Background Despite advances in understanding the pathophysiology of acute respiratory distress syndrome, effective pharmacological interventions have proven elusive. We believe this is a consequence of existing preclinical models being designed primarily to explore biological pathways, rather than predict treatment effects. Here, we describe a mouse model in which both therapeutic intervention and ventilation were superimposed onto existing injury and explored the impact of β-agonist treatment, which is effective in simple models but not clinically. Methods Mice had lung injury induced by intranasal lipopolysaccharide (LPS), which peaked at 48 hours post-LPS based on clinically relevant parameters including hypoxaemia and impaired mechanics. At this peak of injury, mice were treated intratracheally with either terbutaline or tumour necrosis factor (TNF) receptor 1-targeting domain antibody, and ventilated with moderate tidal volume (20 mL/kg) to induce secondary ventilator-induced lung injury (VILI). Results Ventilation of LPS-injured mice at 20 mL/kg exacerbated injury compared with low tidal volume (8 mL/kg). While terbutaline attenuated VILI within non-LPS-treated animals, it was ineffective to reduce VILI in pre-injured mice, mimicking its lack of clinical efficacy. In contrast, anti-TNF receptor 1 antibody attenuated secondary VILI within pre-injured lungs, indicating that the model was treatable. Conclusions We propose adoption of a practical framework like that described here to reduce the number of ultimately ineffective drugs reaching clinical trials. Novel targets should be evaluated alongside interventions which have been previously tested clinically, using models that recapitulate the (lack of) clinical efficacy. Within such a framework, outperforming a failed pharmacologic should be a prerequisite for drugs entering trials.

中文翻译：

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已建立 ARDS 后的通气：提高预测能力的临床前模型框架

背景尽管在理解急性呼吸窘迫综合征的病理生理学方面取得了进展，但已证明有效的药物干预措施难以捉摸。我们认为这是现有临床前模型主要设计用于探索生物途径而不是预测治疗效果的结果。在这里，我们描述了一种小鼠模型，其中治疗性干预和通气都叠加在现有损伤上，并探讨了 β-激动剂治疗的影响，这在简单模型中有效但在临床上无效。方法 鼻内脂多糖 (LPS) 诱导小鼠肺损伤，根据临床相关参数包括低氧血症和力学受损，LPS 后 48 小时达到峰值。在这个伤病高峰期，用特布他林或肿瘤坏死因子 (TNF) 受体 1 靶向域抗体对小鼠进行气管内治疗，并以中等潮气量 (20 mL/kg) 通气以诱导二次呼吸机诱导的肺损伤 (VILI)。结果 与低潮气量 (8 mL/kg) 相比，LPS 损伤小鼠以 20 mL/kg 通气会加剧损伤。虽然特布他林减弱了未经 LPS 治疗的动物体内的 VILI，但它对降低受伤前小鼠的 VILI 是无效的，模仿其缺乏临床疗效。相比之下，抗 TNF 受体 1 抗体减弱了受伤前肺内的继发性 VILI，表明该模型是可治疗的。结论 我们建议采用类似于此处描述的实用框架，以减少最终无效的药物进入临床试验的数量。新目标应与先前已在临床上测试过的干预措施一起评估，使用概括（缺乏）临床疗效的模型。在这样的框架内，超越失败的药理学应该是药物进入试验的先决条件。