAT3‐specific inhibitor AG‐490 was given into mice and then the lung injury in mice was observed. The molecules involved in AG‐490‐mediated events were screened out. Altered expression of miR‐19b, miR‐1281 and NFAT5 was introduced to identify their involvements and roles in lung injury and PTB severity in the mouse model. Consequently, pSTAT3 expression in mice with T2DM‐associated PTB was increased. Down‐regulation of pSTAT3 by AG‐490 prolonged the lifetime of mice and improved the histopathologic conditions, and inhibited the fibrosis, inflammation, Mtb content and number of apoptotic epithelial cells in mouse lung tissues. pSTAT3 transcriptionally suppressed miR‐19b/1281 expression to up‐regulate NFAT5. Inhibition of miR‐19b/1281 or up‐regulation of NFAT5 blocked the protective roles of AG‐490 in mouse lung tissues. To conclude, this study evidenced that pSTAT3 promotes NFAT5 expression by suppressing miR‐19b/1281 transcription, leading to lung injury aggravation and severity in mice with T2DM‐associated PTB.

中文翻译：

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磷酸化 STAT3 抑制 microRNA-19b/1281 加重 2 型糖尿病相关肺结核小鼠肺损伤

2 型糖尿病 (T2DM) 是肺结核 (PTB) 和死亡率增加的危险因素。这项工作的重点是磷酸化 STAT3 在 T2DM 相关 PTB 小鼠肺损伤中的功能及其相关分子。通过施用链脲佐菌素、烟酰胺和结核分枝杆菌 (Mtb) 诱导了患有 T2DM-PTB 的小鼠模型。给小鼠注射 pSTAT3 特异性抑制剂 AG-490，然后观察小鼠的肺损伤情况。筛选出参与 AG-490 介导的事件的分子。引入了 miR-19b、miR-1281 和 NFAT5 的改变表达，以确定它们在小鼠模型中肺损伤和 PTB 严重程度的参与和作用。因此，T2DM 相关 PTB 小鼠中 pSTAT3 的表达增加。AG-490 对 pSTAT3 的下调延长了小鼠的寿命，改善了组织病理学状况，并抑制了小鼠肺组织中的纤维化、炎症、Mtb 含量和凋亡上皮细胞的数量。pSTAT3 转录抑制 miR-19b/1281 表达以上调 NFAT5。抑制 miR-19b/1281 或上调 NFAT5 可阻断 AG-490 在小鼠肺组织中的保护作用。总之，本研究证明 pSTAT3 通过抑制 miR-19b/1281 转录促进 NFAT5 表达，导致 T2DM 相关 PTB 小鼠的肺损伤加重和严重程度。抑制 miR-19b/1281 或上调 NFAT5 可阻断 AG-490 在小鼠肺组织中的保护作用。总之，本研究证明 pSTAT3 通过抑制 miR-19b/1281 转录促进 NFAT5 表达，导致 T2DM 相关 PTB 小鼠的肺损伤加重和严重程度。抑制 miR-19b/1281 或上调 NFAT5 可阻断 AG-490 在小鼠肺组织中的保护作用。总之，本研究证明 pSTAT3 通过抑制 miR-19b/1281 转录促进 NFAT5 表达，导致 T2DM 相关 PTB 小鼠的肺损伤加重和严重程度。