Metabolic and Epigenetic Regulation of SMAD7 by STC1 Ameliorates Lung Fibrosis.

As shown in our previous studies, the intratracheal-administration of STC1 (stanniocalcin-1) ameliorates pulmonary fibrosis by reducing oxidative and endoplasmic reticulum stress through the uncoupling of respiration in a bleomycin-treated mouse model. However, the overall effect of STC1 on metabolism was not examined. Therefore, we first conducted a comprehensive metabolomics analysis to screen the overall metabolic changes induced by STC1 in an alveolar epithelial cell line using capillary electrophoresis time-of-flight mass spectrometry. The results were subsequently validated in multiple alveolar epithelial and fibroblast cell lines by performing precise analyses of each substance. STC1 stimulated glycolysis, acetyl-CoA synthesis, and the methionine and cysteine-glutathione pathways, which are closely related to the uncoupling of respiration, modulation of epigenetics, and reduction in oxidative stress. These results are consistent with our previous study. Subsequently, we focused on the inhibitory factor SMAD7, which exerts an antifibrotic effect and is susceptible to epigenetic regulation. STC1 upregulates SMAD7 in an uncoupling protein 2-dependent manner, induces demethylation of the SMAD7 promoter region and acetylation of the SMAD7 protein in human alveolar epithelial and fibroblast cell lines and a bleomycin-treated mouse model, and subsequently attenuates fibrosis. The antifibrotic effects of STC1 may partially depend on the regulation of SMAD7. In the evaluation using lung tissue from patients with idiopathic pulmonary fibrosis, SMAD7 expression and acetylation were high in the alveolar structure-preserving region and low in the fibrotic region. The intratracheal administration of STC1 may prevent the development of pulmonary fibrosis by regulating the metabolism-mediated epigenetic modification of SMAD7 in patients.

Technical standards for respiratory oscillometry.

Oscillometry (also known as the forced oscillation technique) measures the mechanical properties of the respiratory system (upper and intrathoracic airways, lung tissue and chest wall) during quiet tidal breathing, by the application of an oscillating pressure signal (input or forcing signal), most commonly at the mouth. With increased clinical and research use, it is critical that all technical details of the hardware design, signal processing and analyses, and testing protocols are transparent and clearly reported to allow standardisation, comparison and replication of clinical and research studies. Because of this need, an update of the 2003 European Respiratory Society (ERS) technical standards document was produced by an ERS task force of experts who are active in clinical oscillometry research.The aim of the task force was to provide technical recommendations regarding oscillometry measurement including hardware, software, testing protocols and quality control.The main changes in this update, compared with the 2003 ERS task force document are 1) new quality control procedures which reflect use of "within-breath" analysis, and methods of handling artefacts; 2) recommendation to disclose signal processing, quality control, artefact handling and breathing protocols (e.g. number and duration of acquisitions) in reports and publications to allow comparability and replication between devices and laboratories; 3) a summary review of new data to support threshold values for bronchodilator and bronchial challenge tests; and 4) updated list of predicted impedance values in adults and children.

Improvement of native pulmonary alveolar proteinosis after contralateral single living-donor lobar lung transplantation: A case report.

PAP is a rare disease characterized by the accumulation of surfactant materials in the alveolar spaces due to the imbalance of surfactant homeostasis (production and clearance). We herein report a case of an 8-year-old girl who developed PAP after BMT from her mother for the treatment of DBA. The anemia was improved by BMT; however, respiratory dysfunction due to graft-versus-host disease gradually progressed. She eventually underwent right single LDLLT from her mother when she was 14 years old. A pathological examination of the excised lung confirmed the finding of diffuse bronchiolitis obliterans and unexpectedly revealed widespread alveolar proteinosis. Interestingly, the GGO of her native left lung on chest X-ray was improved after LDLLT. We present the very unique clinical course of this patient and discuss the mechanisms underlying the development of PAP after BMT and its improvement after LDLLT from the same donor.

Association between Family History of Cancer and Lung Cancer Risk among Japanese Men and Women.

Although cigarette smoking is a major risk factor for lung cancer, genetic susceptibility may also affect lung cancer risk. To explore the role of genetic risk, this case-control study investigated the association between family history of cancer at several sites and lung cancer risk. A total of 1,733 lung cancer cases and 6,643 controls were selected from patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2009. Information on family history of cancer was collected using a self-administered questionnaire and odds ratios (ORs) were estimated by unconditional logistic regression. Family history of lung cancer in first-degree relatives was associated with an increased risk of lung cancer among both sexes. According to histology and type of relatives, a parental history of lung cancer was significantly associated with an increased risk of female adenocarcinoma (OR = 1.72). Stratification by smoking status revealed that this significant positive association in women was limited to ever-smokers (OR = 4.13). In men, a history of lung cancer in siblings was significantly associated with an increased risk of small cell carcinoma (OR = 2.28) and adenocarcinoma (OR = 2.25). Otherwise, positive associations between history of breast (OR = 1.99) and total (OR = 1.71) cancers in siblings and the risk of male adenocarcinoma were observed. These results suggest that inherited genetic susceptibility may contribute to the development of lung cancer. In men, shared exposure to environmental factors among siblings may also be responsible for the increase in lung cancer risk.

Mesenchymal stem cells correct inappropriate epithelial-mesenchyme relation in pulmonary fibrosis using stanniocalcin-1.

Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-ß1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-ß1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum (ER) stress, and TGF-ß1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 (UCP2) and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for IPF.

A STUDY OF INSPIRATORY RESISTANCE OF DRY POWDER INHALER OF AGENTS FOR ASTHMA CONTROL.

OBJECTIVE: Because dry powder inhalers (DPI) aerosolize agents by means of inspiration of patients themselves, inspiratory resistance of DPI is an important factor for increasing inhalation efficiency. Therefore, we measured inspiratory resistance of DPI of agents for asthma control. METHODS: Using Flow/Volume Simulator, when setting flow rates at 6, 30, 60, 90, and 120L/min, we read off suction pressures and find inspiratory resistances by calculation (=suction pressure/flow rate) at each flow rate. RESULTS: In all DPI, inspiratory resistance increases with the increasing flow rate. To maintain flow rate of 60L/min, suction pressure of around 20-cmH2O for Diskus(®) and Ellipta(®), between 35- and 45-cmH2O for Turbuhaler (®), and about 60-cmH2O for Twisthaler(®) were needed. CONCLUSION: It is suggested that we should instruct patients to inhaler DPI based on inspiratory resistance of the DPI.

[Outline of JRS COPD guideline Ed. 4].

JRS COPD guideline Edition 4 updated current concept for clinical management of COPD in Japan. Minor but substantial changes were added to the definition and subtype of the disease. In pharmacological treatment, single use of LAMA or LABA is equally the first choice. If it is not enough, those combination are recommended. A-D classification that was presented in GOLD report 2011 was not adopted. In non-pharmacological treatment, pulmonary rehabilitation is steadily effective and essential. In terms of survival prognosis, at least, the concept of physical activity is important. Those improvement and maintenance were newly added to the objectives of the clinical management of COPD.

Pulmonary function testing in bronchial asthma.

The lung function of asthma is characterized by the following points: - Airflow limitation that reverses after administration of a bronchodilator - Variable airflow limitation Airway hyperresponsiveness, that is, an excessive decrease in airflow in response to an aerosolized provocation that elicits little or no response in a normal person. Airflow limitation from asthma usually demonstrates some degree of reversibility following acute inhalation with a beta-agonist. But patients with mild asthma often do not show this reversibility. Patients can measure peak expiratory flow(PEF) by themselves using a simple device. We can assess the patient's condition by monitoring their PEF. The circadian variation of PEF usually indicates the existence of airway hyperresponsiveness. Airway hyperresponsive- ness is directly measured by bronchoprovocation testing using direct inhalation of meth- acholine or histamine. Indications for bronchoprovocation testing include the accurate diag- nosis of asthma in selected patients, such as patients who do not show airway reversibility, assessment of severity of asthma and assessment of the response to asthma therapy.

Current advances in pulmonary functional imaging.

Recent advances in imaging analysis have enabled evaluation of ventilation and perfusion in specific regions by chest computed tomography (CT) and magnetic resonance imaging (MRI), in addition to modalities including dynamic chest radiography, scintigraphy, positron emission tomography (PET), ultrasound, and electrical impedance tomography (EIT). In this review, an overview of current functional imaging techniques is provided for each modality. Advances in chest CT have allowed for the analysis of local volume changes and small airway disease in addition to emphysema, using the Jacobian determinant and parametric response mapping with inspiratory and expiratory images. Airway analysis can reveal characteristics of airway lesions in chronic obstructive pulmonary disease (COPD) and bronchial asthma, and the contribution of dysanapsis to obstructive diseases. Chest CT is also employed to measure pulmonary blood vessels, interstitial lung abnormalities, and mediastinal and chest wall components including skeletal muscle and bone. Dynamic CT can visualize lung deformation in respective portions. Pulmonary MRI has been developed for the estimation of lung ventilation and perfusion, mainly using hyperpolarized 129Xe. Oxygen-enhanced and proton-based MRI, without a polarizer, has potential clinical applications. Dynamic chest radiography is gaining traction in Japan for ventilation and perfusion analysis. Single photon emission CT can be used to assess ventilation-perfusion (V˙/Q˙) mismatch in pulmonary vascular diseases and COPD. PET/CT V˙/Q˙ imaging has also been demonstrated using "Galligas". Both ultrasound and EIT can detect pulmonary edema caused by acute respiratory distress syndrome. Familiarity with these functional imaging techniques will enable clinicians to utilize these systems in clinical practice.

Phase angle as an indicator of sarcopenia and malnutrition in patients with chronic obstructive pulmonary disease.

BACKGROUND: Phase angle (PhA), which is measured using bioelectrical impedance analysis, is an indicator of muscle quality and malnutrition. PhA has been shown to be correlated with sarcopenia and malnutrition; however, studies on patients with chronic obstructive pulmonary disease (COPD) are limited. In this study, we investigated the correlation between PhA and sarcopenia and malnutrition and determined the cutoff values of PhA for those in patients with COPD. METHODS: This study included 105 male patients with COPD (mean age 75.7 ± 7.7 years, mean forced expiratory volume in 1s % predicted [%FEV1] 57.0 ± 20.1%) and 12 male controls (mean age 74.1 ± 3.8 years) who were outpatients between December 2019 and March 2024. PhA was measured using the InBody S10, and its correlation with sarcopenia and malnutrition was assessed. The cutoff PhA values for sarcopenia and malnutrition were determined using receiver operating characteristic curves. RESULTS: The prevalence rates of sarcopenia and malnutrition were 31% and 22%, respectively, in patients with COPD. PhA significantly correlated with sarcopenia- and malnutrition-related indicators. Multivariate logistic regression analysis independently correlated PhA with sarcopenia and malnutrition. The cutoff values of the PhA for sarcopenia and malnutrition were 4.75° (AUC = 0.78, 95% CI = 0.68-0.88) and 4.25° (AUC = 0.75, 95% CI = 0.63-0.86), respectively. CONCLUSIONS: PhA was significantly correlated with sarcopenia and malnutrition in Japanese patients with COPD and may be a useful diagnostic indicator.

[Evaluation of airway narrowing by MostGraph and spirometry -examination using a reversibility test-].

BACKGROUND AND OBJECTIVE: MostGraph is an apparatus for measuring respiratory resistance and respiratory reactance, using the forced oscillation technique. Because these parameters are measured during tidal breathing of subjects, measuring technique is easy with little burden on subjects. In the present study, we conducted spirometry and MostGraph at the same time and examined the clinical significance of parameters of MostGraph. METHODS: Subjects were 52 out-patients who underwent a reversibility test. Spirometry and MostGraph are simultaneously practiced both before and after short acting ß2 agonist (SABA) inhalation. RESULTS: Between each parameter of both methods before SABA inhalation, we confirmed significant correlations between many indexes of both manners. Above all, the strongest correlation was found between Fres and FEV1. In relationships between the percent changes of each parameter of both techniques by SABA inhalation, we also found a significant correlation between percent change of Fres and that of FEV1. In addition, there was a hyperbolic relation between change in Fres and that in FEV1 by SABA inhalation. CONCLUSION: We confirmed not only that airway narrowing itself significantly correlates with Fres, but also that elastic resistance of respiratory system changes in association with change of airway narrowing. Thus, our findings suggest that the percent change of Fres may provide a diagnostic criterion for a reversibility test in all parameters of MostGraph.

A case report of Indium lung with progressive emphysema and fibrosis underwent lung unilateral transplantation 20 years after the end of the exposure.

BACKGROUND: Indium lung is characterized by interstitial pneumonia and/or emphysema which occurs in indium-tin oxide (ITO) workers. Indium lung is now known to progress after stopping exposure to ITO, but the long-term influences of ITO remain unclear. CASE PRESENTATION: Forty seven years old, a never-smoker, who had been engaged in an ITO manufacturing process for 8 years. Emphysema was indicated by the medical check-up for ex-ITO workers, and he was diagnosed with indium lung. He underwent partial lung resections for pneumothorax two times, and obstructive pulmonary dysfunction had progressed through the years. He underwent right single lung transplant 20 years after ITO exposure. Pathologically, his lung showed severe distal acinar emphysema and honeycomb change. Fibrosis and destruction of the lung tissue significantly progressed compared to the previous partial resections. Scanning electron microscopy combined with energy dispersive spectroscopy revealed that the deposited particles contained indium and tin. After the transplantation, his respiratory function was improved. CONCLUSIONS: In this case, ITO resided in the lung tissue for 20 years, and lung tissue destruction kept progressing. Careful medical follow-up is recommended for ITO-workers even if they are asymptomatic.

Association between Fathers' Use of Heated Tobacco Products and Urinary Cotinine Concentrations in Their Spouses and Children.

Heated tobacco products (HTPs) have become increasingly popular among smokers, especially among young adults in Japan in recent years. Assessments of secondhand tobacco smoke (SHS) exposure due to HTPs are scarce. The present study aimed to assess the urinary levels of total nicotine metabolites (TNMs) of non-smoking spouses and their children following SHS exposure due to their fathers' use of HTPs. A total of 41 families including 129 participants were recruited between 2018 and 2021. The number of non-smoking spouses and children of the fathers who smoke combustion cigarettes, the fathers who use HTPs, and the fathers who are non-users or have never smoked was 27, 66, and 36, respectively. The urinary levels of TNMs, including cotinine (Cot) and 3'-hydroxycotinine (3-OHCot), were measured using liquid chromatography/tandem mass spectrometry (LC/MS/MS). The spouses and children of fathers who use HTPs had significantly higher levels of TNMs in their urine compared to those with fathers who were non-smokers or non-users. The current study is the first to assess SHS exposure due to HTP use, and to suggest the importance of strategies to prevent exposure to SHS from HTP use in public places and educational strategies to protect non-smokers from secondhand HTP aerosol exposure in households and other private places.

A Novel Development of Sarcoidosis Following COVID-19 Vaccination and a Literature Review.

BNT162b2 (Pfizer/BioNTech) is a coronavirus disease 2019 (COVID-19) vaccine containing nucleoside-modified messenger RNA encoding the severe acute respiratory syndrome coronavirus 2 spike glycoprotein. Recently, ocular complications of mRNA vaccines have been reported increasingly frequently. However, immunological adverse events due to mRNA vaccines in real-world settings are not fully known. We herein report the novel development of sarcoidosis manifested as uveitis, bilateral hilar lymphadenopathy, angiotensin-converting enzyme elevation, and epithelioid and giant cell granuloma formation in the lung soon after the first BNT162b2 injection and review the current literature, including three reported cases of sarcoid-like reaction following COVID-19 vaccination.

Clinical significance and applications of oscillometry.

Recently, "Technical standards for respiratory oscillometry" was published, which reviewed the physiological basis of oscillometric measures and detailed the technical factors related to equipment and test performance, quality assurance and reporting of results. Here we present a review of the clinical significance and applications of oscillometry. We briefly review the physiological principles of oscillometry and the basics of oscillometry interpretation, and then describe what is currently known about oscillometry in its role as a sensitive measure of airway resistance, bronchodilator responsiveness and bronchial challenge testing, and response to medical therapy, particularly in asthma and COPD. The technique may have unique advantages in situations where spirometry and other lung function tests are not suitable, such as in infants, neuromuscular disease, sleep apnoea and critical care. Other potential applications include detection of bronchiolitis obliterans, vocal cord dysfunction and the effects of environmental exposures. However, despite great promise as a useful clinical tool, we identify a number of areas in which more evidence of clinical utility is needed before oscillometry becomes routinely used for diagnosing or monitoring respiratory disease.

Time lag between oscillatory pressure and flow affecting accuracy of forced oscillation technique.

BACKGROUND: The forced oscillation technique (FOT) is a simple method for assessing the oscillatory mechanics of the respiratory system. The oscillatory properties, respiratory system resistance (Rrs) and reactance (Xrs), are calculated from the oscillatory pressure/flow relationship. Although the FOT has been a well-established technique, some detailed experimental conditions would be different among institutions. METHODS: We evaluated whether time lags produced by the experimental conditions such as different positions of the sensors can affect the accuracy of the FOT. If the position of the pressure sensor is different from the flow sensor, a time lag may occur in the measurements. The effect of the time lag was studied by numerical analysis. RESULTS: Rrs was estimated to be increased and Xrs decreased with an increase in the time lag, especially at a high oscillatory frequency of the medium-frequency range (5-35 Hz). At the high-frequency range (10-500 Hz), Rrs and Xrs were strikingly different in the values of the time lag. CONCLUSION: A time lag between the oscillatory pressure and flow may be involved in the accuracy of the FOT, suggesting that it needs to be minimized or compensated for with signal processing. Researchers should pay attention to such detailed experimental conditions of the FOT apparatus.

[Successful preoperative respiratory rehabilitation in patients with aortic valve stenosis associated with severe respiratory dysfunction].

We describe 2 cases of aortic valve stenosis with severe pulmonary dysfunction. Preoperative respiratory rehabilitation programmed by the rehabilitation doctors was cautiously undertaken to improve their exercise tolerance and respiratory reserve. These 2 patients underwent aortic valve replacement eventually. Postoperative course in each patient was uneventful without respiratory complication. Preoperative respiratory rehabilitation can be performed in the high risk patient with severe pulmonary dysfunction as long as careful risk management is guaranteed.

[Diagnostic imaging--CT, dynamic CT, and others].

Technical advances have raised computed tomography(CT) as a strong diagnostic tool of clinical imaging. Emphysematous changes can be quantitatively analyzed as low attenuation area which correlated with diffusion capacity, quality of life, and nutritional states, but not so much with forced expiratory volume in one second. With co-analyzing airway wall thickness, those are possibly useful to understand phenotypes. Dynamics of airway during breathing can be visualized by dynamic CT such as electron-beam CT. Dynamic airway narrowing is a representative feature in emphysematous lung.

Questionnaire survey on nurses and speech therapists regarding dysphagia rehabilitation in Japan.

OBJECTIVE: Current interventions of dysphagia are not generalizable, and treatments are commonly used in combination. We conducted a questionnaire survey on nurses and speech therapists regarding dysphagia rehabilitation to understand the current situation in Japan. METHODS: The questionnaire was sent to 616 certified nurses in dysphasia nursing and 254 certified speech-language-hearing therapists for dysphagia. Based on "Summaries of training methods in 2014" by JSDR, 24 local indirect exercises, 11 general indirect exercises, and 13 direct exercises were selected. The Likert scale "How do you feel about each method" was used as follows: A; Frequency, B; Ease, C; Adherence, D; Effectiveness (1-5))?". RESULTS: Two hundred fifty (40%) nurses and 145 (57%) speech-language-hearing therapists (ST) responded to the questionnaire. The direct exercise was associated with a significantly high score in every question. In indirect exercises, "Cervical range of motion exercise," "Orofacial myofunctional exercise," "Lip closure exercise." "Ice massage of pharynx" and "Huffing" were used relatively frequently. "Balloon dilatation therapy" and "Tube exercise" was associated with a relatively high discrepancy for two questions. Frequency" and the sum of "Ease," "Adherence," and "Effectiveness." was significantly correlated for local indirect exercises (r2 = 0.928, P < 0.01), general indirect exercises (r2 = 0.987, P < 0.01), and direct exercises (r2 = 0.996, P < 0.01) (Fig. 5). CONCLUSION: This study examined the current situation of dysphagia rehabilitation in Japan. Our results aid to increase understanding and selection of rehabilitative treatments for dysphagia patients in Japan.

Risk prediction for new-onset atrial fibrillation using the Minnesota code electrocardiography classification system.

BACKGROUND: Few risk models are available to predict future onset of atrial fibrillation (AF) in workers. We aimed to develop risk prediction models for new-onset AF, using annual health checkup (HC) data with electrocardiogram findings. METHODS AND RESULTS: We retrospectively included 56,288 factory or office workers (mean age = 51.5 years, 33.0% women) who underwent a HC at a medical center and fulfilled the following criteria; age ≥ 40 years, no history of AF, and greater than 1 annual follow-up HC in 2013-2016. Using Cox models with the Akaike information criterion, we developed and compared prediction models for new-onset AF with and without the Minnesota code information. We externally validated the discrimination accuracy of the models in a general Japanese population cohort, the Hisayama cohort. During the median 3.0-year follow-up, 209 (0.37%) workers developed AF. Age, sex, waist circumference, blood pressure, LDL cholesterol, and γ-GTP were associated with new-onset of AF. Using the Minnesota code information, the AUC significantly improved from 0.82 to 0.84 in the derivation cohort and numerically improved from 0.78 to 0.79 in the validation cohort, and from 0.77 to 0.79 in the Hisayama cohort. The NRI and IDI significantly improved in all and male subjects in both the derivation and validation cohorts, and in female subjects in both the validation and the Hisayama cohorts. CONCLUSIONS: We developed useful risk model with Minnesota code information for predicting new-onset AF from large worker population validated in the original and external cohorts, although study interpretation is limited by small improvement of AUC.