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Metformin attenuates chronic lung allograft dysfunction: evidence in rat models

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机构： [1]Department of Thoracic Surgery, West China Hospital, Sichuan University, 610041, Chengdu, China. [2]Lung Transplant Research Laboratory, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China. [3]Heart and Lung Transplant Research Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China. [4]Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China. [5]Department of Pathology, Nanchong Central Hospital, Nanchong, 637000, China. [6]Department of Pathology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China. [7]Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, China. [8]Department of Respiratory and Critical Care Medicine, University of Chinese Academy of Sciences Shenzhen Hospital, Shenzhen, 518000, China. [9]Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China.

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关键词： Metformin Lung transplantation Chronic lung allograft rejection Chronic lung allograft dysfunction AMP-activated kinase

摘要：

Chronic lung allograft dysfunction (CLAD) directly causes an abysmal long-term prognosis after lung transplantation (LTx), but effective and safe drugs are not available. Metformin exhibits high therapeutic potential due to its antifibrotic and immunomodulatory effects; however, it is unclear whether metformin exerts a therapeutic effect in CLAD. We sought to investigate the effect of metformin on CLAD based on rat models.Allogeneic LTx rats were treated with Cyclosporin A (CsA) in the first week, followed by metformin, CsA, or vehicle treatment. Syngeneic LTx rats received only vehicles. All rats were sacrificed on post-transplant week 4. Pathology of lung graft, spleen, and thymus, extent of lung fibrosis, activity of profibrotic cytokines and signaling pathway, adaptive immunity, and AMPK activity were then studied.Allogeneic recipients without maintenance CsA treatment manifested CLAD pathological characteristics, but these changes were not observed in rats treated with metformin. For the antifibrotic effect, metformin suppressed the fibrosis extent and profibrotic cytokine expression in lung grafts. Regarding immunomodulatory effect, metformin reduced T- and B-cell infiltration in lung grafts, spleen and thymus weights, the T- and B-cell zone areas in the spleen, and the thymic medullary area. In addition, metformin activated AMPK in lung allografts and in α-SMA+ cells and T cells in the lung grafts.Metformin attenuates CLAD in rat models, which could be attributed to the antifibrotic and immunomodulatory effects. AMPK activation suggests the potential molecular mechanism. Our study provides an experimental rationale for further clinical trials.© 2023. The Author(s).

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大类 | 2 区医学

小类 | 2 区呼吸系统

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大类 | 2 区医学

小类 | 2 区呼吸系统

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Q1 RESPIRATORY SYSTEM

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Q1 RESPIRATORY SYSTEM

影响因子： 4.7 最新[2023版] 5.3 最新五年平均 4.7 出版当年[2023版] 5.3 出版当年五年平均 5.8 出版前一年[2022版]

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第一作者机构： [1]Department of Thoracic Surgery, West China Hospital, Sichuan University, 610041, Chengdu, China. [2]Lung Transplant Research Laboratory, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China. [3]Heart and Lung Transplant Research Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.

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Metformin attenuates chronic lung allograft dysfunction: evidence in rat models

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