Tetsutaro Nagaoka

Background and Objective: The progression of pulmonary arterial hypertension (PAH) is associated with pulmonary artery (PA) remodelling by M2 macrophages through excessive tissue repair, although some M2 macrophages have a vascular protective role. A quality and quantity culture method (MNC‐QQc) increases the number of M2 macrophages in mononuclear cells (MNCs) from peripheral blood. Several studies demonstrate that MNC‐QQc has vascular protective effects in ischemic lesions. This study aimed to investigate whether MNC‐QQc transplantation ameliorates PAH development in a rat model. Methods: MNC‐QQc extracted from GFP positive donor rats were administered into recipient rats with PAH via the cervical vein. Pulmonary haemodynamics and PA remodelling were assessed. Immunohistochemistry and flow cytometry analysis were performed to identify the donor‐derived MNC‐QQc cell types in the lungs. The effects of MNC‐QQc on the functions of vascular constituent cells were evaluated, and gene expression related to the pathological abnormalities in PA was assessed using microarray analysis. Results: MNC‐QQc transplantation reversed the PAH‐induced pulmonary haemodynamics and PA remodelling. GFP‐positive MNC‐QQc cells, predominantly CD14‐positive M2 macrophages, were found around the recipient's PAs. The therapeutic effect was reduced in MNC‐QQc without M2 cells. MNC‐QQc also enhanced angiogenesis in pulmonary endothelial cells. Microarray analysis of the lung tissue showed that MNC‐QQc decreased the expression of Tachykinin Receptor 1, associated with PAH progression, with this reduction linked to CD14‐ and CD163‐positive M2 macrophages. Conclusions: These findings suggest that MNC‐QQc, particularly through CD14‐ and CD163‐positive M2 macrophages, could be a novel treatment for PAH.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare diffuse lung disease that is strongly associated with cigarette smoking, with the BRAF V600E mutation identified in approximately half of all cases. In Japan, combination therapy with BRAF and MEK inhibitors has recently been approved as an alternative treatment option. We report the case of a 30‐year‐old woman diagnosed with BRAF V600E–mutant PLCH who was treated with dabrafenib in combination with trametinib. Chest computed tomography performed 3 months after the initiation of therapy demonstrated improvement in pericystic opacities, and this radiological response was sustained for over 1 year. Improvements in exercise tolerance, pulmonary function, and pulmonary haemodynamics have been observed clinically. These findings suggest that dabrafenib plus trametinib is a promising therapeutic option for patients with PLCH.

Pulmonary hypertension (PH) associated with interstitial pneumonia (IP) has a poor prognosis, and lung transplantation (LT) is the only effective treatment option for severe cases. However, the waiting period for LT often exceeds the median survival time in these patients, and the effectiveness of pulmonary vasodilators during this period is not well established. In Case 1, a patient with scleroderma‐related IP and PH was treated with sildenafil, which resulted in improved PH and successful single‐lung transplantation. In Case 2, a patient with rheumatoid arthritis‐related IP and PH was treated with tadalafil and macitentan, leading to successful single‐lung transplantation. These cases suggest that pulmonary vasodilators may be valuable bridging therapies for patients with PH associated with IP who are awaiting LT.

Benralizumab treatment reduces exacerbations and improves symptom control and quality of life in patients with severe eosinophilic asthma. However, the determination of biomarkers that predict therapeutic effectiveness is required for precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical effectiveness after 1 year of benralizumab treatment in severe asthma in a real-world setting. Thirty-six patients with severe asthma were treated with benralizumab for 1 year. Lymphocyte subsets in peripheral blood samples were analyzed using flow cytometry. Treatment effectiveness was determined based on the ACT score, forced expiratory volume in 1 s (FEV1), and the number of exacerbations. Benralizumab provided symptomatic improvement in severe asthma. Benralizumab significantly decreased peripheral blood eosinophil and basophil counts and the frequencies of regulatory T cells (Tregs), and increased the frequencies of Th2 cells. To our knowledge, this is the first study to show benralizumab treatment increasing circulating Th2 cells and decreasing circulating Tregs. Finally, the ROC curve to discriminate patients who achieved clinical effectiveness of benralizumab treatment revealed that the frequency of circulating Th17 cells and FeNO levels might be used as parameters for predicting the real-world response of benralizumab treatment in patients with severe asthma.

Although there is strong evidence that SARS-CoV-2 infection is associated with adverse outcomes in certain ethnic groups, the association of disease severity and risk factors such as comorbidities and biomarkers with racial disparities remains undefined. This retrospective study between March 2020 and February 2021 explores COVID-19 risk factors as predictors for patients’ disease progression through country comparison. Disease severity predictors in Germany and Japan were cardiovascular-associated comorbidities, dementia, and age. We adjusted age, sex, body mass index, and history of cardiovascular disease comorbidity in the country cohorts using a propensity score matching (PSM) technique to reduce the influence of differences in sample size and the surprisingly young, lean Japanese cohort. Analysis of the 170 PSM pairs confirmed that 65.29% of German and 85.29% of Japanese patients were in the uncomplicated phase. More German than Japanese patients were admitted in the complicated and critical phase. Ethnic differences were identified in patients without cardiovascular comorbidities. Japanese patients in the uncomplicated phase presented a suppressed inflammatory response and coagulopathy with hypocoagulation. In contrast, German patients exhibited a hyperactive inflammatory response and coagulopathy with hypercoagulation. These differences were less pronounced in patients in the complicated phase or with cardiovascular diseases. Coagulation/fibrinolysis-associated biomarkers rather than inflammatory-related biomarkers predicted disease severity in patients with cardiovascular comorbidities: platelet counts were associated with severe illness in German patients. In contrast, high D-dimer and fibrinogen levels predicted disease severity in Japanese patients. Our comparative study indicates that ethnicity influences COVID-19-associated biomarker expression linked to the inflammatory and coagulation (thrombo-inflammatory) response. Future studies will be necessary to determine whether these differences contributed to the less severe disease progression observed in Japanese COVID-19 patients compared with those in Germany.

Allergen immunotherapy is a promising treatment for allergic diseases that induce immune tolerance through the administration of specific allergens. In this study, we investigate the efficacy of sublingual immunotherapy (SLIT) in asthmatic patients with SAR-JCP and the dynamics of the parameters before and after treatment in a real-world setting. This was a prospective single-center observational study. Patients with asthma and SAR-JCP (n = 24) were recruited for this study and assessed using symptom questionnaires before SLIT and a year after the SLIT. In addition, a respiratory function test, forced oscillation technique, and blood sampling test were performed during the off-season before and after SLIT. The one-year SLIT for asthma patients with SAR-JCP significantly improved not only allergic rhinitis symptoms, but also asthma symptoms during the JCP dispersal season, and significantly improved airway resistance during the off-season. The change in the asthma control test and the visual analog scale score during the season before and after SLIT was negatively and positively correlated with the change in peripheral blood γδ T cells off-season before and after SLIT, respectively. It was suggested that improvement in asthma symptoms during the JCP dispersal season after SLIT was associated with reduced peripheral blood γδ T cells.

Background and objective: Remodelling of pulmonary arteries (PA) contributes to the progression of pulmonary hypertension (PH). Periostin, a matricellular protein, has been reported to be involved in the development of PH. We examined the role of periostin in the pathogenesis of PH using different types of experimental PH.Methods: PH was induced by vascular endothelial growth factor receptor antagonist (Sugen5416) plus hypoxic exposure (SuHx) and venous injection of monocrotaline‐pyrrole (MCT‐P) in wild‐type (WT) and periostin^−/− mice. Pulmonary haemodynamics, PA remodelling, expression of chemokines and fibroblast growth factor (FGF)‐2, accumulation of macrophages to small PA and the right ventricle (RV) were examined in PH‐induced WT and periostin^−/− mice. Additionally, the role of periostin in the migration of macrophages, human PA smooth muscle (HPASMCs) and endothelial cells (HPMVECs) was investigated.Results: In PH induced by SuHx and MCT‐P, PH and accumulation of M2 macrophage to small PA were attenuated in periostin^−/− mice. PA remodelling post‐SuHx treatment was also mild in periostin^−/− mice compared to WT mice. Expression of macrophage‐associated chemokines and FGF‐2 in lung tissue, and accumulation of CD68‐positive cells in the RV were less in SuHx periostin^−/− than in SuHx WT mice. Periostin secretion in HPASMCs and HPMVECs was enhanced by transforming growth factor‐β. Periostin also augmented macrophage, HPASMCs and HPMVECs migration. Separately, serum periostin levels were significantly elevated in patients with PH compared to healthy controls.Conclusion: Periostin is involved in the development of different types of experimental PH, and may also contribute to the pathogenesis of human PH.