Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States.
Front Immunol. 2020 Oct 26;11:584966. doi: 10.3389/fimmu.2020.584966. eCollection 2020.
Intravenous injection of nanopharmaceuticals can induce severe hypersensitivity reactions (HSRs) resulting in anaphylactoid shock in a small percentage of patients, a phenomenon explicitly reproducible in pigs. However, there is a debate in the literature on whether the pig model of HSRs can be used as a safety test for the prediction of severe adverse reactions in humans. Given the importance of using appropriate animal models for toxicity/safety testing, the choice of the right species and model is a critical decision. In order to facilitate the decision process and to expand the relevant information regarding the pig or no pig dilemma, this review examines an ill-fated clinical development program conducted by Baxter Corporation in the United States 24 years ago, when HemeAssist, an αα (diaspirin) crosslinked hemoglobin-based O carrier (HBOC) was tested in trauma patients. The study showed increased mortality in the treatment group relative to controls and had to be stopped. This disappointing result had far-reaching consequences and contributed to the setback in blood substitute research ever since. Importantly, the increased mortality of trauma patients was predicted in pig experiments conducted by US Army scientists, yet they were considered irrelevant to humans. Here we draw attention to that the underlying cause of hemoglobin-induced aggravation of hemorrhagic shock and severe HSRs have a common pathomechanism: cardiovascular distress due to vasoconstrictive effects of hemoglobin (Hb) and reactogenic nanomedicines, manifested, among others, in pulmonary hypertension. The main difference is that in the case of Hb this effect is due to NO-binding, while nanomedicines can trigger the release of proinflammatory mediators. Because of the higher sensitivity of cloven-hoof animals to this kind of cardiopulmonary distress compared to rodents, these reactions can be better reproduced in pigs than in murine or rat models. When deciding on the battery of tests and the appropriate models to identify the potential hazard for nanomedicine-induced severe HSR, the pros and cons of the various species must be considered carefully.
静脉内注射纳米药物会在一小部分患者中引起严重的过敏反应 (HSR)，导致类过敏休克，这一现象在猪身上可以明确重现。然而，文献中存在争议，即 HSR 猪模型是否可用于预测人类的严重不良反应。鉴于使用适当的动物模型进行毒性/安全性测试的重要性，选择正确的物种和模型是一个关键决策。为了促进决策过程，并扩展有关猪或无猪困境的相关信息，本综述审查了 24 年前美国 Baxter 公司进行的一项不幸的临床开发计划，当时 HemeAssist，一种 αα（二氮嗪）交联血红蛋白基 O 载体 (HBOC) 在创伤患者中进行了测试。该研究显示，治疗组的死亡率相对于对照组增加，因此不得不停止。这一令人失望的结果产生了深远的影响，并导致自那时以来血液替代品研究的倒退。重要的是，美国陆军科学家进行的猪实验预测了创伤患者的死亡率增加，但这些实验被认为与人类无关。在这里，我们提请注意，血红蛋白引起的出血性休克和严重 HSR 加重的根本原因具有共同的病理机制：血红蛋白 (Hb) 的血管收缩作用和反应性纳米药物引起的心血管不适，除其他外，表现为肺动脉高压。主要区别在于，在 Hb 的情况下，这种作用是由于与 NO 结合，而纳米药物可以触发促炎介质的释放。由于蹄类动物对这种心肺不适的敏感性高于啮齿动物，因此与小鼠或大鼠模型相比，这些反应在猪中可以更好地重现。在决定测试组合和适当的模型以识别纳米药物引起的严重 HSR 的潜在危害时，必须仔细考虑各种物种的优缺点。
