Doxorubicin-induced respiratory dysfunction and the protective effects of exercise

多柔比星（DOX）是一种蒽环类抗生素，用于治疗广谱人类癌症， 包括急性白血病、淋巴瘤、胃癌、乳腺癌和卵巢癌。不幸的是， 这种高效的抗癌药物由于呼吸肌和膈肌的发育而受到限制 患者的功能障碍。多柔比星诱导的功能障碍是一种使人衰弱的疾病， 出现呼吸困难、疲劳和运动不耐受。虽然负责DOX诱导的呼吸道疾病的机制 通气功能不全尚不清楚，以前的工作表明通气功能障碍的发生率很大 与隔膜吸收的DOX浓度相关。DOX在体内迅速积累， 暴露后的膈肌，在那里它优先定位于线粒体，并促进游离 激进生产。线粒体中自由基产生的增加可导致严重的破坏性事件 导致细胞死亡，有证据表明，预防线粒体功能障碍足以 减弱DOX对隔膜的毒性作用。因此，阐明线粒体 DOX的积累可以减少，这可能导致开发一种治疗方法来减轻 DOX的肌肉毒性作用。在这方面，我们最近发现，耐力运动训练之前，DOX 治疗足以减少DOX的线粒体积累并保护隔膜和膈肌 功能虽然运动引起的膈肌水平降低的机制 线粒体DOX是未知的，我们假设活性诱导的外源性表达增加， 需要转运蛋白。具体而言，ATP结合盒（ABC）转运蛋白是一类蛋白质 具有促进化疗剂从隔膜流出的能力。此外，四 在横膈膜中表达位于胞浆的ABC转运蛋白（即ABCB 6、ABCB 7、ABCB 8和ABCB 8）。 ABCB 10），所有这些都随着运动而上调。因此，本提案的目标是建立 这些转运蛋白在介导运动诱导的DOX从横膈膜挤出中的作用，以及 以确定其预防DOX诱导的呼吸功能障碍的治疗潜力。我们会完成的 通过测试以下具体目标：具体目标1）将确定运动介导的保护是否 DOX诱导的呼吸功能障碍依赖于肺泡局部ABC转运水平的增加 蛋白质;和特异性目的2）将确定是否在细胞中过表达线粒体ABC转运蛋白。 隔膜足以减少DOX积聚并防止DOX诱导的呼吸功能障碍。

Doxorubicin (DOX) is an anthracycline antibiotic used in the treatment of a broad spectrum of human cancers, including acute leukemia, lymphomas, stomach, breast and ovarian cancers. Unfortunately, the clinical use of this highly efficacious anticancer drug is limited due to the development of respiratory and diaphragm muscle dysfunction in patients. Doxorubicin-induced ventilatory impairment is a debilitating condition that promotes the onset dyspnea, fatigue and exercise intolerance. While the mechanisms responsible for DOX-induced respiratory insufficiency are unclear, previous work demonstrates that the incidence of ventilatory dysfunction greatly correlates to the concentration of DOX taken up by the diaphragm. DOX accumulates rapidly within the diaphragm muscle following exposure, where it preferentially localizes to the mitochondria and promotes free radical production. Elevated free radical production in the mitochondria can lead to severe damaging events resulting in cell death, and evidence suggests that prevention of mitochondrial dysfunction is sufficient to attenuate the toxic effects of DOX on the diaphragm. Therefore, elucidating ways in which the mitochondrial accumulation of DOX can be reduced could result in the development of a therapeutic approach to mitigate the myotoxic effects of DOX. In this regard, we recently discovered that endurance exercise training prior to DOX treatment is sufficient to reduce the mitochondrial accumulation of DOX and preserve diaphragm and ventilatory function. While the mechanisms responsible for the exercise-induced reduction in the levels of diaphragm mitochondrial DOX are unknown, we hypothesize that activity-induced increases in the expression of xenobiotic transport proteins are required. Specifically, the ATP-binding cassette (ABC) transporters are a class of proteins with the capability of facilitating the efflux of chemotherapeutics from the diaphragm. Moreover, four mitochondria-localized ABC transporters are expressed in the diaphragm (i.e. ABCB6, ABCB7, ABCB8 and ABCB10), all of which are upregulated with exercise. Therefore, the goal of this proposal is to establish the effects of these transport proteins in mediating the exercise-induced extrusion of DOX from the diaphragm, and to determine their therapeutic potential to prevent DOX-induced respiratory dysfunction. We will accomplish this by testing the following specific aims: Specific Aim 1) will determine if exercise-mediated protection against DOX-induced respiratory dysfunction is dependent on increased levels of mitochondria-localized ABC transport proteins; and Specific Aim 2) will determine if overexpression of mitochondrial ABC transport proteins in the diaphragm is sufficient to reduce DOX accumulation and prevent DOX-induced respiratory dysfunction.