Prior research demonstrated that glucagon has protective roles against inflammation, but its effect on the resolution of inflammation remains elusive. Using in vitro and in vivo approaches, this study aimed to investigate the pro-resolving potential of glucagon on pulmonary neutrophilic inflammation caused by lipopolysaccharide. Lipopolysaccharide induced an increase in the proportions of neutrophils positives to glucagon receptor (GcgR) in vitro. In addition, lipopolysaccharide induced an increase in the neutrophil accumulation and expression of GcgR by the inflammatory cells in the lungs, however, without altering glucagon levels. Intranasal treatment with glucagon, at the peak of neutrophilic inflammation, reduced the neutrophil number in the bronchoalveolar lavage (BAL), and lung tissue within 24 h. The reduction of neutrophilic inflammation provoked by glucagon was accompanied by neutrophilia in the blood, an increase in the apoptosis rate of neutrophils in the BAL, enhance in the pro-apoptotic Bax protein expression, and decrease in the anti-apoptotic Bcl-2 protein levels in the lung. Glucagon also induced a rise in the cleavage of caspase-3 in the lungs; however, it was not significant. Glucagon inhibited the levels of IL-1β and TNF-α while increasing the content of pro-resolving mediators transforming growth factor (TGF-β1) and PGE2 in the BAL and lung. Finally, glucagon inhibited lipopolysaccharide-induced airway hyper-reactivity, as evidenced by the reduction in lung elastance values in response to methacholine. In conclusion, glucagon-induced resolution of neutrophilic inflammation by promoting cessation of neutrophil migration and a rise of neutrophil apoptosis and the levels of pro-resolving mediators TGF-β1 and PGE2.

先前的研究表明，胰高血糖素具有抗炎症的保护作用，但其对炎症消退的作用仍然难以捉摸。本研究旨在利用体外和体内方法研究胰高血糖素对脂多糖引起的肺部中性粒细胞炎症的促消退潜力。脂多糖在体外诱导胰高血糖素受体（GcgR）阳性的中性粒细胞比例增加。此外，脂多糖诱导肺部炎症细胞中性粒细胞积累和 GcgR 表达增加，但不改变胰高血糖素水平。在中性粒细胞炎症高峰期进行胰高血糖素鼻内治疗，可在 24 小时内减少支气管肺泡灌洗液 (BAL) 和肺组织中的中性粒细胞数量。胰高血糖素引起的中性粒细胞炎症的减少伴随着血液中中性粒细胞增多，BAL中中性粒细胞凋亡率增加，促凋亡Bax蛋白表达增强，抗凋亡Bcl-2蛋白水平降低在肺里。胰高血糖素还诱导肺部 caspase-3 裂解增加；然而，这并不重要。胰高血糖素抑制 IL-1β 和 TNF-α 的水平，同时增加 BAL 和肺中促分解介质转化生长因子 (TGF-β1) 和 PGE2 的含量。最后，胰高血糖素抑制脂多糖诱导的气道高反应性，乙酰甲胆碱引起的肺弹性值降低就证明了这一点。总之，胰高血糖素通过促进中性粒细胞迁移的停止、中性粒细胞凋亡的增加以及促消退介质 TGF-β1 和 PGE2 的水平来诱导中性粒细胞炎症的消退。