03.03 - Mechanisms of lung injury and repair最新文献

{"title":"Released mediators in ex vivo 3D-model of lung fibrosis correspond to elevated serum biomarkers in IPF","authors":"D. Kalafatis, A. Löfdahl, P. Näsman, L. E. Rendin, G. Westergren-Thorsson, M. Sköld","doi":"10.1183/23120541.LSC-2021.59","DOIUrl":"https://doi.org/10.1183/23120541.LSC-2021.59","url":null,"abstract":"Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with limited treatment options and a considerable diagnostic delay. Studies for diagnostic and prognostic biomarkers are therefore warranted. In an unpublished study, we discovered elevated levels of inflammatory and oncology-related proteins in a novel ex-vivo model where human healthy lung fibroblasts are cultured on decellularized lung tissue derived from IPF patients or healthy individuals. Aim: Evaluate potential biomarkers found elevated in ex vivo model in serum from a cohort of IPF patients. Methods: A panel of 92 proteins were examined with proximity extension assay in serum from 38 IPF patients and in 77 individuals with normal lung function. Protein data were correlated to clinical measures of disease severity. Results: After adjustment for multiple testing with Bonferroni correction, we were able to demonstrate that proteins elevated in the ex-vivo model, were also significantly elevated in serum from IPF patients compared to controls, with higher levels of CCL19, CXCL13 and MMP7 observed. In addition, MMP7 correlated negatively with both percent predicted forced vital capacity (FVC%, r= -0.48, p=0.0020) and total lung capacity (TLC%, r= -0.49, p=0.0017). Conclusion: We conclude that the ex vivo model may mimic fibrotic lung disease with elevated levels of CCL19, CXCL13 and MMP7 observed both ex-vivo and in IPF patients. An association with measures of disease severity strengthens our findings. Our results highlight the identified proteins in their roles as important drivers of fibrotic processes and the model’s applicability as an innovative way of studying pathological responses in IPF.","PeriodicalId":382910,"journal":{"name":"03.03 - Mechanisms of lung injury and repair","volume":"10 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131171273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial characteristics of CD169+ resident conducting airway macrophages during Aspergillus fumigatus-induced inflammation","authors":"M. Shevchenko, A. Bogorodskiy, E. Bolkhovitina, J. Vavilova, V. Borshchevskiy, A. Sapozhnikov","doi":"10.1183/23120541.LSC-2021.64","DOIUrl":"https://doi.org/10.1183/23120541.LSC-2021.64","url":null,"abstract":"CD169+ resident tissue macrophages reportedly prevent excessive neutrophil-mediated response by cloaking the damaged tissues in the site of inflammation. Such macrophages were demonstrated to maintain the homeostasis in the peritoneum (Uderhardt S. et al. Cell. 2019; 18;177(3):541-555), however, their role in airway inflammation is not characterized. In this study, we investigate the implication of CD169+ resident conducting airway macrophages in the inflammatory response induced by inhalation of Aspergillus fumigatus conidia. Since the airway epithelium is exposed to inhaled pathogens, we aimed to examine whether these macrophages contribute to the epithelium defense. C57BL/6 mice received an oropharyngeal application of A. fumigatus conidia. The lungs were fixed and conducting airways were stained immunohistochemically. Three-dimensional images were obtained using fluorescent confocal laser scanning microscopy. In intact mice, we identified CD169+CD11c– resident conducting airway macrophages possessing special irregular morphology beneath the smooth muscles and in close proximity to them, however, not in contact with epithelium. Moreover, resident macrophages were separated from the epithelium with basement membrane and smooth muscle layer in the acute and the late stage of A. fumigatus conidia-induced inflammation. While CD11c+ intraepithelial dendritic cells interacted with invading airway mucosa neutrophils, resident macrophages did not change their location beneath the smooth muscles. Thus, in A. fumigatus conidia-induced airway inflammation, resident conducting airway macrophages are unlikely to prevent the damage of the airway epithelium or the basement membrane but might control the integrity of the smooth muscle layer. The work was funded by RFBR, project 20-04-60311.","PeriodicalId":382910,"journal":{"name":"03.03 - Mechanisms of lung injury and repair","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132228862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial DNA stress activates MHC class I antigen presentation and CD8+ T-cell immunity: implications for pulmonary fibrosis","authors":"Xinyuan Wang, T. Meul, I. Kammerl, Y. Wang, C. Mayr, H. Schiller, S. Meiners","doi":"10.1183/23120541.LSC-2021.105","DOIUrl":"https://doi.org/10.1183/23120541.LSC-2021.105","url":null,"abstract":"Mitochondrial dysfunction is a hallmark of IPF and promotes the development of pulmonary fibrosis. Mitochondrial stress can activate innate immunity via mitochondrial (mt) DNA sensing. However, whether mitochondrial stress also regulates adaptive immune is unknown. We here investigated regulation of MHC I antigen presentation by mitochondrial stress using a mouse cell model of chronic mitochondrial dysfunction as well as an acute mtDNA stress model in human primary lung fibroblasts(phLF). Mouse embryonic fibroblasts derived from the mitochondrial function, PolgA mutator mouse model, demonstrated concerted upregulation of the MHC I as revealed by proteomic and FACS analysis. Importantly, expression and activity of the immunoproteasome, a specialized type of proteasome involved in the generation of antigenic MHC I peptides, was strongly upregulated compared to controls. Induction was driven by the activation of STAT1/type I interferon signaling via the cGAS/STING. And CD8+ T cells were activated when co-cultured with the PolgA mutator cells. In phLF, transfected mtDNA increased the immunoproteasome/MHC I and promoted generation of influenza MHC class I antigenic peptides to activate influenza-specific CD8+T cells as shown by FACS analysis and CD8+ T cell activation assays. Furthermore, single cell RNA seq analysis from publicly available ILD data sets revealed an enrichment for type I interferon and MHC I in AT1 and ciliated cells as well as CD8+ T cell responses. In conclusion, dysfunctional mitochondria activate adaptive CD8+ T cell responses via immunoproteasome and MHC I antigen presentation. In the lung, the defective mitochondrial function might contribute to fibrosis via imbalanced MHC class I antigen presentation in lung epithelial cells driving T cell autoimmunity.","PeriodicalId":382910,"journal":{"name":"03.03 - Mechanisms of lung injury and repair","volume":"214 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115585385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL11 negatively impacts adult lung alveolar organoid formation","authors":"R. Kortekaas, J. Burgess, M. Webster, R. Gosens","doi":"10.1183/23120541.LSC-2021.81","DOIUrl":"https://doi.org/10.1183/23120541.LSC-2021.81","url":null,"abstract":"Introduction: IL11 was recently reported to induce the formation of myofibroblasts and their secretion of collagen, while its subcutaneous administration drives the development of pulmonary fibrosis in mice. Less is known as to how IL11 affects epithelial-mesenchymal communication associated with epithelial repair, and regarding which cell types are the main producers and responders to IL11 in vivo. Here we aim to investigate the role of IL11 in alveolar regeneration. Methods: Epithelial progenitor cell behavior was studied using an organoid model, comprised of a co-culture of primary mouse CD31-CD45-Epcam+ cells with either CCL206 fibroblasts or primary human fibroblasts. After 14 days, the number and size of the organoids were determined, and immunofluorescent staining for Surfactant protein C (SPC) and acetylated tubulin (ACT) was performed to define alveolar vs airway organoids. Immunohistochemical staining of IL11 and IL11R was performed on human lung tissue to observe producer and responder cells of IL11 signaling. Results: The presence of rhIL11 significantly decreased the number of both mouse and human organoids formed in a concentration-dependent manner, and the fraction of SPC+ organoids was reduced by rhIL11 whereas the fraction of SPC-ACT- organoids was increased. Organoid size was not affected. Finally, immunohistochemistry revealed that IL11R is found in smooth muscle, airway epithelium and endothelium, whereas IL11 was primarily observed in airway epithelium, alveolar type 2 cells and macrophages. Conclusions: IL11 may impair epithelial progenitor function by suppressing their activation and by suppressing the formation of mature alveolar cell types. IL11R localization suggests mesenchymal activation by IL11 may contribute to observed effects on progenitor function.","PeriodicalId":382910,"journal":{"name":"03.03 - Mechanisms of lung injury and repair","volume":"76 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114103859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RANKL contributes to lung tissue repair via promoting type II epithelial cell proliferation","authors":"H. Habibie, Shanshan Song, K. S. Putri, C. Boorsma, R. Cool, Xinhui Wu, R. Gosens, Yizhou Wang, W. Quax, P. Olinga, C. Brandsma, W. Timens, J. Burgess, B. Melgert","doi":"10.1183/13993003.congress-2020.5029","DOIUrl":"https://doi.org/10.1183/13993003.congress-2020.5029","url":null,"abstract":"Higher levels of receptor activator for NF-κβ ligand (RANKL) are found in serum of emphysema patients. RANKL is a well-known stimulator of bone tissue degradation, possibly explaining the association of COPD with osteoporosis. However, RANKL is also reported to be involved in epithelial cell regeneration in breast and thymus. Given RANKL is produced directly in lung tissue, we hypothesized a role for RANKL in lung epithelial cell regeneration. The aim of this study was to elucidate the role of RANKL in lung epithelial repair. Mouse soluble RANKL (sRANKL) treatment of murine precision-cut lung slices resulted in a higher number of proliferating cells compared to untreated controls. We also found that sRANKL stimulated proliferation of type II alveolar (A549 cells) but not airway (16HBE) epithelial cells. Using an organoid model of epithelial development by co-culturing primary EpCAM+ cells with fibroblasts, we found higher numbers of alveolar organoids in cultures derived from murine epithelial cells upon sRANKL treatment compared to control. Importantly, this effect was similar in RANKL-treated organoids derived from epithelial cells isolated from lung tissue of COPD patients. The effect of sRANKL was abrogated upon addition of osteoprotegerin, the soluble, inhibitory, receptor for RANKL. In conclusion, we found that sRANKL promotes type II alveolar epithelial cell proliferation and may therefore contribute to lung tissue repair. Our data suggest that the higher levels of RANKL found in emphysema, may reflect an attempt at epithelial repair by the lung to counteract the lung tissue destruction that characterizes emphysema.","PeriodicalId":382910,"journal":{"name":"03.03 - Mechanisms of lung injury and repair","volume":"6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126643977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COL4A3 degradation is increased in severe, type 2 exacerbating asthmatics","authors":"M. Weckmann, T. Bahmer, J. Sand, S. Rønnow, D. Leeming, M. Karsdal, L. Lunding, M. Wegmann, B. Oliver, J. Duhn, Y. Laumonnier, O. Danov, K. Sewald, U. Zissler, M. Jonker, I. König, G. Hansen, E. Mutius, O. Fuchs, A. Dittrich, B. Schaub, C. Happle, K. Rabe, M. Berge, J. Burgess, M. Kopp","doi":"10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a5632","DOIUrl":"https://doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a5632","url":null,"abstract":"Introduction: Remodeling of the airway wall is a hallmark feature of asthma. Under physiological conditions, a finely tuned balance maintains a functional state of the extracellular matrix. This balance is disrupted in asthma. COL4A3 is reduced 18-fold in lung tissue from asthmatics, however, the mechanism leading to the diminished levels of COL4A3 has remained elusive. Methods: The COL4A3 fibrolysis marker C4Ma3 (Nordic Bioscience, Denmark) was measured in the ALLIANCE cohort study participants (Fuchs et al. 2018). Pediatric controls/cases: 34/134; Adult control/cases 31/149. C4Ma3 data was correlated with clinical data, serum cytokine profiles (27-Bioplex, Biorad). Female 6-8 week old Balb/C mice were sensitized (OVA i.p., day 1, 14, 21) and challenged with aerosol (OVA i.n., day 26, 27, 28) to induce acute allergic airway inflammation. Acute exacerbations were provoked by instillation of poly(cytidylic-inosinic, i.n. day 28). Murine precision cut lung slices (PCLS) were used to elucidate the role of sensitisation for COL4A3 degradation. Results: Increased C4Ma3 correlated with asthma exacerbation (pl0.01) and elevated levels of Th2/Th9 cytokines in the ALLIANCE cohort. Serum levels of C4Ma3 were elevated in OVA challenged mice (pl0.0001) and correlated with lung tissue levels of mast cell chymase (pl0.01), but not with neutrophils or matrix-metallo-proteinase 9. C4MA3 was elevated in PCLS of allergic, HDM challenged mice (pl0.05) with no further increase after PolyIC. Conclusion: COL4A3 degradation (circulating C4Ma3), is elevated in severe, exacerbating type 2 asthmatics. C4Ma3 levels correlate with chymase positive mast cells in a mouse model of asthma exacerbation. These data highlight that the degradation of COL4A3 is a central part of the pathology of asthma.","PeriodicalId":382910,"journal":{"name":"03.03 - Mechanisms of lung injury and repair","volume":"103 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121826764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}