肺上皮精氨酸酶ii在成纤维细胞活化和肺部炎症中的作用

IF 8 1区 医学 Q1 CELL BIOLOGY Aging Cell Pub Date : 2023-02-15 DOI:10.1111/acel.13790
Cui Zhu, Duilio M. Potenza, Yang Yang, Guillaume Ajalbert, Kirsten D. Mertz, Stephan von Gunten, Xiu-Fen Ming, Zhihong Yang
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引用次数: 2

摘要

据报道,精氨酸酶升高,包括i型(Arg-I)和ii型同工酶(Arg-II)在衰老、与年龄相关的器官炎症和纤维化中发挥作用。精氨酸酶在肺老化中的作用及其潜在机制尚未探讨。我们目前的研究表明,衰老的雌性小鼠肺中Arg-II水平升高,在支气管纤毛上皮、俱乐部细胞、肺泡2型(AT2)肺细胞和成纤维细胞(但不包括血管内皮细胞和平滑肌细胞)中检测到。在人肺活检中也观察到类似的Arg-II细胞定位。在arg-ii缺陷(arg-ii−/−)小鼠中,肺纤维化和炎性细胞因子(包括IL-1β和TGF-β1,它们在支气管上皮、AT2细胞和成纤维细胞中高度表达)与年龄相关的增加得到改善。与雌性动物相比,arg-ii−/−对雄性动物肺部炎症的影响较弱。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−/−细胞的条件培养基(CM),激活成纤维细胞产生各种细胞因子,包括TGF-β1和胶原,这些细胞因子被IL-1β受体拮抗剂或TGF-β I型受体阻滞剂所消除。相反,TGF-β1或IL-1β也增加Arg-II的表达。在小鼠模型中,我们证实了上皮细胞中IL-1β和TGF-β1的年龄相关增加和成纤维细胞的激活,这在arg-ii−/−小鼠中被抑制。综上所述,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在肺成纤维细胞活化中起关键作用,促进肺炎症和纤维化。这些结果为Arg-II在肺衰老中的作用提供了新的机制见解。
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Role of pulmonary epithelial arginase-II in activation of fibroblasts and lung inflammaging

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.

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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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