Chronic obstructive pulmonary disease (COPD) is an incurable and progressive disease. Emphysema is the principal manifestation of COPD, and the main cause of this condition is cigarette smoke (CS). Natural products have shown antioxidant and anti-inflammatory properties that can prevent acute lung inflammation and emphysema, but there are few reports in the literature regarding therapeutic approaches to emphysema. We hypothesized that supplementation with natural extracts would repair lung damage in emphysema caused by CS exposure. Mice were exposed to 60 days of CS and then treated or not with three different natural extracts (mate tea, grape and propolis) orally for additional 60 days. Histological analysis revealed significant improvements in lung histoarchitecture, with recovery of alveolar spaces in all groups treated with natural extracts. Propolis was also able to recovery alveolar septa and elastic fibers. Propolis also increased MMP-2 and decreased MMP-12 expression, favoring the process of tissue repair. Additionally, propolis recruited leukocytes, including macrophages, without ROS release. These findings led us to investigate the profile of these macrophages, and we showed that propolis could promote macrophage alternative activation, thus increasing the number of arginase-positive cells and IL-10 levels and favoring an anti-inflammatory microenvironment. We further investigated the participation of Nrf2 in lung repair, but no Nrf2 translocation to the nucleus was observed in lung cells. Proteins and enzymes related to Nrf2 were not altered, other than NQO1, which seemed to be activated by propolis in a Nrf2-independent manner. Finally, propolis downregulated IGF1 expression. In conclusion, propolis promoted lung repair in a mouse emphysema model via macrophage polarization from M1 to M2 in parallel to the downregulation of IGF1 expression in a Nrf2-independent manner.

慢性阻塞性肺疾病（COPD）是一种无法治愈的进行性疾病。肺气肿是COPD的主要表现，而这种情况的主要原因是香烟烟雾（CS）。天然产物已显示出可以预防急性肺部炎症和肺气肿的抗氧化剂和抗炎特性，但是关于肺气肿的治疗方法的文献报道很少。我们假设补充天然提取物可以修复CS暴露引起的肺气肿肺损伤。将小鼠暴露于60天的CS中，然后再口服或不接受三种不同的天然提取物（伴侣茶，葡萄和蜂胶）处理60天。组织学分析显示，在用天然提取物治疗的所有组中，肺组织结构都有了明显改善，肺泡间隙得到了恢复。蜂胶还能够恢复肺泡间隔和弹性纤维。蜂胶还增加了MMP-2并降低了MMP-12的表达，有利于组织修复过程。另外，蜂胶募集的白细胞，包括巨噬细胞，没有ROS释放。这些发现促使我们研究了这些巨噬细胞的概况，并且我们证明了蜂胶可以促进巨噬细胞的替代激活，从而增加了精氨酸酶阳性细胞的数量和IL-10的含量，并有利于消炎性微环境的发展。我们进一步调查了Nrf2在肺修复中的参与，但在肺细胞中未观察到Nrf2易位至细胞核。除NQO1外，与Nrf2相关的蛋白质和酶没有改变，NQO1似乎被蜂胶以与Nrf2无关的方式激活。最后，蜂胶下调了IGF1的表达。