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Emphysema, the progressive destruction of gas exchange surfaces in the lungs, is a hallmark of chronic obstructive pulmonary disease (COPD) that is presently incurable. This therapeutic gap is largely due to a poor understanding of potential drivers of impaired tissue regeneration, such as abnormal lung epithelial progenitor cells, including alveolar type II (ATII) and airway club cells. We discovered an emphysema-specific sub-population of ATII cells located in enlarged distal alveolar sacs, termed asATII cells. Single cell RNA-seq and in situ localisation revealed that asATII cells co-express the alveolar marker surfactant protein C (SPC) and the club cell marker secretaglobin-3A2 (SCGB3A2). A similar ATII sub-population derived from club cells was also identified in mouse COPD models using lineage labeling. Human and mouse ATII sub-populations formed 80-90% fewer alveolar organoids than healthy controls, indicating reduced progenitor function. Targeting asATII cells or their progenitor club cells could reveal novel COPD treatment strategies., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

COPD is a devastating respiratory condition that manifests via persistent inflammation, emphysema development and small airway remodelling. Lung regeneration is defined as the ability of the lung to repair itself after injury by the proliferation and differentiation of progenitor cell populations, and becomes impaired in the COPD lung as a consequence of cell intrinsic epithelial stem cell defects and signals from the micro-environment. Although the loss of structural integrity and lung regenerative capacity are critical for disease progression, our understanding of the cellular players and molecular pathways that hamper regeneration in COPD remains limited. Intriguingly, despite being a key driver of COPD pathogenesis, the role of the immune system in regulating lung regenerative mechanisms is understudied. In this review, we summarise recent evidence on the contribution of immune cells to lung injury and regeneration. We focus on four main axes: 1) the mechanisms via which myeloid cells cause alveolar degradation; 2) the formation of tertiary lymphoid structures and the production of autoreactive antibodies; 3) the consequences of inefficient apoptotic cell removal; and 4) the effects of innate and adaptive immune cell signalling on alveolar epithelial proliferation and differentiation. We finally provide insight on how recent technological advances in omics technologies and human ex vivo lung models can delineate immune cell-epithelium cross-talk and expedite precision pro-regenerative approaches toward reprogramming the alveolar immune niche to treat COPD., Competing Interests: Conflict of interest: M. Lehmann reports fees for a podcast from Berlin-Chemie outside the submitted work. All other authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

In this review, the Basic and Translational Science Assembly of the European Respiratory Society provides an overview of the 2022 International Congress highlights. We discuss the consequences of respiratory events from birth until old age regarding climate change related alterations in air quality due to pollution caused by increased ozone, pollen, wildfires and fuel combustion as well as the increasing presence of microplastic and microfibres. Early life events such as the effect of hyperoxia in the context of bronchopulmonary dysplasia and crucial effects of the intrauterine environment in the context of pre-eclampsia were discussed. The Human Lung Cell Atlas (HLCA) was put forward as a new point of reference for healthy human lungs. The combination of single-cell RNA sequencing and spatial data in the HLCA has enabled the discovery of new cell types/states and niches, and served as a platform that facilitates further investigation of mechanistic perturbations. The role of cell death modalities in regulating the onset and progression of chronic lung diseases and its potential as a therapeutic target was also discussed. Translational studies identified novel therapeutic targets and immunoregulatory mechanisms in asthma. Lastly, it was highlighted that the choice of regenerative therapy depends on disease severity, ranging from transplantation to cell therapies and regenerative pharmacology., Competing Interests: Conflict of interest: S. Cuevas Ocaña was supported by an Action for Pulmonary Fibrosis award to support attendance at the European Respiratory Society International Congress 2022. S. Rolandsson Enes declares personal consulting fees from Swedish StromaBio AB outside the submitted work. C. Voss declares research funding and salary from the European Union's Horizon 2020 research and innovation programme under grant agreement number 953183 (HARMLESS) and number 686098 (SmartNanoTox); and nonfinancial interests in spin-off company Infinite from H2020 SmartNanoTox. L.S.N. Dean reports being a postdoctoral research associate on a Biotechnology and Biological Sciences Research Council (BBSRC) David Phillips Fellowship (BB/V004573/1) and an NIHR Southampton Biomedical Research Centre (BRC) Senior Research Fellowship, and that they received a British Association for Lung Research Travel Award to the European Respiratory Society International Congress 2022. M. Loxham reports a BBSRC David Phillips Fellowship (BB/V004573/1) and an NIHR Southampton BRC Senior Research Fellowship to fund research and salary for a fellow; as well as research and equipment grants (total ∼GBP 13 000) from Asthma, Allergy, and Inflammation Research Charity (UK), in the 36 months prior to manuscript submission. C.M. Greene declares research funding paid to their institution by the National Institutes of Health, Vertex and the Alpha-1 Foundation; and an honorarium from Insmed, all in the 36 months prior to manuscript submission; as well as support for travel and accommodation at the European Respiratory Society International Congress 2022. I.H. Heijink declares research funding from Boehringer Ingelheim and Roche, outside the submitted work. A. Joannes declares research funding to their institution, and support for attending meetings and/or travel from AIR de Bretagne, in the 36 months prior to manuscript submission. A.M. van der Does declares an unpaid role as Secretary of European Respiratory Society Group 03.02 (Airway cell biology and immunopathology). D.E. Wagner declares research grants from the Swedish Research Council, the European Research Council, Vinnova, the Alternatives Research and Development Foundation and the Knut and Alice Wallenberg Foundation; and support from AstraZeneca for attendance at the company's Science Day 2022 in Gothenburg; and receipt of electrospun membranes to their lab from Cellevate AB, all in the 36 months prior to manuscript submission; as well as patents relating to “De- and recellularization of whole organs” and “Microwave processing for calcium phosphate nanowhiskers”; personal stock investments in Merck, Pfizer, Thermofisher and Viatris; and an unpaid role as Secretary of European Respiratory Society Group 03.03 (Mechanisms of lung injury and repair). All other authors declare no competing interests., (Copyright ©The authors 2023.)

A workshop entitled "Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases" was hosted by the University of Vermont Larner College of Medicine in collaboration with the National Heart, Lung and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, the International Society for Cell and Gene Therapy and the Pulmonary Fibrosis Foundation. The event was held from July 15 to 18, 2019 at the University of Vermont, Burlington, Vermont. The objectives of the conference were to review and discuss the current status of the following active areas of research: 1) technological advancements in the analysis and visualisation of lung stem and progenitor cells; 2) evaluation of lung stem and progenitor cells in the context of their interactions with the niche; 3) progress toward the application and delivery of stem and progenitor cells for the treatment of lung diseases such as cystic fibrosis; 4) progress in induced pluripotent stem cell models and application for disease modelling; and 5) the emerging roles of cell therapy and extracellular vesicles in immunomodulation of the lung. This selection of topics represents some of the most dynamic research areas in which incredible progress continues to be made. The workshop also included active discussion on the regulation and commercialisation of regenerative medicine products and concluded with an open discussion to set priorities and recommendations for future research directions in basic and translation lung biology., Competing Interests: Conflict of interest: D.E. Wagner reports a grant from the US NIH (R13 HL149436, conference grant), and grants for conference support from the Alpha-1 Foundation, the International Society for Cell and Gene Therapy, and the Pulmonary Fibrosis Foundation, during the conduct of the study; and honoraria from Boehringer Ingelheim outside the submitted work. In addition, D.E. Wagner has patent US20160067378A1 pending. Conflict of interest: L. Ikonomou has nothing to disclose. Conflict of interest: S.E. Gilpin has nothing to disclose. Conflict of interest: C.M. Magin reports consulting fees from Sharklet Technologies, Inc., outside the submitted work; and a patent, “3D in vitro models of lung tissue”, pending. Conflict of interest: F. Cruz has nothing to disclose. Conflict of interest: A. Greaney has nothing to disclose. Conflict of interest: M. Magnusson has nothing to disclose. Conflict of interest: Y-W. Chen has nothing to disclose. Conflict of interest: B. Davis has nothing to disclose. Conflict of interest: K. Vanuytsel has nothing to disclose. Conflict of interest: S. Rolandsson Enes has nothing to disclose. Conflict of interest: A. Krasnodembskaya reports grants from the Medical Research Council (MRC) UK during the writing of this article. She is funded by the MRC (national funder for medical and translational research) to conduct research in the area of stem cell-based therapies for lung diseases. Conflict of interest: M. Lehmann has nothing to disclose. Conflict of interest: G. Westergren-Thorsson has nothing to disclose. Conflict of interest: J. Stegmayr has nothing to disclose. Conflict of interest: H.N. Alsafadi has nothing to disclose. Conflict of interest: E.T. Hoffman has nothing to disclose. Conflict of interest: D.J. Weiss reports grants from the NIH during the conduct of the study. Conflict of interest: A.L. Ryan reports grants from the Cystic Fibrosis Foundation and the NIH, outside the submitted work., (Copyright ©ERS 2020.)

Most chronic and acute lung diseases have no cure, leaving lung transplantation as the only option. Recent work has improved our understanding of the endogenous regenerative capacity of the lung and has helped identification of different progenitor cell populations, as well as exploration into inducing endogenous regeneration through pharmaceutical or biological therapies. Additionally, alternative approaches that aim at replacing lung progenitor cells and their progeny through cell therapy, or whole lung tissue through bioengineering approaches, have gained increasing attention. Although impressive progress has been made, efforts at regenerating functional lung tissue are still ineffective. Chronic and acute lung diseases are most prevalent in the elderly and alterations in progenitor cells with ageing, along with an increased inflammatory milieu, present major roadblocks for regeneration. Multiple cellular mechanisms, such as cellular senescence and mitochondrial dysfunction, are aberrantly regulated in the aged and diseased lung, which impairs regeneration. Existing as well as new human in vitro models are being developed, improved and adapted in order to study potential mechanisms of lung regeneration in different contexts. This review summarises recent advances in understanding endogenous as well as exogenous regeneration and the development of in vitro models for studying regenerative mechanisms., Competing Interests: Conflict of interest: M.C. Melo-Narváez has nothing to disclose. Conflict of interest: J. Stegmayr has nothing to disclose. Conflict of interest: D.E. Wagner reports grants from the Knut and Alice Wallenberg Foundation and the Swedish Research Council, during the conduct of the study; and personal fees from Boehringer Ingelheim, outside the submitted work. In addition, D.E. Wagner has a patent WO2014169111A1 pending. Conflict of interest: M. Lehmann reports grants from The German Federal Institute for Risk Assessment (BfR), during the conduct of the study., (Copyright ©ERS 2020.)

In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine., Competing Interests: Conflict of interest: N.D. Ubags has nothing to disclose. Conflict of interest: J. Baker has nothing to disclose. Conflict of interest: A. Boots has nothing to disclose. Conflict of interest: R. Costa has nothing to disclose. Conflict of interest: N. El-Merhie has nothing to disclose. Conflict of interest: A. Fabre has nothing to disclose. Conflict of interest: A. Faiz has nothing to disclose. Conflict of interest: I.H. Heijink has nothing to disclose. Conflict of interest: P.S. Hiemstra has nothing to disclose. Conflict of interest: M. Lehmann has nothing to disclose. Conflict of interest: S. Meiners has nothing to disclose. Conflict of interest: S. Rolandsson Enes reports an ERS/EU Marie-Curie Post-doctoral Research Fellowship (RESPIRE3) during the writing of this article. Conflict of interest: S. Bartel reports grants and personal fees from Bencard Allergie GmbH outside the submitted work., (Copyright ©ERS 2020.)

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor prognosis and limited therapeutic options. The incidence of IPF increases with age, and ageing-related mechanisms such as cellular senescence have been proposed as pathogenic drivers. The lung alveolar epithelium represents a major site of tissue injury in IPF and senescence of this cell population is probably detrimental to lung repair. However, the potential pathomechanisms of alveolar epithelial cell senescence and the impact of senolytic drugs on senescent lung cells and fibrosis remain unknown. Here we demonstrate that lung epithelial cells exhibit increased P16 and P21 expression as well as senescence-associated β-galactosidase activity in experimental and human lung fibrosis tissue and primary cells.Primary fibrotic mouse alveolar epithelial type (AT)II cells secreted increased amounts of senescence-associated secretory phenotype (SASP) factors in vitro , as analysed using quantitative PCR, mass spectrometry and ELISA. Importantly, pharmacological clearance of senescent cells by induction of apoptosis in fibrotic ATII cells or ex vivo three-dimensional lung tissue cultures reduced SASP factors and extracellular matrix markers, while increasing alveolar epithelial markers . These data indicate that alveolar epithelial cell senescence contributes to lung fibrosis development and that senolytic drugs may be a viable therapeutic option for IPF., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)