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Backgound Alveolar type 2 (AT2) cells play important roles in maintaining adult lung homeostasis. AT2 cells isolated from the lung have revealed the cell-specific functions of AT2 cells. Comprehensive molecular and transcriptional profiling of purified AT2 cells would be helpful for elucidating the underlying mechanisms of their cell-specific functions. To enable the further purification of AT2 cells, we aimed to discriminate AT2 cells from non-AT2 lung epithelial cells based on surface antigen expression via fluorescence activated cell sorting (FACS). Methods Single-cell suspensions obtained from enzymatically digested murine lungs were labeled for surface antigens (CD45/CD31/epithelial cell adhesion molecule (EpCAM)/ major histocompatibility complex class II (MHCII)) and for pro-surfactant protein C (proSP-C), followed by FACS analysis for surface antigen expression on AT2 cells. AT2 cells were sorted, and purity was evaluated by immunofluorescence and FACS. This newly developed strategy for AT2 cell isolation was validated in different strains and ages of mice, as well as in a lung injury model. Results FACS analysis revealed that EpCAM + epithelial cells existed in 3 subpopulations based on EpCAM and MHCII expression: EpCAM med MHCII + cells (Population1:P1), EpCAM hi MHCII − cells (P2), and EpCAM low MHCII − cells (P3). proSP-C + cells were enriched in P1 cells, and the purity values of the sorted AT2 cells in P1 were 99.0% by immunofluorescence analysis and 98.0% by FACS analysis. P2 cells were mainly composed of ciliated cells and P3 cells were composed of AT1 cells, respectively, based on the gene expression analysis and immunofluorescence. EpCAM and MHCII expression levels were not significantly altered in different strains or ages of mice or following lipopolysaccharide (LPS)-induced lung injury. Conclusions We successfully classified murine distal lung epithelial cells based on EpCAM and MHCII expression. The discrimination of AT2 cells from non-AT2 epithelial cells resulted in the isolation of pure AT2 cells. Highly pure AT2 cells will provide accurate and deeper insights into the cell-specific mechanisms of alveolar homeostasis.

BackgroundThere is considerable heterogeneity among patients with emphysematous chronic obstructive pulmonary disease (COPD). We hypothesised that in addition to emphysema severity, ventilation distribution in emphysematous regions would be associated with clinical-physiological impairments in these patients.ObjectiveTo evaluate whether the discordance between respiratory volume change distributions (from expiration to inspiration) in emphysematous and non-emphysematous regions affects COPD outcomes using two cohorts.MethodsEmphysema was quantified using a low attenuation volume percentage on inspiratory CT (iLAV%). Local respiratory volume changes were calculated using non-rigidly registered expiratory/inspiratory CT. The Ventilation Discordance Index (VDI) represented the log-transformed Wasserstein distance quantifying discordance between respiratory volume change distributions in emphysematous and non-emphysematous regions.ResultsPatients with COPD in the first cohort (n=221) were classified into minimal emphysema (iLAV% <10%; n=113) and established emphysema with high VDI and low VDI groups (n=46 and 62, respectively). Forced expiratory volume in 1 s (FEV1) was lower in the low VDI group than in the other groups, with no difference between the high VDI and minimal emphysema groups. Higher iLAV%, more severe airway disease and hyperventilated emphysematous regions in the upper-middle lobes were independently associated with lower VDI. The second cohort analyses (n=93) confirmed these findings and showed greater annual FEV1 decline and higher mortality in the low VDI group than in the high VDI group independent of iLAV% and airway disease on CT.ConclusionLower VDI is associated with severe airflow limitation and higher mortality independent of emphysema severity and airway morphological changes in patients with emphysematous COPD.

In patients with chronic obstructive pulmonary disease (COPD), emphysema, airway disease, and extrapulmonary comorbidities may cause various symptoms and impair physical activity. To investigate the relative associations of pulmonary and extrapulmonary manifestations with physical activity in symptomatic patients, this study enrolled 193 patients with COPD who underwent chest inspiratory/expiratory CT and completed COPD assessment test (CAT) and the Life-Space Assessment (LSA) questionnaires to evaluate symptom and physical activity. In symptomatic patients (CAT ≥ 10, n = 100), emphysema on inspiratory CT and air-trapping on expiratory CT were more severe and height-adjusted cross-sectional areas of pectoralis muscles (PM index) and adjacent subcutaneous adipose tissue (SAT index) on inspiratory CT were smaller in those with impaired physical activity (LSA < 60) than those without. In contrast, these findings were not observed in less symptomatic patients (CAT < 10). In multivariable analyses of the symptomatic patients, severe air-trapping and lower PM index and SAT index, but not CT-measured thoracic vertebrae bone density and coronary artery calcification, were associated with impaired physical activity. These suggest that increased air-trapping and decreased skeletal muscle and subcutaneous adipose tissue quantity are independently associated with impaired physical activity in symptomatic patients with COPD.

Abnormal enlargement of the alveolar spaces is a hallmark of conditions such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. Notch signaling is crucial for differentiation and regeneration and repair of the airway epithelium. However, how Notch influences the alveolar compartment and integrates this process with airway development remains little understood. Here we report a prominent role of Notch signaling in the epithelial–mesenchymal interactions that lead to alveolar formation in the developing lung. We found that alveolar type II cells are major sites of Notch2 activation and show by Notch2-specific epithelial deletion (Notch2cNull ) a unique contribution of this receptor to alveologenesis. Epithelial Notch2 was required for type II cell induction of the PDGF-A ligand and subsequent paracrine activation of PDGF receptor-α signaling in alveolar myofibroblast progenitors. Moreover, Notch2 was crucial in maintaining the integrity of the epithelial and smooth muscle layers of the distal conducting airways. Our data suggest that epithelial Notch signaling regulates multiple aspects of postnatal development in the distal lung and may represent a potential target for intervention in pulmonary diseases.

Chronic respiratory failure (CRF) is a critical complication in patients with chronic obstructive pulmonary disease (COPD) and is characterized by an increase in the arterial-alveolar oxygen gradient (A-aDO2). The long-term trajectory and prognostic significance remain unclear. This study aimed to assess the prognostic impact of A-aDO2 and elucidate its trajectory over ten years. We enrolled 170 outpatients with COPD from a prospective cohort study. Arterial blood gas (ABG) analyses were conducted annually for ten years while monitoring the development of CRF. 157 patients completed the observation period, of whom 21 developed CRF (CRF group) and 136 did not (non-CRF group). In the CRF group, there was a gradual increase in A-aDO2 along with decreases in partial pressure of oxygen (PaO2) and partial pressure of carbon dioxide (PaCO2) over ten years, although there were no changes in the non-CRF group. The CRF group had higher baseline A-aDO2 and higher ΔA-aDO2 in the first year than the non-CRF group (3.76 vs. 0.42 Torr/year, p = 0.030). Kaplan-Meier analyses, and multivariate Cox proportional hazards analysis revealed that both baseline A-aDO2 and ΔA-aDO2 were significantly associated with the development of CRF. Retrospective tracking from the initiation of long-term oxygen therapy (LTOT) revealed significant increases in A-aDO2 from 5 years prior to LTOT initiation in the CRF group when compared to the non-CRF group. An increasing trend in A-aDO2 may be a significant sign for the future development of CRF. A transition of the annual change of A-aDO2 from a stable state to a deterioration phase can serve as a prognostic factor for developing CRF within 5 years.

This study characterizes the optimal regulation of risky activities when the assessment of the probability of an accident is subjective. The optimism of stakeholders forms subjective risk perceptions, which substantially affect the optimal intervention. To explore this issue, we construct a moral hazard model with a limited liability constraint, where stakeholders have heterogeneous beliefs about the probability of an accident. First, we show that the optimism of a monopolist reduces the level of the preventive effort when regulatory instruments are fixed. We then analyze the case in which the regulator can set both a fine and a product price as regulatory instruments. The optimal product price increases with the monopolist’s degree of optimism, as the loose product market regulation encourages the preventive effort of the optimistic monopolist. Consequently, under such an optimal scheme, an increase in the optimism of the monopolist may increase the level of preventive effort.

J-PARC, the Japan Proton Accelerator Research Complex, is an accelerator, which provides a high-intensity proton beam. Recently as a very attractive project, the acceleration of heavy ions produced by supplementary ion sources, called J-PARC-HI , is seriously contemplated by domestic as well as international communities. The planned facility would accelerate heavy ions up to U 92+ with a beam energy 20 AGeV ([see formula in PDF] of 6.2 AGeV). The highlight of the J-PARC-HI project is its very high beam rate up to ~10 11 Hz, which will enable the study of very rare events. Taking advantage of this high intensity, J-PARC-HI will carry out frontier studies of new and rare observables in this energy region: (i) nuclear medium modification of chiral property of vector mesons through low-mass di-lepton signal, (ii) QCD critical pointcharacterization through event-by-event fluctuation signals of particle production, (iii) systematic measurements related to the equation of state through collective flow signal or two-particle momentum correlation signal, or (iv) the search of hyper nuclei with multi strangeness including or exceeding S = 3. The current plan of J-PARC-HI aims to carrying out the first experimental measurements in 2025.

PurposeLate-onset noninfectious pulmonary complications (LONIPCs) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are fatal, and lung transplantation is the only curative treatment. Although lung transplantation for LONIPCs may confer good survival rates, it is unclear whether or how impaired physical functioning is restored. Thus, this study aimed to investigate the long-term course and associated changes in physical functions after lung transplantation in patients with LONIPCs after allo-HSCT.MethodsThis prospective cohort study enrolled 15 patients who received lung transplantation for LONIPCs after allo-HSCT between 2012 and 2018. Dyspnea scores, performance status, physical function, and exercise tolerance were assessed before lung transplantation and up to 2 years after transplantation.ResultsTwo years after lung transplantation, the dyspnea scores and performance status improved, but did not recover completely. Physical function was assessed using the knee extensor strength (KES) and 6-min walk test (6MWT); the results were poor until 3 months after transplantation but improved over 2 years. The 6MWT distance showed improvement to a nearly healthy level (562.7 m). Recovery of exercise tolerance was associated with recovery in % vital capacity (%VC; r=0.5) and KES (r=0.4) from 3 months to 2 years after lung transplantation. Furthermore, a flat thorax, which is a characteristic of patients with LONIPCs, affected the %VC at 2 years after transplantation (r=0.8).ConclusionLung transplantation for LONIPCs may restore impaired physical function. A multifaceted rehabilitation program should be considered, especially to improve muscle weakness and pulmonary function.

Epithelial dysfunction in the small airways may cause the development of emphysema in chronic obstructive pulmonary disease. C/EBPα (CCAAT/enhancer binding protein-α), a transcription factor, is required for lung maturation during development, and is also important for lung homeostasis after birth, including the maintenance of serine protease/antiprotease balance in the bronchiolar epithelium. This study aimed to show the roles of C/EBPα in the distal airway during chronic cigarette smoke exposure in mice and in the small airways in smokers. In a model of chronic smoke exposure using epithelial cell-specific C/EBPα-knockout mice, significant pathological phenotypes, such as higher protease activity, impaired ciliated cell regeneration, epithelial cell barrier dysfunction via reduced zonula occludens-1 (Zo-1), and decreased alveolar attachments, were found in C/EBPα-knockout mice compared with control mice. We found that Spink5 (serine protease inhibitor kazal-type 5) gene (encoding lymphoepithelial Kazal-type-related inhibitor [LEKTI], an anti-serine protease) expression in the small airways is a key regulator of protease activity in this model.