Brominated indoles from a marine mollusc inhibit inflammation in a murine model of acute lung injury

New drug leads for the treatment of inflammation are urgently needed. Marine molluscs are widely used as traditional medicines for the treatment of inflammation. Here we report the positive effects of a hypobranchial gland (HBG) extract and the dominant bioactive compound 6-bromoisatin from the Muricidae mollusc Dicathais orbita, for reducing lipopolysaccharide (LPS) induced acute lung inflammation in a mouse model. Both 6-bromoisatin and the HBG extract suppressed the inflammatory response in mice that were pre-treated by oral gavage at 48, 24 and 1 h prior to LPS infusion. The inflammatory antagonists were tested at concentrations of 0.5 mg/g and 0.1 mg/g HBG extract and 0.1 mg/g and 0.05 mg/g 6-bromoisatin in carrier oil and all treatments reduced inflammation as indicated by a significant suppression of inflammatory markers present in bronchoalveolar lavage fluid (BALF), in comparison to LPS induced positive control mice administered the carrier oil alone (p < 0.0001). Tumour necrosis factor-alpha (TNFα) and interleukin-1 beta (IL-1β) levels, in addition to total protein concentration were all significantly reduced in BALF from mice treated with the extract or 6-bromoisatin. Furthermore, all treatment groups showed significant reductions in neutrophil sequestration and preservation of the lung tissue architecture compared to the positive control (p < 0.0001). The combined results from this study and our previous in vitro studies indicate that 6-bromoisatin in the HGB extracts inhibit the activation of inflammatory signalling pathway. The results from this study further confirm that the HBG extract from Muricidae molluscs and 6-bromoisatin are bioavailable and effective in vivo, thus have potential for development as natural therapeutic agents for inflammation.

临床亟需用于炎症治疗的新型药物先导化合物。海洋软体动物作为传统抗炎药物被广泛应用。本研究报道了骨螺科（Muricidae）软体动物Dicathais orbita的鳃下腺（hypobranchial gland, HBG）提取物及其主要活性成分6-溴靛红（6-bromoisatin）在小鼠模型中减轻脂多糖（lipopolysaccharide, LPS）诱导的急性肺部炎症的积极效果。在脂多糖输注前48、24及1小时通过灌胃给药进行预处理的小鼠中，6-溴靛红与鳃下腺提取物均能抑制炎症反应。本研究以赋形油为溶剂，分别以0.5 mg/g、0.1 mg/g的鳃下腺提取物浓度，以及0.1 mg/g、0.05 mg/g的6-溴靛红浓度开展抗炎活性测试。与仅给予赋形油的脂多糖诱导阳性对照组小鼠相比，各给药组均能显著抑制支气管肺泡灌洗液（bronchoalveolar lavage fluid, BALF）中的炎症标志物水平，从而减轻炎症（p < 0.0001）。经提取物或6-溴靛红处理的小鼠支气管肺泡灌洗液中，肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）水平及总蛋白浓度均显著降低。此外，与阳性对照组相比，各给药组均能显著减少中性粒细胞扣留，并维持肺部组织结构完整（p < 0.0001）。本研究与此前体外研究的综合结果表明，鳃下腺提取物中的6-溴靛红可抑制炎症信号通路的激活。本研究结果进一步证实，骨螺科软体动物的鳃下腺提取物与6-溴靛红具有生物利用度且在体内具备抗炎活性，因此具备开发为天然抗炎治疗药物的潜力。