PKM2介导糖代谢重编程诱导巨噬细胞M1极化参与肺癌放射性肺炎发生及关键机制

Radiation pneumonitis (RP) is a severe and potentially fatal complication of radiation therapy in patients with lung cancer. It’s urgent to know the mechanisms underlying the pathogenesis of RP, which will allow clinician to intervene the inflammatory lung injury and hopefully to save their lung function. In clinical practice, we found that RP inflammation manifests on 18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) as enhanced FDG uptake. We further demonstrated that 18F-FDG PET is a more effective method for visualizing and quantitatively assessing RP inflammation. In our preliminary proteomics study with RP mouse model, we found that proteins enriched in the glycolysis pathway and pyruvate kinase M2 unregulated most prominently. In our further study using RP mouse model, we found that cytokines including interleukin-1 (IL-1) and IL-6 increased; the expression of phosphorylation of PKM2 on tyrosine 105 and the level of lactate (both as the hallmarks of metabolic reprogramming) increased; M1 macrophage polarization increased. Based on reviewing the advanced studies in the field of immunometabolism, we propose the hypotheses that PKM2 regulates metabolic reprogramming and promotes M1 macrophage polarization in the process of RP. To test these hypotheses, we will utilize cell experiment, RP mouse model and blood samples from non-small cell lung cancer to demonstrate the immunometabolism mechanisms underlying the pathogenesis of RP. The research will possibly provide the theory basis and potential molecular target to timely intervene RP to limit its extent or prevent it entirely.

放射性肺炎是肺癌放疗后严重甚至致命的并发症，揭示其发生的分子机制并探索其治疗策略是亟待解决的临床难题。我们发现18F-FDG PET作为反映糖代谢的影像手段可以检测和量化放射性肺炎的严重程度。我们的预实验通过蛋白质组学分析，发现放射性肺炎小鼠的肺脏组织中糖代谢通路相关蛋白富集显著，以丙酮酸激酶M2（PKM2）蛋白上调最明显。进一步在放射性肺炎动物模型中发现，与放射性肺炎相关的炎症因子IL-1和IL-6增加；糖代谢重编程的标志，乳酸和PKM2第105位点酪氨酸磷酸化增加；M1型巨噬细胞升高。结合免疫代谢的前沿研究，我们提出科学假设“PKM2介导糖代谢重编程诱导巨噬细胞M1极化可能参与肺癌放射性肺炎的发生”。我们拟在分子、细胞、动物和临床水平研究PKM2介导的糖代谢重编程在放射性肺炎发生中的作用以及探索PKM2诱导巨噬细胞M1极化的分子机制，这将为治疗放射性肺炎提供科学基础和潜在的分子靶点。

放射性肺炎是肺癌放疗后严重甚至致命的并发症，揭示其发生的分子机制并探索其治疗策略是亟待解决的临床难题。我们发现18F-FDG PET作为反映糖代谢的影像手段可以检测和量化放射性肺炎的严重程度。我们通过分子、细胞、动物和临床水平研究PKM2介导的糖代谢重编程在放射性肺炎发生中的作用以及探索PKM2诱导巨噬细胞M1极化的分子机制。本研究探索了18F-FDG PET对放射性肺炎的显像作用，结果显示18F-FDG PET不能准确评估无菌性放射性肺炎，但联合LPS模拟的放射性肺炎伴细菌感染模型可以通过FDG-PET显像。其背后的机制可能是Warburg效应，Warburg效应促进葡萄糖代谢从三羧酸循环转化为有氧糖酵解，导致葡萄糖摄取增加。单纯放疗不能激活Warburg效应，但可加重细菌性感染激发的Warburg效应对肺部的影响。这将为治疗放射性肺炎提供科学基础和潜在的分子靶点。