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Background: COPD is an incurable disease and a leading cause of death worldwide. In mice, fibroblast growth factor (FGF)10 is essential for lung morphogenesis, and in humans, polymorphisms in the human FGF10 gene correlate with an increased susceptibility to develop COPD., Methods: We analysed FGF10 signalling in human lung sections and isolated cells from healthy donor, smoker and COPD lungs. The development of emphysema and PH was investigated in Fgf10 +/- and Fgfr2b +/- (FGF receptor 2b) mice upon chronic exposure to cigarette smoke. In addition, we overexpressed FGF10 in mice following elastase- or cigarette smoke-induced emphysema and pulmonary hypertension (PH)., Results: We found impaired FGF10 expression in human lung alveolar walls and in primary interstitial COPD lung fibroblasts. In contrast, FGF10 expression was increased in large pulmonary vessels in COPD lungs. Consequently, we identified impaired FGF10 signalling in alveolar walls as an integral part of the pathomechanism that leads to emphysema and PH development: mice with impaired FGF10 signalling ( Fgf10 +/- and Fgfr2b +/- ) spontaneously developed lung emphysema, PH and other typical pathomechanistic features that generally arise in response to cigarette smoke exposure., Conclusion: In a therapeutic approach, FGF10 overexpression successfully restored lung alveolar and vascular structure in mice with established cigarette smoke- and elastase-induced emphysema and PH. FGF10 treatment triggered an initial increase in the number of alveolar type 2 cells that gradually returned to the basal level when the FGF10-mediated repair process progressed. Therefore, the application of recombinant FGF10 or stimulation of the downstream signalling cascade might represent a novel therapeutic strategy in the future., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023.)

Background: Electronic cigarette (e-cigarette) vapour is gaining popularity as an alternative to tobacco smoking and can induce acute lung injury. However, the specific role of nicotine in e-cigarette vapour and its long-term effects on the airways, lung parenchyma and vasculature remain unclear., Results: In vitro exposure to nicotine-containing e-cigarette vapour extract (ECVE) or to nicotine-free e-cigarette vapour extract (NF ECVE) induced changes in gene expression of epithelial cells and pulmonary arterial smooth muscle cells (PASMCs), but ECVE in particular caused functional alterations ( e.g. a decrease in human and mouse PASMC proliferation by 29.3±5.3% and 44.3±8.4%, respectively). Additionally, acute inhalation of nicotine-containing e-cigarette vapour (ECV) but not nicotine-free e-cigarette vapour (NF ECV) increased pulmonary endothelial permeability in isolated lungs. Long-term in vivo exposure of mice to ECV for 8 months significantly increased the number of inflammatory cells, in particular lymphocytes, compared to control and NF ECV in the bronchoalveolar fluid (BALF) (ECV: 853.4±150.8 cells·mL -1 ; control: 37.0±21.1 cells·mL -1 ; NF ECV: 198.6±94.9 cells·mL -1 ) and in lung tissue (ECV: 25.7±3.3 cells·mm -3 ; control: 4.8±1.1 cells·mm -3 ; NF ECV: 14.1±2.2 cells·mm -3 ). BALF cytokines were predominantly increased by ECV. Moreover, ECV caused significant changes in lung structure and function ( e.g. increase in airspace by 17.5±1.4% compared to control), similar to mild tobacco smoke-induced alterations, which also could be detected in the NF ECV group, albeit to a lesser degree. In contrast, the pulmonary vasculature was not significantly affected by ECV or NF ECV., Conclusions: NF ECV components induce cell type-specific effects and mild pulmonary alterations, while inclusion of nicotine induces significant endothelial damage, inflammation and parenchymal alterations., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)

Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO-cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways, e.g. related to matrix metalloproteinases (MMPs). MMP activity was decreased in vivo by riociguat. In PH-COPD patients treated with riociguat (n=7), the pulmonary vascular resistance, airway resistance and circulating MMP levels decreased, while oxygenation at rest was not significantly changed.Riociguat may be beneficial for treatment of PH-COPD. Further long-term prospective studies are necessary to investigate the tolerability, efficacy on functional parameters and effect specifically on pulmonary emphysema in COPD patients., Competing Interests: Conflict of interest: A. Pichl has nothing to disclose. Conflict of interest: N. Sommer has nothing to disclose. Conflict of interest: M. Bednorz has nothing to disclose. Conflict of interest: M. Seimetz has nothing to disclose. Conflict of interest: S. Hadzic has nothing to disclose. Conflict of interest: S. Kuhnert reports nonfinancial (travel) support from Teva, Bayer and Astellas, personal fees for advisory board work from Chiesi, personal fees for advisory board work and nonfinancial (travel) support from GSK, personal fees for advisory board work, honoraria and nonfinancial (travel) support from Novartis, honoraria from Berlin-Chemie Menarini and AstraZeneca, outside the submitted work. Conflict of interest: S. Kraut has nothing to disclose. Conflict of interest: E.T. Roxlau has nothing to disclose. Conflict of interest: B. Kojonazarov has nothing to disclose. Conflict of interest: J. Wilhelm has nothing to disclose. Conflict of interest: M. Gredic has nothing to disclose. Conflict of interest: H. Gall reports grants and personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen Cilag, Lilly, MSD, Novartis, Pfizer, and United Therapeutics/OMT, outside the submitted work. Conflict of interest: K. Tello has nothing to disclose. Conflict of interest: M.J. Richter reports grants from United Therapeutics, grants and personal fees for consultancy and lecturing from Bayer, personal fees for lecturing from Actelion, Mundipharma, Roche and OMT, outside the submitted work. Conflict of interest: O. Pak has nothing to disclose. Conflict of interest: A. Petrovic has nothing to disclose. Conflict of interest: M. Hecker has nothing to disclose. Conflict of interest: R.T. Schermuly has nothing to disclose. Conflict of interest: F. Grimminger has nothing to disclose. Conflict of interest: W. Seeger has received honoraria for consultant activities from Bayer, United Therapeutics and Liquidia, outside the submitted work. Conflict of interest: H.A. Ghofrani reports personal fees for advisory board work from Actelion, Bayer, GSK, Novartis and Pfizer, personal fees for consultancy from Actelion, Bayer, GSK, MSD, Novartis and Pfizer, personal fees for lecturing from Actelion, Bayer, GSK, Novartis and Pfizer, personal fees for meeting attendance from Actelion, Bayer, GSK, MSD, Novartis and Pfizer, and grants from Deutsche Forschungsgemeinschaft (DFG), outside the submitted work. Conflict of interest: N. Weissmann has nothing to disclose., (Copyright ©ERS 2019.)