Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, 277#, Yanta West Road, Xi'an, Shaanxi Province, China; Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Wenzhou Medical University, Wenzhou, China.
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
Phytomedicine. 2024 Dec;135:156089. doi: 10.1016/j.phymed.2024.156089. Epub 2024 Sep 20.
Acute lung injury (ALI)-induced acute respiratory syndromes is a critical pathological sequala of sepsis. Araloside A (ARA), extracted from Aralia taibaiensis, possesses anti-oxidative and pro-apoptotic effects, as well as a protective effect against inflammatory diseases such as gastric ulcers. However, its impact on progression of ALI remains unknown. This study seeks to assess the therapeutic effect of ARA in sepsis-induced ALI, and to elucidate the underlying mechanism.
Sepsis-induced ALI was induced in C57BL/6 mice using lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) along with simultaneous administration of ARA. In vitro, bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were exposed to LPS to activate proinflammatory macrophages in the presence/absence of ARA. RNA sequencing of BMDMs was then conducted to elucidate the detailed mechanism.
Treatment of mice with ARA led to a significant reduction in serum level of inflammatory cytokines, ameliorated sepsis-induced ALI (i.e., impaired barrier integrity, cell apoptosis), and increased survival of septic mice. In vitro, ARA effectively inhibited activation of proinflammatory BMDMs. In addition, RNA sequencing revealed that the PHD2/HIF-1α signaling played a critical role in the anti-inflammatory effects of ARA. ARA suppressed proinflammatory macrophages to ameliorate lung inflammation in septic mice by restoring PHD2/HIF-1α signaling.
ARA prevented mice from the fatal effects of sepsis by restoring PHD2/HIF-1α signaling, thereby inhibiting activation of proinflammatory macrophages. These findings suggest that ARA could be a promising therapy for sepsis-induced ALI.
急性肺损伤（ALI）诱导的急性呼吸综合征是脓毒症的关键病理后果。从刺五加中提取的阿拉瑞辛 A（ARA）具有抗氧化和促凋亡作用，以及对胃溃疡等炎症性疾病的保护作用。然而，其对 ALI 进展的影响尚不清楚。本研究旨在评估 ARA 在脓毒症诱导的 ALI 中的治疗作用，并阐明其潜在机制。
采用脂多糖（LPS）或盲肠结扎穿孔（CLP）联合 ARA 给药的方法，在 C57BL/6 小鼠中诱导脓毒症诱导的 ALI。在体外，用 LPS 处理骨髓来源的巨噬细胞（BMDMs）和 RAW264.7 细胞，在存在/不存在 ARA 的情况下激活促炎巨噬细胞。然后对 BMDMs 进行 RNA 测序，以阐明详细的机制。
ARA 治疗可显著降低血清中促炎细胞因子水平，改善脓毒症诱导的 ALI（即，受损的屏障完整性、细胞凋亡），并提高脓毒症小鼠的存活率。在体外，ARA 可有效抑制促炎 BMDMs 的激活。此外，RNA 测序显示，PHD2/HIF-1α 信号通路在 ARA 的抗炎作用中起关键作用。ARA 通过恢复 PHD2/HIF-1α 信号通路抑制促炎巨噬细胞，从而改善脓毒症小鼠的肺炎症。
ARA 通过恢复 PHD2/HIF-1α 信号通路，防止小鼠受到脓毒症的致命影响，从而抑制促炎巨噬细胞的激活。这些发现表明，ARA 可能是治疗脓毒症诱导的 ALI 的一种有前途的方法。
