Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-α, IL-1β, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 μM). We further revealed that IAL suppressed LPS-induced NF-κB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-κB, contributed to the anti-inflammatory effects of IAL. ALI was induced in mice by intratracheal injection of LPS (5 mg/kg). Administration of IAL (20 mg/kg, i.p.) significantly suppressed pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro-inflammatory cytokine expression. Our results demonstrate that IAL is a potential therapeutic reagent against inflammation and ALI.

中文翻译：

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异戊内酯通过抑制TRAF6泛素化来抑制LPS诱导的炎症，并减轻急性肺损伤。

异戊内酯（IAL）是从Inula helenium L的根中提取的倍半萜内酯，具有抗炎作用。在这项研究中，我们研究了IAL对急性肺损伤（ALI）的治疗作用，并阐明了其在体内外的抗炎潜力的潜在机制。用脂多糖（LPS，100 ng / mL）处理可极大地刺激小鼠骨髓源性巨噬细胞（BMDMs）中炎性介质的生成，例如NO，TNF-α，IL-1β和IL-6的产生，而剂量依赖性地抑制了炎症介质的产生。通过用IAL（2.5、5、10、20μM）进行预处理。我们进一步揭示了IAL抑制LPS诱导的NF-κB，ERK和Akt激活。而且，NF-κB的上游转录因子TRAF6的不可降解的K63连接的多泛素化的下调，有助于IAL的抗炎作用。通过气管内注射LPS（5 mg / kg）在小鼠中诱导ALI。IAL（20 mg / kg，ip）的给药显着抑制了肺部病理变化，中性粒细胞浸润，肺通透性和促炎性细胞因子的表达。我们的结果表明，IAL是抗发炎和ALI的潜在治疗剂。