Department of Pathology, Xijing Hospital, Xi’an, PR China.
Am J Respir Cell Mol Biol. 2011 Nov;45(5):1028-35. doi: 10.1165/rcmb.2011-0113OC. Epub 2011 May 26.
Inhibiting hypoxia-inducible factor (HIF)-1α activity has been proposed as a novel therapeutic target in LPS-induced sepsis syndrome. We have reported that tanshinone IIA (TIIA) can reduce LPS-induced lethality and lung injury in mice, but the precise mechanisms have not been fully described. Therefore, the present study investigated whether the protective effect of TIIA was related to the inhibition of LPS-induced HIF-1α expression and what mechanisms accounted for it. This study showed that TIIA pretreatment improved LPS-induced biochemical and cellular changes and reduced the production of inflammatory cytokines. Pretreatment with TIIA decreased LPS-induced HIF-1α expression in vivo and in vitro. TIIA did not affect the LPS-induced HIF-1α mRNA level but inhibited HIF-1α protein translation by the inhibition of the PI3K/AKT and MAPK pathways and related protein translational regulators, such as p70S6K1, S6 ribosomal protein, 4E-BP1, and eIF4E, and promoted HIF-1α protein degradation via the proteasomal pathway in LPS-stimulated macrophages. These observations partially explain the antiinflammatory effects of TIIA, which provides scientific basis for its application for the treatment of acute lung injury/acute respiratory distress syndrome or sepsis.
抑制缺氧诱导因子 (HIF)-1α 活性已被提议作为 LPS 诱导的脓毒症综合征的一种新的治疗靶点。我们已经报道，丹参酮 IIA（TIIA）可以降低 LPS 诱导的小鼠致死率和肺损伤，但确切的机制尚未完全描述。因此，本研究探讨了 TIIA 的保护作用是否与抑制 LPS 诱导的 HIF-1α 表达有关，以及其机制是什么。本研究表明，TIIA 预处理可改善 LPS 诱导的生化和细胞变化，并减少炎症细胞因子的产生。TIIA 预处理可降低体内和体外 LPS 诱导的 HIF-1α 表达。TIIA 不影响 LPS 诱导的 HIF-1α mRNA 水平，但通过抑制 PI3K/AKT 和 MAPK 途径及其相关蛋白翻译调节剂，如 p70S6K1、S6 核糖体蛋白、4E-BP1 和 eIF4E，抑制 HIF-1α 蛋白翻译，并通过蛋白酶体途径促进 LPS 刺激的巨噬细胞中 HIF-1α 蛋白降解。这些观察结果部分解释了 TIIA 的抗炎作用，为其在治疗急性肺损伤/急性呼吸窘迫综合征或脓毒症中的应用提供了科学依据。
