Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States.
Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, Virginia, United States.
Am J Physiol Lung Cell Mol Physiol. 2023 Jun 1;324(6):L863-L869. doi: 10.1152/ajplung.00439.2022. Epub 2023 Apr 11.
Radiation-induced lung injury (RILI) is a consequence of therapeutic thoracic irradiation (TR) for many cancers, and there are no FDA-approved curative strategies. Studies report that 80% of patients who undergo TR will have CT-detectable interstitial lung abnormalities, and strategies to limit the risk of RILI may make radiotherapy less effective at treating cancer. Our lab and others have reported that lung tissue from patients with idiopathic pulmonary fibrosis (IPF) exhibits metabolic defects including increased glycolysis and lactate production. In this pilot study, we hypothesized that patients with radiation-induced lung damage will exhibit distinct changes in lung metabolism that may be associated with the incidence of fibrosis. Using liquid chromatography/tandem mass spectrometry to identify metabolic compounds, we analyzed exhaled breath condensate (EBC) in subjects with CT-confirmed lung lesions after TR for lung cancer, compared with healthy subjects, smokers, and cancer patients who had not yet received TR. The lung metabolomic profile of the irradiated group was significantly different from the three nonirradiated control groups, highlighted by increased levels of lactate. Pathway enrichment analysis revealed that EBC from the case patients exhibited concurrent alterations in lipid, amino acid, and carbohydrate energy metabolism associated with the energy-producing tricarboxylic acid (TCA) cycle. Radiation-induced glycolysis and diversion of lactate to the extracellular space suggests that pyruvate, a precursor metabolite, converts to lactate rather than acetyl-CoA, which contributes to the TCA cycle. This TCA cycle deficiency may be compensated by these alternate energy sources to meet the metabolic demands of chronic wound repair. Using an "omics" approach to probe lung disease in a noninvasive manner could inform future mechanistic investigations and the development of novel therapeutic targets. We report that exhaled breath condensate (EBC) identifies cellular metabolic dysregulation in patients with radiation-induced lung injury. In this pilot study, untargeted metabolomics revealed a striking metabolic signature in EBC from patients with radiation-induced lung fibrosis compared to patients with lung cancer, at-risk smokers, and healthy volunteers. Patients with radiation-induced fibrosis exhibit specific changes in tricarboxylic acid (TCA) cycle energy metabolism that may be required to support the increased energy demands of fibroproliferation.
放射性肺损伤（RILI）是许多癌症患者接受胸部放疗（TR）治疗的后果，目前尚无 FDA 批准的治愈策略。研究报告称，80%接受 TR 的患者将出现 CT 可检测到的间质性肺异常，而限制 RILI 风险的策略可能会降低放疗治疗癌症的效果。我们实验室和其他实验室已经报告称，特发性肺纤维化（IPF）患者的肺组织表现出代谢缺陷，包括糖酵解和乳酸生成增加。在这项初步研究中，我们假设放射性肺损伤患者的肺代谢将发生明显变化，这可能与纤维化的发生有关。我们使用液相色谱/串联质谱法来鉴定代谢物，分析了肺癌 TR 后 CT 证实有肺损伤的患者、健康对照者、吸烟者和尚未接受 TR 的癌症患者的呼出气冷凝液（EBC）。与三组非照射对照组相比，照射组的肺代谢组图谱明显不同，其特征是乳酸水平升高。途径富集分析显示，病例组 EBC 同时存在与三羧酸（TCA）循环相关的脂质、氨基酸和碳水化合物能量代谢改变。放射性诱导的糖酵解和乳酸向细胞外空间的转移表明，丙酮酸作为前体代谢物转化为乳酸而不是乙酰辅酶 A，这有助于 TCA 循环。这种 TCA 循环缺陷可能会被这些替代能源来弥补，以满足慢性伤口修复的代谢需求。使用“组学”方法以非侵入性方式探测肺部疾病可以为未来的机制研究和新型治疗靶点的开发提供信息。我们报告称，呼出气冷凝液（EBC）可识别放射性肺损伤患者的细胞代谢失调。在这项初步研究中，非靶向代谢组学揭示了与肺癌患者相比，放射性肺纤维化患者的 EBC 中存在显著的代谢特征，与有风险的吸烟者和健康志愿者相比也是如此。放射性肺纤维化患者表现出三羧酸（TCA）循环能量代谢的特定变化，这可能是支持成纤维细胞增殖增加的能量需求所必需的。
