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Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury. However, much less is known about their function in lung disease. In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease.

Background: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported., Research Question: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?, Study Design and Methods: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum)., Results: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m 2 ), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively., Interpretation: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling., Objective: To report safety and efficacy results from enrolled participants with available data from CLAVIER., Methods: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm 2 of basement membrane (cells/mm 2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling., Results: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm 2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV 1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies., Conclusions & Clinical Relevance: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling., Clinical Trial Registration: NCT02099656., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

As burden of chronic respiratory diseases is constantly increasing, improving in vitro lung models is essential in order to reproduce as closely as possible the complex pulmonary architecture, responsible for oxygen uptake and carbon dioxide clearance. The study of diseases that affect the respiratory system has benefited from in vitro reconstructions of the respiratory epithelium with inserts in air/liquid interface (2D) or in organoids able to mimic up to the arborescence of the respiratory tree (3D). Recent development in the fields of pluripotent stem cells-derived organoids and genome editing technologies has provided new insights to better understand pulmonary diseases and to find new therapeutic perspectives., (© 2020 médecine/sciences – Inserm.)

Options to achieve oral corticosteroid (OCS)-sparing have been triggering increasing interest since the 1970s because of the side-effects of OCSs, and this has now become achievable with biologics. The Société de Pneumologie de Langue Française workshop on OCSs aimed to conduct a comprehensive review of the basics for OCS use in asthma and issue key research questions. Pharmacology and definition of regular use were reviewed by the first working group (WG1). WG2 examined whether regular OCS use is associated with T2 endotype. WG3 reported on the specificities of the paediatric area. Key "research statement proposals" were suggested by WG4. It was found that the benefits of regular OCS use in asthma outside episodes of exacerbations are poorly supported by the existing evidence. However, complete OCS elimination couldn't be achieved in any available studies for all patients and the panel felt that it was too early to conclude that regular OCS use could be declared criminal. Repeated or prolonged need for OCS beyond 1 g·year -1 should indicate the need for referral to secondary/tertiary care. A strategic sequential plan aiming at reducing overall exposure to OCS in severe asthma was then held as a conclusion of the workshop., Competing Interests: Conflict of interest: A. Bourdin reports institutional fees for board membership from AstraZeneca, Novartis, GSK, Boehringer Ingelheim, Chiesi, Actelion, Pfizer and Teva, outside the submitted work. Conflict of interest: I. Adcock reports grants from EU-IMI, during the conduct of the study. Conflict of interest: P. Berger reports non-financial support from AstraZeneca, during the conduct of the study; personal fees and non-financial support from AstraZeneca, Sanofi, Circassia and Menarini grants, personal fees and non-financial support from Boehringer Ingelheim, and grants and personal fees from Novartis, outside the submitted work. Conflict of interest: P. Bonniaud reports personal fees and other from Roche, Boehringer, Novartis, personal fees from TEVA and AstraZeneca, and other from Chiesi and Stallergene, outside the submitted work. Conflict of interest: P. Chanson has nothing to disclose. Conflict of interest: C. Chenivesse reports grants and personal fees from AstraZeneca and Novartis, and personal fees from AIR LIQUIDE, ALK Abello, Boehringher Ingelheim, Chiesi, GSK, Sanofi and Teva, outside the submitted work. Conflict of interest: J. de Blic reports institutional fees for board membership from GSK, Boehringer Ingelheim, AstraZeneca, Novartis, Chiesi and Stallergenes, outside the submitted work. Conflict of interest: A. Deschildre reports personal fees from Novartis, TEVA, Stallergenes Greer, AImmune, Zambon, personal fees and other from ALK, GSK, Chiesi, AstraZeneca and DBV technologies, outside the submitted work. Conflict of interest: P. Devillier reports personal fees and non-financial support from AstraZeneca and Boehringer Ingelheim, and personal fees from Chiesi, GlaxoSmithKline, Novartis and Sanofi, outside the submitted work. Conflict of interest: G. Devouassoux reports personal fees from GSK, Astra Zeneca and Novartis, during the conduct of the study. Conflict of interest: A. Didier reports institutional fees for board membership from AstraZeneca, Novartis, GSK, Boehringer Ingelheim, Chiesi and Menarini, outside the submitted work. Conflict of interest: G. Garcia reports institutional fees for board membership from AstraZeneca, Novartis, GSK, Boehringer Ingelheim, Chiesi, Actelio, Pfizer and Teva, outside the submitted work. Conflict of interest: A. Magnan has nothing to disclose. Conflict of interest: Y. Martinat reports institutional fees for board membership from AstraZeneca, Novartis, GSK, Boehringer Ingelheim, Chiesi, Actelio, Pfizer and Teva, outside the submitted work. Conflict of interest: T. Perez reports institutional fees for board membership from Novartis, GSK, Boehringer Ingelheim and Chiesi, grants from AstraZeneca, and fees for travel from Chiesi, AstraZeneca, and Boehringer Ingelheim, outside the submitted work. Conflict of interest: N. Roche reports grants and personal fees from Boehringer Ingelheim, Novartis and Pfizer, and personal fees from Teva, GSK, AstraZeneca, Chiesi, Mundipharma, Sanofi, Sandoz, 3M, Zambon and Trudell, outside the submitted work. Conflict of interest: C. Taillé reports personal fees, non-financial support and other from AstraZeneca and from Novartis, grants, personal fees, non-financial support and other from GSK and Sanofi, and personal fees from Teva, during the conduct of the study. Conflict of interest: P. Val has nothing to disclose. Conflict of interest: P. Chanez reports grants and personal fees from Almirall, Boehringer Ingelheim, ALK, GSK, AstraZeneca, Novartis, Teva and Chiesi, and grants from AMU, outside the submitted work., (Copyright ©ERS 2020.)

Chronic obstructive pulmonary disease (COPD) is characterised by nonreversible proximal bronchial obstruction leading to major respiratory disability. However, patient phenotypes better capture the heterogeneously reported complaints and symptoms of COPD. Recent studies provided evidence that classical bronchial obstruction does not properly reflect respiratory disability, and symptoms now form the new paradigm for assessment of disease severity and guidance of therapeutic strategies. The aim of this review was to explore pathways addressing COPD pathogenesis beyond proximal bronchial obstruction and to highlight innovative and promising tools for phenotyping and bedside assessment. Distal small airways imaging allows quantitative characterisation of emphysema and functional air trapping. Micro-computed tomography and parametric response mapping suggest small airways disease precedes emphysema destruction. Small airways can be assessed functionally using nitrogen washout, probing ventilation at conductive or acinar levels, and forced oscillation technique. These tests may better correlate with respiratory symptoms and may well capture bronchodilation effects beyond proximal obstruction.Knowledge of inflammation-based processes has not provided well-identified targets so far, and eosinophils probably play a minor role. Adaptative immunity or specific small airways secretory protein may provide new therapeutic targets. Pulmonary vasculature is involved in emphysema through capillary loss, microvascular lesions or hypoxia-induced remodelling, thereby impacting respiratory disability., Competing Interests: Conflict of interest: T. Capron has nothing to disclose. Conflict of interest: A. Bourdin reports personal fees from Novartis, Sanofi, Genentech and Chiesi Farma, and grants and personal fees from GSK, AstraZeneca and Boeringher Ingelheim, outside the submitted work. Conflict of interest: T. Perez reports personal fees from Novartis, Chiesi and Boehringer Ingelheim, and grants from Astra Zeneca, outside the submitted work. Conflict of interest: P. Chanez reports grants and personal fees from ALK, Almirall, Boehringer Ingelheim, GSK, AstraZeneca, Novartis, TEVA and Chiesi, and grants from AMU, outside the submitted work., (Copyright ©ERS 2019.)

Endobronchial coil treatment (ECT) is a minimally invasive procedure developed for palliative care of patients with severe emphysema. ECT has demonstrated a decrease in hyperinflation, an improvement in quality of life, and an acceptable safety profile in randomized controlled trials (RCTs). Because alpha-1 antitrypsin deficiency (AATD) is a classical exclusion criterion in RCTs, there is no available data for ECT in AATD. In this post hoc analysis of the REVOLENS study (Réduction volumique endobronchique par spirales; ClinicalTrials.gov Identifier: NCT01822795), a multicenter 1:1 RCT which compared bilateral ECT with usual care in severe emphysema, we analyzed the efficacy and safety results at 1 year in six patients with AATD (five males, one female; mean age: 52±9 years) who underwent ECT. A significant decrease in hyperinflation (0.35 L decrease in residual volume [RV]) was observed in four out of six patients at 6 months and three out of six patients at 12 months, and an improvement in quality of life (improvement of 4 points in the St George's Respiratory Questionnaire [SGRQ]) was observed in four out of six patients at both 6 and 12 months. Efficacy results at 6 and 12 months from the six AATD patients were compared with 84 non-AATD patients who underwent ECT, and no statistically significant differences were found for FEV 1 , RV, 6MWT score and SGRQ score. Respiratory-related serious adverse event was limited to pneumonia in one AATD patient at 1 year post-ECT. This post hoc study suggests that AATD patients may have similar efficacy and safety outcomes at 1 year as non-AATD patients. Because of the paucity of available data, appropriately powered studies are needed to determine the effects of ECT in AATD., Competing Interests: Disclosure Gaëtan Deslee has been involved as an investigator in previous studies sponsored by BTG/PneumRx, and received travel reimbursements and speaker fees for educational sessions and consulting from BTG/PneumRx. Hervé Mal received honorarium from Boehringer, Bayer, Roche, Astellas, Chiesi, Actellion, Pfizer, Novartis, and GlaxoSmithKline outside the submitted work. Hervé Dutau received travel reimbursements and speaker fees for educational sessions and consulting from BTG/PneumRx. Arnaud Bourdin received honorarium from Astra Zeneca, GlaxoSmithKline, Boehringer, Novartis, Teva, Chiesi, Actellion, Gilead, and Roche outside the submitted work. Jean Michel Vergnon received travel reimbursements and speaker fees for educational sessions from BTG/PneumRx. Christophe Pison received honorarium from BTG/PneumRx and his hospital received funds to conduct trials from Holaira, PulmonX, and BTG/PneumRx. Charles Hugo Marquette has been involved as an investigator in previous studies sponsored by BTG/PneumRx, and received travel reimbursements and speaker fees for educational sessions and consulting from BTG/PneumRx. The authors report no other conflicts of interest in this work.

Background: The REVOLENS study compared lung volume reduction coil treatment to usual care in patients with severe emphysema at 1 year, resulting in improved quality-adjusted life-year (QALY) and higher costs. Durability of the coil treatment benefit and its cost-effectiveness at 2 years are now assessed., Methods: After one year, the REVOLENS trial's usual care group patients received coil treatment (second-line coil treatment group). Costs and QALYs were assessed in both arms at 2 years and an incremental cost-effectiveness ratio in cost per QALY gained was calculated. The uncertainty of the results was estimated by probabilistic bootstrapping., Results: The average cost of coil treatment in both groups was estimated at €24,356. The average total cost at 2 years was €9655 higher in the first-line coil treatment group (p = 0.07) and the difference in QALY between the two groups was 0.127 (p = 0.12) in favor of first-line coil treatment group. The 2-year incremental cost-effectiveness ratio (ICER) was €75,978 / QALY. The scatter plot of the probabilistic bootstrapping had 92% of the replications in the top right-hand quadrant., Conclusion: First-line coil treatment was more expensive but also more effective than second-line coil treatment at 2 years, with a 2-year ICER of €75,978 / QALY., Trial Registration: ClinicalTrials.gov Identifier NCT01822795 .

Lungs have a complex structure composed of different cell types that form approximately 17 million airway branches of gas-delivering bronchioles connected to 500 million gas-exchanging alveoli. Airways and alveoli are lined by epithelial cells that display a low rate of turnover at steady-state, but can regenerate the epithelium in response to injuries. Here, we review the key points of lung development, homeostasis and epithelial cell plasticity in response to injury and disease, because this knowledge is required to develop new lung disease treatments. Of note, canonical signaling pathways that are essential for proper lung development during embryogenesis are also involved in the pathophysiology of most chronic airway diseases. Moreover, the perfect control of these interconnected pathways is needed for the successful differentiation of induced pluripotent stem cells (iPSC) into lung cells. Indeed, differentiation of iPSC into airway epithelium and alveoli is based on the use of biomimetics of normal embryonic and fetal lung development. In vitro iPSC-based models of lung diseases can help us to better understand the impaired lung repair capacity and to identify new therapeutic targets and new approaches, such as lung cell therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Several protocols have illustrated the possibility of deriving cells, such as fibroblasts, from different organs. These techniques generally concern organs sampled from living persons, but have already been described for cadavers, especially concerning the skin and tendons. We present, for the first time, an easy way to derive pulmonary fibroblasts from a lung tissue sampled from a cadaver and directly culture plated. The fibroblast output was checked daily. We obtained lung fibroblasts from 3 (60%) cadavers and 2 (100%) living persons. The fibroblast output took about 3 days for cells from living persons and took up to 39 days for those from cadavers. We did not clearly identify any parameters that could explain these differences. Nevertheless, these derived cells had the same features as the source cells, especially in terms of morphology and proliferation, and could potentially be used in different research domains such as forensic or regeneration medicine., (© 2017 American Academy of Forensic Sciences.)

The landscape of asthma has considerably changed after 40 years of inhaled corticosteroid development and nearly 20 years since the first monoclonal antibodies (mAbs) were approved. New members of pharmacological families and more effective drug-delivery devices have been designed but the proportion of uncontrolled patients, unfortunately, remains stable. The most promising treatments now rely on targeted therapies that encourage the improvement of the characterisation of our patients. These clinical (phenotype) or new biological (endotype) tools lead to palpable personalised medicine. This review examines not only the future of mAbs and other new ways of treating asthma but also describes futuristic views based on the paradigm shifts that are ready to occur., (Copyright ©ERS 2016.)

Asthma is a chronic inflammatory disorder of the airways that leads to acute symptoms, exacerbations and sometimes, for a small part of the asthmatic population, fatal or near-fatal exacerbations. This as yet significant minority of individuals present with severe asthma and have persisting daily symptoms, and exacerbations despite compliance with high doses of inhaled steroids and additional treatment. For more than a decade, the pharmacological management of patients with severe asthma has focused on evaluating specific cytokines. The rationale of this approach is based on the distinguished key role played by eosinophils in the asthma inflammatory processes. Eosinophils are recruited from the circulation to airways where they cause airway damage via different mechanisms. Eosinophils are regulated in terms of their recruitment, activation, growth, differentiation and survival by interleukin (IL)-5. Abundant data from in vitro experiments, animal models and clinical trials has confirmed that IL-5 inhibition may be an effective approach for the treatment of asthma, especially severe asthma. Interfering with eosinophil function or reducing their numbers has been one of the most important goals of therapeutic monoclonal antibodies, which target cytokine receptor interactions in asthma, particularly IL-5. This review will consider new treatments options for severe asthma, particularly those targeting IL-5, that have already been evaluated in clinical trials in asthmatic patients.

Bronchoalveolar lavage fluid (BALF) provides a source of mucosal CD4(+) T cells. We investigated the physiological properties of T lymphocytes from BALF and blood and their role on the dynamic of HIV-1 replication among AIDS patients with active lung infections. Pulmonary CD4(+) T cells consist mainly of effector memory cells (CD45RO(+) and CCR7(-)) with increased expression of activation markers (HLA-DR(+) and CD69(+)) when compared to the blood counterpart. We observed a high frequency of BALF cells capable of secreting HIV-1-Ags suggesting that the local lung environment may support favorable conditions for CD4(+) T lymphocytes harboring HIV-1 DNA to initiate the viral cycle. Nevertheless, the high number of IFN-γ-producing cells and the predominance of Th1 immune response in the lung could limit the secretion of HIV-1 RNA. In conclusion, the capacity of activated CD4(+) T cells to produce HIV-1 is driven by both the level and quality of cellular activation in the lung., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Severe asthma is characterized by neutrophilic inflammation and high levels of interleukin (IL)-8. Airway epithelial cells play a pivotal role in the pathogenesis and chronicity of asthma. The objective of this work was to determine whether CXC receptors were involved in human small airway epithelial cell (SAEC) activity by incubating them with IL-8; the investigation also included a proteomic approach., Methods: IL-6 and intercellular adhesion molecule-1 (ICAM-1) were assessed by ELISA and flow cytometry, respectively. CXCR-1 and CXCR-2 receptor mRNA and protein expressions were analyzed by RT-PCR, immunocytochemistry and flow cytometry. Cells were incubated with different concentrations (0-100 ng/ml) of IL-8. The involvement of both receptors was assessed using specific antibodies., Results: Only the CXCR-1 receptor was expressed in SAECs. IL-8 (50 ng/ml, 12 h) induced the release of IL-6 and had no effect on ICAM-1. Supernatants analyzed by surface enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) showed very weak differences in peptide profiles. Interestingly, 4,820-m/z peptide release was detected in the presence of IL-8 and abolished by CXCR-1 antibody., Discussion: The present study illustrated the fact that IL-8 mediated by CXCR-1 increased IL-6. We also highlight the usefulness of SELDI ProteinChip technology to confirm the potential variation of peptide profile. Moreover, we were able to detect the 4,820-m/z peptide secreted in vitro by human airway epithelial cells induced by IL-8 via CXCR-1 receptor. Determination of the protein secretion profile in response to inflammatory stimuli could be an important therapeutic strategy in severe asthma., (Copyright 2009 S. Karger AG, Basel.)

BACKGROUND: The forced vital capacity (FVC) of healthy individuals depends on their age, sex, ethnicity and height. Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by loss of FVC. We compared FVC values in the subjects with SSc-ILD in the SENSCIS trial of nintedanib versus placebo with values from hypothetical matched healthy references. METHODS: The SENSCIS trial enrolled subjects with SSc with first non-Raynaud symptom in the prior ≤ 7 years, extent of fibrotic ILD on HRCT ≥ 10%, and FVC ≥ 40% predicted. FVC at baseline and decline in FVC over 52 weeks were compared with FVC values in hypothetical healthy reference subjects matched 1:1 to the subjects in the trial for age, sex, ethnicity and height, determined using equations published by the European Respiratory Society Global Lung Function Initiative. RESULTS: At baseline, mean (SD) FVC was 2460 (737) mL in the nintedanib group (n = 287) compared with 3403 (787) mL in the hypothetical matched healthy references. Mean (SD) FVC was 2544 (817) mL in the placebo group (n = 286) compared with 3516 (887) mL in the hypothetical matched healthy references. Mean (SE) changes in FVC at week 52, i.e., age-related loss of lung function, in the hypothetical healthy references matched to the nintedanib and placebo groups, respectively, were - 26.3 (0.5) mL and - 25.8 (0.5) mL. The difference in the change in FVC at week 52 between the nintedanib group and the hypothetical healthy references was 26.6 mL (95% CI: 1.2, 52.0; p = 0.04). The difference in the change in FVC at week 52 between the placebo group and the hypothetical healthy references was 77.5 mL (95% CI: 51.4, 103.7; p