Laboratory of Cardiovascular and Aging Research, Department of Endocrinology, Metabolism, and Cardiovascular System, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Institute for Pathology, Cantonal Hospital Baselland, Liestal, Switzerland.
Aging Cell. 2023 Apr;22(4):e13790. doi: 10.1111/acel.13790. Epub 2023 Feb 15.
Elevated arginases including type-I (Arg-I) and type-II isoenzyme (Arg-II) are reported to play a role in aging, age-associated organ inflammaging, and fibrosis. A role of arginase in pulmonary aging and underlying mechanisms are not explored. Our present study shows increased Arg-II levels in aging lung of female mice, which is detected in bronchial ciliated epithelium, club cells, alveolar type 2 (AT2) pneumocytes, and fibroblasts (but not vascular endothelial and smooth muscle cells). Similar cellular localization of Arg-II is also observed in human lung biopsies. The age-associated increase in lung fibrosis and inflammatory cytokines, including IL-1β and TGF-β1 that are highly expressed in bronchial epithelium, AT2 cells, and fibroblasts, are ameliorated in arg-ii deficient (arg-ii ) mice. The effects of arg-ii on lung inflammaging are weaker in male as compared to female animals. Conditioned medium (CM) from human Arg-II-positive bronchial and alveolar epithelial cells, but not that from arg-ii cells, activates fibroblasts to produce various cytokines including TGF-β1 and collagen, which is abolished by IL-1β receptor antagonist or TGF-β type I receptor blocker. Conversely, TGF-β1 or IL-1β also increases Arg-II expression. In the mouse models, we confirmed the age-associated increase in IL-1β and TGF-β1 in epithelial cells and activation of fibroblasts, which is inhibited in arg-ii mice. Taken together, our study demonstrates a critical role of epithelial Arg-II in activation of pulmonary fibroblasts via paracrine release of IL-1β and TGF-β1, contributing to pulmonary inflammaging and fibrosis. The results provide a novel mechanistic insight in the role of Arg-II in pulmonary aging.
研究表明，包括 I 型（Arg-I）和 II 型同工酶（Arg-II）在内的升高的精氨酸酶在衰老、与年龄相关的器官炎症和纤维化中发挥作用。精氨酸酶在肺衰老中的作用及其潜在机制尚不清楚。本研究显示，雌性小鼠衰老肺中 Arg-II 水平升高，在支气管纤毛上皮细胞、克拉细胞、肺泡 II 型（AT2）型肺细胞和成纤维细胞中检测到（但血管内皮细胞和平滑肌细胞中未检测到）。在人肺活检组织中也观察到类似的 Arg-II 细胞定位。与年龄相关的肺纤维化和炎症细胞因子增加，包括在支气管上皮细胞、AT2 细胞和成纤维细胞中高表达的白细胞介素-1β（IL-1β）和转化生长因子-β1（TGF-β1），在 Arg-II 缺陷（arg-ii）小鼠中得到改善。与雌性动物相比，arg-ii 对肺炎症老化的影响在雄性动物中较弱。来自人 Arg-II 阳性支气管和肺泡上皮细胞的条件培养基（CM），而不是来自 arg-ii 细胞的 CM，可激活成纤维细胞产生各种细胞因子，包括 TGF-β1 和胶原，而 IL-1β 受体拮抗剂或 TGF-β 型 I 受体阻滞剂可阻断这种作用。相反，TGF-β1 或 IL-1β 也会增加 Arg-II 的表达。在小鼠模型中，我们证实了与年龄相关的上皮细胞中 IL-1β和 TGF-β1 的增加以及成纤维细胞的激活，在 arg-ii 小鼠中这种激活被抑制。总之，我们的研究表明，上皮细胞 Arg-II 通过旁分泌释放 IL-1β 和 TGF-β1 ，在激活肺成纤维细胞中起关键作用，导致肺炎症和纤维化。该研究结果为 Arg-II 在肺衰老中的作用提供了新的机制见解。
