Fessel Joshua P, West James D
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Pulm Circ. 2015 Dec;5(4):599-609. doi: 10.1086/683814.
Through detailed interrogation of the molecular pathways that contribute to the development of pulmonary arterial hypertension (PAH), the separate but related processes of oxidative stress and cellular metabolic dysfunction have emerged as being critical pathogenic mechanisms that are as yet relatively untargeted therapeutically. In this review, we have attempted to summarize some of the important existing studies, to point out areas of overlap between oxidative stress and metabolic dysfunction, and to do so under the unifying heading of redox biology. We discuss the importance of precision in assessing oxidant signaling versus oxidant injury and why this distinction matters. We endeavor to advance the discussion of carbon-substrate metabolism beyond a focus on glucose and its fate in the cell to encompass other carbon substrates and some of the murkiness surrounding our understanding of how they are handled in different cell types. Finally, we try to bring these ideas together at the level of the mitochondrion and to point out some additional points of possible cognitive dissonance that warrant further experimental probing. The body of beautiful science regarding the molecular and cellular details of redox biology in PAH points to a future that includes clinically useful therapies that target these pathways. To fully realize the potential of these future interventions, we hope that some of the issues raised in this review can be addressed proactively.
通过对导致肺动脉高压（PAH）发生发展的分子途径进行详细探究，氧化应激和细胞代谢功能障碍这两个既相互独立又相互关联的过程已成为关键的致病机制，然而在治疗上它们相对而言尚未得到有效靶向。在本综述中，我们试图总结一些重要的现有研究，指出氧化应激与代谢功能障碍之间的重叠领域，并在氧化还原生物学这一统一主题下进行阐述。我们讨论了精确评估氧化信号与氧化损伤的重要性以及这种区分为何重要。我们努力将碳底物代谢的讨论从仅关注葡萄糖及其在细胞中的命运拓展到涵盖其他碳底物，以及围绕我们对不同细胞类型中它们如何被处理的理解所存在的一些模糊之处。最后，我们试图在线粒体层面将这些观点整合起来，并指出一些可能存在认知失调的额外要点，这些要点值得进一步的实验探索。关于PAH中氧化还原生物学分子和细胞细节的大量精彩科学研究指向了一个未来，其中包括针对这些途径的临床有用疗法。为了充分实现这些未来干预措施的潜力，我们希望本综述中提出的一些问题能够得到积极解决。
