PAI-1 Derived from Alveolar Type 2 Cells Drives Aging-Associated Pulmonary Fibrosis  

作　　者：Rui Quan Chenhong Shi Yanan Sun Chengying Zhang Ran Bi Yiran Zhang Xin Bi Bin Liu Ziheng Dong Dekui Jin Yixuan Li 

机构地区：[1]Key Laboratory of Functional Dairy,Co-Constructed by the Ministry of Education and Beijing Municipality,Beijing 100083,China [2]Department of General Practice,The Third Medical Center of the Chinese PLA General Hospital,Beijing 100039,China [3]Department of Thoracic Surgery,The Third Medical Center of the Chinese PLA General Hospital,Beijing 100039,China [4]Center for Nanomedicine and Department of Anesthesiology,Brigham and Women’s Hospital,Harvard Medical School,Boston,MA 02115,USA [5]School of Computer and Information Engineering,Luoyang Institute of Science and Technology,Luoyang 471023,China

出　　处：《Engineering》2024年第11期74-87,共14页工程（英文）

基　　金：supported by the Young Elite Scientist Sponsorship Program by CAST(2022QNRC001);the 111 project of the Education Ministry of China(B18053).

摘　　要：Pulmonary fibrosis(PF)is a lethal lung disease that predominantly affects older adults;however,whether and how aging triggers fibrosis remains unclear.To pinpoint the predominant initiating factors of PF,we first analyzed single-cell RNA sequencing(scRNA-seq)data from the lung tissues of 45 normal donors and 51 PF patients and found that aging might serve as the primary catalyst for PF development.To further investigate the influence of aging on PF formation,we conducted a comprehensive and thorough study employing a natural aging mouse model.We found that dynamic alterations in the quantity and types of collagen fibers during aging-induced PF progression,especially in collagenous(Col)I,emerged as the predominant driver of PF.We then investigated the regulation of Col I synthesis during aging using primary alveolar type 2(AT2)cells and A549 cells line through conditioned media and Transwell cocul-ture,and found that secretions—particularly plasminogen activator inhibitor(PAI)-1—from aged AT2 cells promoted fibrosis and enhanced collagen type I alpha 1(Col1al)production via the transforming growth factor(TGF)-b/small mother against decapentaplegic(Smad)2/3 pathway.Furthermore,scRNA-seq and a histological analysis of human lung tissue demonstrated a significant upregulation of SERPINE1(the gene encoding PAI-1)and PAI-1 expression in both aging lung tissue and AT2 cells,which was consistent with our findings from animal experiments,providing additional evidence for the pivotal role of PAI-1 during aging and the development of PF.Our research demonstrates that PAI-1,a crucial factor secreted by aging AT2 cells,exerts a pivotal role in promoting the synthesis of Col1a1 in fibroblasts,subsequently leading to Col I deposition,and in driving the progression of PF by mediating the TGF-b/Smad2/3 pathway.Our find-ings offer critical evidence for the involvement of epithelial dysfunction in age-related PF and provides potential novel therapeutic targets for clinical intervention.

关 键 词：Aging Pulmonary fibrosis Alveolar type 2 cells PAI-1 

分 类 号：R563[医药卫生—呼吸系统]