Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, 634028 Tomsk, Russia.
Stem Cell Biology and Regenerative Medicine Group, School of Pharmacy, University of Reading, Whiteknights campus, Reading, RG6 6AP, UK.
Int J Mol Sci. 2019 Oct 30;20(21):5414. doi: 10.3390/ijms20215414.
In clinical practice, the metabolic syndrome (MetS) is often associated with chronic obstructive pulmonary disease (COPD). Although gender differences in MetS are well documented, little is known about sex-specific differences in the pathogenesis of COPD, especially when combined with MetS. Consequently, it is not clear whether the same treatment regime has comparable efficacy in men and women diagnosed with MetS and COPD. In the present study using sodium glutamate, lipopolysaccharide, and cigarette smoke extract, we simulated lipid metabolism disorders, obesity, hyperglycemia, and pulmonary emphysema (comorbidity) in male and female C57BL/6 mice. We assessed the gender-specific impact of lipid metabolism disorders and pulmonary emphysema on angiogenic precursor cells (endothelial progenitor cells (EPC), pericytes, vascular smooth muscle cells, cells of the lumen of the nascent vessel), as well as the biological effects of pegylated glucagon-like peptide 1 (pegGLP-1) in this experimental paradigm. Simulation of MetS/COPD comorbidity caused an accumulation of EPC (CD45CD31CD34), pericytes, and vascular smooth muscle cells in the lungs of female mice. In contrast, the number of cells involved in the angiogenesis decreased in the lungs of male animals. PegGLP-1 had a positive effect on lipids and area under the curve (AUC), obesity, and prevented the development of pulmonary emphysema. The severity of these effects was stronger in males than in females. Furthermore, PegGLP-1 stimulated regeneration of pulmonary endothelium. At the same time, PegGLP-1 administration caused a mobilization of EPC (CD45CD31CD34) into the bloodstream in females and migration of precursors of angiogenesis and vascular smooth muscle cells to the lungs in male animals. Gender differences in stimulatory action of pegGLP-1 on CD31 endothelial lung cells in vitro were not observed. Based on these findings, we postulated that the cellular mechanism of in vivo regeneration of lung epithelium was at least partly gender-specific. Thus, we concluded that a pegGLP-1-based treatment regime for metabolic disorder and COPD should be further developed primarily for male patients.
在临床实践中，代谢综合征（MetS）常与慢性阻塞性肺疾病（COPD）相关。尽管代谢综合征的性别差异已有大量文献记载，但对于 COPD 的发病机制中性别特异性差异知之甚少，尤其是当与 MetS 合并时。因此，尚不清楚在诊断为 MetS 和 COPD 的男性和女性中，相同的治疗方案是否具有可比的疗效。在本研究中，我们使用谷氨酸钠、脂多糖和香烟烟雾提取物，模拟了雄性和雌性 C57BL/6 小鼠的脂质代谢紊乱、肥胖、高血糖和肺肺气肿（合并症）。我们评估了脂质代谢紊乱和肺肺气肿对血管生成前体细胞（内皮祖细胞（EPC）、周细胞、血管平滑肌细胞、新生血管管腔细胞）的性别特异性影响，以及聚乙二醇化胰高血糖素样肽 1（pegGLP-1）在这种实验模型中的生物学效应。MetS/COPD 合并症的模拟导致雌性小鼠肺部 EPC（CD45CD31CD34）、周细胞和血管平滑肌细胞的积累。相比之下，参与血管生成的细胞数量在雄性动物的肺部减少。pegGLP-1 对脂质和曲线下面积（AUC）、肥胖有积极作用，并可预防肺气肿的发展。这些影响在男性中的强度强于女性。此外，pegGLP-1 刺激肺内皮的再生。同时，pegGLP-1 给药导致 EPC（CD45CD31CD34）动员到女性血液中，以及血管生成和血管平滑肌细胞的前体向男性动物肺部迁移。体外观察到 pegGLP-1 对 CD31 肺内皮细胞的刺激作用无性别差异。基于这些发现，我们假设体内肺上皮再生的细胞机制至少部分是性别特异性的。因此，我们得出结论，基于 pegGLP-1 的代谢紊乱和 COPD 治疗方案应主要针对男性患者进一步开发。
