Cell-Based Therapy for Fibrosing Interstitial Lung Diseases, Current Status, and Potential Applications of iPSC-Derived Cells.

Fibrosing interstitial lung diseases (FILDs), e.g., due to idiopathic pulmonary fibrosis (IPF), are chronic progressive diseases with a poor prognosis. The management of these diseases is challenging and focuses mainly on the suppression of progression with anti-fibrotic drugs. Therefore, novel FILD treatments are needed. In recent years, cell-based therapy with various stem cells has been investigated for FILD, and the use of mesenchymal stem cells (MSCs) has been widely reported and clinical studies are also ongoing. Induced pluripotent stem cells (iPSCs) have also been reported to have an anti-fibrotic effect in FILD; however, these have not been as well studied as MSCs in terms of the mechanisms and side effects. While MSCs show a potent anti-fibrotic effect, the possibility of quality differences between donors and a stable supply in the case of donor shortage or reduced proliferative capacity after cell passaging needs to be considered. The application of iPSC-derived cells has the potential to overcome these problems and may lead to consistent quality of the cell product and stable product supply. This review provides an overview of iPSCs and FILD, followed by the current status of cell-based therapy for FILD, and then discusses the possibilities and perspectives of FILD therapy with iPSC-derived cells.

Tezepelumab improved chronic eosinophilic pneumonia in severe asthma patients with liver cirrhosis.

Systemic administration of corticosteroids is used in the treatment of chronic eosinophilic pneumonia (CEP). However, in patients with CEP as well as other comorbidities, the adverse effects of corticosteroids should be minimized as much as possible. A 71-year-old woman was presented with aggravating asthma with CEP and sinusitis, and she had uncompensated liver cirrhosis (LC) with a Child-Pugh score of 7. Initial treatment with a low dose of oral corticosteroids (OCSs) in combination with tezepelumab, an anti-thymic stromal lymphopoietin (TSLP) antibody, resulted in rapid improvement of asthma and CEP without deteriorating LC. Sinusitis also improved after ceasing OCS. This case suggested that tezepelumab may be useful as a treatment option for patients with CEP, especially those with liver dysfunction.

Pulmonary granulomas confirmed in Blau syndrome using TBLC specimens: Case report.

Blau syndrome (BS), is an autoinflammatory granulomatosis disease characterized by a distinct triad of skin, joint, and eye disorders similar to those of sarcoidosis, but the lung involvement frequently observed in sarcoidosis are rare. Granulomas from patients with BS displayed a distinct morphology indicating an exuberant chronic inflammatory response. Patients with BS may have granulomatous lung lesions, which require early diagnosis. To determine whether therapeutic intervention is needed for lung lesions, examining transbronchial lung cryobiopsy specimens and accumulating cases of BS with lung involvement could be contributed to improving BS management in the future.

Physical Activity and Health of Middle-Aged and Older Japanese Across the COVID-19 Pandemic: Differential Outcomes Highlight a Problematic Life Stage.

INTRODUCTION: COVID-19 caused major disruptions across the super-aged nation of Japan, yet few studies explored temporal changes among middle-aged and older cohorts from baseline to the height of community transmission. Changes in physical activity and sedentary behavior during global pandemics may alter patterns of morbidity and mortality among susceptible aging populations. OBJECTIVES: This study investigated patterns of physical activity, sitting behavior, and health among representative samples of middle-aged and older adults in Tokyo before and during the pandemic. METHODS: Repeated online surveys were conducted with quota samples of 800 Tokyo residents in 2019 and 2021 using validated Japanese-language measures, including the short form-International Physical Activity Questionnaire and the Basic Ecological Health Scale-6. Statistical analyses included comparative evaluations of activity parameters by age cohort, gender, and selected covariates. Statistical tests included the Kruskal-Wallis test, Mann-Whitney U test, chi-square test for Independence and Hierarchical Regression. RESULTS: Over 34% of respondents were inactive at each data collection point, and 72% reported negative impacts of COVID-19 on their physical activities. Older adults showed no significant changes in their activity and sitting behavior and reported better health compared with those in middle age across the pandemic. Middle-aged males reported a significant decline in total activity of 33% across the pandemic period (U = 16,958, z = -2.64, p = .008, r = .13). Middle-aged females reported the lowest levels of physical activity, and health, and showed a 29% increase in sitting behavior across the pandemic (U = 16,925, z = -2.68, p = .007, r = .13). Subjective health status was consistently associated with higher overall activity and walking before and during the pandemic. CONCLUSION: Differential outcomes were identified between age and gender regarding health, physical activity, walking, and sitting across the pandemic with significantly worse impacts reported among middle-aged samples. IMPLICATIONS: These results have implications for healthy transitions to later life and the design of postpandemic interventions to address activity opportunities in Japan.

Potential of MAIT cells to modulate asthma.

Despite recent advances in asthma treatments, the search for novel therapies remains necessary because there are still patients with recurrent asthma exacerbations and poor responses to the existing treatments. Since group 2 innate lymphoid cells (ILC2) play a pivotal role in asthma by triggering and exacerbating type 2 inflammation, controlling ILC2s function is key to combating severe asthma. Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans and are activated both in a T cell receptor-dependent and -independent manner. MAIT cells are composed of MAIT1 and MAIT17 based on the expression of transcription factors T-bet and RORγt, respectively. MAIT cells play pivotal roles in host defense against pathogens and in tissue repair and are essential for the maintenance of immunity and hemostasis. Our recent studies revealed that MAIT cells inhibit both ILC2 proliferation and functions in a mouse model of airway inflammation. MAIT cells may alleviate airway inflammation in two ways, by promoting airway epithelial cell barrier repair and by repressing ILC2s. Therefore, reagents that promote MAIT cell-mediated suppression of ILC2 proliferation and function, or designer MAIT cells (genetically engineered to suppress ILC2s or promote repair of airway damage), may be effective therapeutic agents for severe asthma.

A prospective cohort study of periostin as a serum biomarker in patients with idiopathic pulmonary fibrosis treated with nintedanib.

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

Periostin Is a Biomarker of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Periostin was investigated as a biomarker for rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This prospective study measured serum monomeric and total periostin, Klebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), and lactate dehydrogenase (LDH) in 19 patients with RA-ILD, 20 RA without ILD, and 137 healthy controls (HC). All biomarkers were higher in RA-ILD than HC or RA without ILD. KL-6 accurately detected ILD in RA patients (area under curve [AUC] = 0.939) and moderately detected SP-D and monomeric and total periostin (AUC = 0.803, =0.767, =0.767, respectively). Monomeric and total periostin were negatively correlated with normal lung area and positively correlated with honeycombing, reticulation, fibrosis score, and the traction bronchiectasis grade but not inflammatory areas. Serum levels of SP-D, KL-6, and LDH did not correlate with the extent of those fibrotic areas on high-resolution CT. Serum monomeric and total periostin were higher in patients with RA-ILD with definite usual interstitial pneumonia pattern compared with other ILD patterns. Immunohistochemical analyses of biopsy or autopsy lung tissues from RA-ILD during the chronic phase and acute exacerbation showed that periostin was expressed in fibroblastic foci but not inflammatory or dense fibrosis lesions. Periostin is a potential biomarker for diagnosis, evaluating fibrosis, and deciding therapeutic strategies for patients with RA-ILD.

Changes in Peripheral Blood Eosinophil Counts and Risk of Eosinophilic Granulomatosis with Polyangiitis Onset after Initiation of Dupilumab Administration in Adult Patients with Asthma.

BACKGROUND: The purpose of this study is to clarify the changes in peripheral blood eosinophil (PBE) counts and eosinophilic granulomatosis with polyangiitis (EGPA) onset in patients with asthma who were treated with dupilumab in clinical practice. METHODS: The primary outcome of this study is to determine the onset of EGPA in patients whose PBE counts continued to rise within 6 months of dupilumab initiation (rising group) and in patients whose PBE counts peaked and subsequently declined within 6 months (peaked and declined group). As a secondary outcome, the incidence of developing EGPA in patients with PBE counts greater than 1500 cells/µL at 3 or 6 months after dupilumab administration is investigated. RESULTS: A total of 37 individual were enrolled (male/female = 14/23, median age = 57.0 years old). The development of EGPA was significantly more frequent in the rising group compared with the peaked and declined group (p = 0.042, effect size = 0.455, moderate association). Patients with PBE counts greater than 1500 cells/µL showed a significantly higher risk of developing EGPA (p = 0.017, effect size = 0.678, strong association). CONCLUSIONS: Physicians should check for the onset of EGPA by monitoring the elevation of eosinophils within 6 months after dupilumab administration, especially in patients with PBE counts greater than 1500 cells/µL at 3 months.

Transcutaneous gas monitoring is a useful tool to detect respiratory depression during bronchoscopy performed under propofol sedation.

BACKGROUND: Bronchoscopy is a relatively invasive procedure where patients are often sedated. However, adequate sedation is not always achieved. Propofol is often used for difficult-to-sedate patients undergoing bronchoscopy despite a potential risk of respiratory depression. Transcutaneous carbon dioxide (tcpCO2) monitoring, introduced recently, is recognized as a convenient surrogate method for continuous monitoring of the partial pressure of arterial carbon dioxide (PaCO2). This study examined the safety of switching to propofol during bronchoscopy by using transcutaneous carbon dioxide monitoring. METHODS: Patients in whom transcutaneous gas monitoring had been performed during bronchoscopy were included in this study. The participants were divided into two groups: 1) the midazolam + fentanyl group (MF group), and 2) the group in which midazolam was switched to propofol owing to inadequate sedation obtained with midazolam + fentanyl (MFP group). We retrospectively analyzed the transcutaneous gas measurement data collected in patients under propofol sedation for bronchoscopy. RESULTS: This study included 61 (MF, n = 41; MFP, n = 20) patients. The duration of elevated tcpCO2 (>50 mm Hg) was greater in the MFP group (MF 8.5 min vs. MFP 22.1 min, p = 0.042). CONCLUSION: Switching midazolam to propofol during bronchoscopy was significantly associated with a higher risk of elevated tcpCO2, which is indicative of respiratory depression. Therefore, continuous tcpCO2 monitoring is required to ensure the safety of patients under propofol sedation for bronchoscopy.

A Protective Effect of Pirfenidone in Lung Fibroblast-Endothelial Cell Network via Inhibition of Rho-Kinase Activity.

Pulmonary fibrosis is a life-threatening disease that has been attributed to several causes. Specifically, vascular injury is thought to be involved in the pathogenesis of fibrosis. The effects of the antifibrotic drug pirfenidone on angiogenesis have not been fully elucidated. This study aimed to investigate the effects of pirfenidone in human lung fibroblast-endothelial cell co-culture network formation and to analyze the underlying molecular mechanisms. Human lung fibroblasts were co-cultured with human umbilical vein endothelial cells to establish a co-culture network cell sheet. The influence of pirfenidone was evaluated for protective effect on the endothelial network in cell sheets stimulated with transforming growth factor ß (TGF-ß). Results indicated that TGF-ß disrupted the network formation. Pirfenidone and Y27632 (Rho-associated coiled-coil containing protein kinase [Rho-kinase or ROCK] inhibitor) protected against the TGF-ß-induced endothelial network disruption. TGF-ß activated Rho-kinase signaling in cells composing the co-culture cell sheet, whereas pirfenidone and Y27632 inhibited these effects. In conclusion, TGF-ß-induced Rho-kinase activation and disrupted endothelial network formation. Pirfenidone suppressed TGF-ß-induced Rho-kinase activity in cell sheets, thereby enabling vascular endothelial cells networks to be preserved in the cell sheets. These findings suggest that pirfenidone has potential vascular network-preserving effect via inhibiting Rho-kinase activity in vascular injury, which is a precursor to pulmonary fibrosis.

Use of Telephone Crisis Hotline by Callers with Suicidality in Japan during the COVID-19 Pandemic.

OBJECTIVE: The purpose of this study was to clarify changes over time in suicidal tendencies among crisis hotline service users in Japan before and during the COVID-19 pandemic. METHOD: We analyzed telephone consultation data from January 2017 to June 2021 held by Inochi No Denwa, a leading organization providing a telephone crisis hotline in Japan. The number of monthly consultations by gender and the monthly counts of consultations identified by counselors as suicidal were collected, and we calculated trends over time in the proportion of suicidal calls by month using Joinpoint regression analysis. RESULTS: The results indicated that the use of telephone crisis hotlines by suicidal callers increased significantly in Japan during the second wave of the pandemic in June to October 2020. These trends were also observed for both male and female users, although the increase began 1 month earlier for females than for males. CONCLUSION: Previous studies reported that mental health deteriorated and suicide risk increased significantly during the second wave of COVID-19 in Japan. These trends are consistent with the present findings, suggesting increased use of the crisis hotline by individuals at high suicide risk.HIGHLIGHTSSuicidal calls to crisis hotline in Japan increased rapidly from June to October 2020.Suicidal calls began to increase 1 month before the suicide rate increased for women.A sharp increase, not seen in the suicide rate for men, was observed in suicidal calls.

Cellular and Molecular Control of Lipid Metabolism in Idiopathic Pulmonary Fibrosis: Clinical Application of the Lysophosphatidic Acid Pathway.

Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is currently difficult to cure and is known to follow a chronic progressive course, with the patient's survival period estimated at about three years. The disease occasionally exacerbates acutely, leading to a fatal outcome. In recent years, it has become evident that lipid metabolism is involved in the fibrosis of lungs, and various reports have been made at the cellular level as well as at the organic level. The balance among eicosanoids, sphingolipids, and lipid composition has been reported to be involved in fibrosis, with particularly close attention being paid to a bioactive lipid "lysophosphatidic acid (LPA)" and its pathway. LPA signals are found in a wide variety of cells, including alveolar epithelial cells, vascular endothelial cells, and fibroblasts, and have been reported to intensify pulmonary fibrosis via LPA receptors. For instance, in alveolar epithelial cells, LPA signals reportedly induce mitochondrial dysfunction, leading to epithelial damage, or induce the transcription of profibrotic cytokines. Based on these mechanisms, LPA receptor inhibitors and the metabolic enzymes involved in LPA formation are now considered targets for developing novel means of IPF treatment. Advances in basic research on the relationships between fibrosis and lipid metabolism are opening the path to new therapies targeting lipid metabolism in the treatment of IPF.

Ingestion of rubber tips of artificial turf fields by goldfish.

Marine microplastics are one of the global environmental issues. The present study examined whether rubber tips of artificial sports fields could be marine microplastics. We observed the migration of rubber tips from the artificial turf field to the surrounding ditch connected to sewer pipes and then examined the ingestion of rubber tips using the goldfish Carassius auratus. The rubber tips found in sediments in the ditch suggest that the rubber tips could be sent to the river and released into the ocean. The goldfish ingested rubber tips with or without fish feed, and rubber tips were found in the intestine. However, the fish discharged the rubber tips within 48 h after ingestion. These results indicate that ingestion of the rubber tips was not accidental but an active behavior. Therefore, artificial turf sports fields could be a source of marine microplastics and may cause hazardous effects on wild fishes through ingestion.

Mucosal-associated invariant T cells repress group 2 innate lymphoid cells in Alternaria alternata-induced model of allergic airway inflammation.

Mucosal-associated invariant T (MAIT) cells, a blossoming member of the innate-like T cells, play a pivotal role in host defense through engaging the mucosal immunity. Although it has been suggested that MAIT cells are somehow implicated in the allergic airway inflammation mediated by group 2 innate lymphoid cells (ILC2s) such as asthma, the precise role(s) of MAIT cells in such inflammation has remained elusive. To explore the possible roles of MAIT cells in the inflammation, we examined whether MAIT cells suppressed the production of T helper (Th) 2 and inflammatory cytokines from ILC2s, and constrained the proliferation of ILC2s, both of which are prerequisite for airway inflammation. Given that laboratory mice are poor at MAIT cells, a novel mouse line rich in MAIT cells was used. We found that mice rich in MAIT cells showed alleviated airway inflammation as evidenced by reduced infiltration of the immune cells and hyperplasia in goblet cells in the lung concomitant with compromised production of Th2 and inflammatory cytokines, while wild type mice exhibited severe inflammation upon challenge with the fungal extracts. In vitro coculture experiments using purified ILC2s and MAIT cells unrevealed that cytokine-stimulated MAIT cells suppressed ILC2s to produce the cytokines as well as to proliferate most likely via production of IFN-γ. Furthermore, reconstitution of the allergic airway inflammation in the highly immunocompromised mice showed that ILC2-mediated inflammation was alleviated in mice that received MAIT cells along with ILC2s. We concluded that MAIT cells played a crucial role in suppressing the cytokine-producing capacity of ILC2s and ILC2 proliferation, that ultimately led to decrease in the allergic airway inflammation. The results open up a novel therapeutic horizon in ILC2-mediated inflammatory diseases by modulating MAIT cell activity.

Health-Related Expectations Regarding Aging among Middle-Aged and Older Japanese: Psychometric Performance and Novel Findings from the ERA-12-J.

BACKGROUND AND OBJECTIVES: Health-related expectations regarding aging is a gerontological construct that is potentially predictive of morbidity and mortality in later life. The Expectations Regarding Ageing scale (ERA-12) is a widely used measure of health-related expectations, although it has not previously been administered in Japanese. The present research aimed to elucidate the psychometric properties of the first Japanese translation of the ERA-12 and evaluate health-related expectations among middle-aged and older Japanese. RESEARCH DESIGN AND METHODS: Repeated online surveys were conducted with representative quota samples of middle-aged and older adults in Tokyo during 2021 (N = 1600). Primary outcome measures included total and subscale scores on a Japanese translation of the ERA-12 (ERA-12-J) addressing perceptions of physical, mental, and cognitive health. Standard measures were also used to gather information regarding respondent demographic details, general health, and health-related behavior. RESULTS: The ERA-12-J and associated subscales showed acceptable test-retest reliability (t(1598) = 0.60, p = 0.63), internal consistency (α > 0.80), inter-item correlation (r = 0.21-0.78) and item-total correlation (r = 0.53-0.73). Confirmatory Factor Analysis verified the hypothesized three-factor structure and construct validity on four common indices of fit (GFI = 0.968; CFI = 0.978; AGFI = 0.950; RMSEA = 0.059). ERA-12-J scores among Japanese respondents revealed prevailing negative sentiments concerning physical and cognitive health, with less negative sentiment regarding mental health. Significant and independent differences emerged concerning gender and age cohort, with middle-aged adults and females holding more negative expectations about their future health. DISCUSSION AND IMPLICATIONS: The ERA-12-J provides a sound basis for the elucidation of health-related expectations about aging in Japan and a useful tool for international comparative studies. Education and workplace intervention may be required in Japan to address age and gender disparities in health-related expectations.

Association between hospitalizations for asthma exacerbation and weather conditions in Qingdao: an ecological study.

Background: The hospitalization for asthma exacerbation has varied with seasons, however, the underlying weather reasons have not been fully explored yet. This study is aimed to explore the effect of weather factors on increased number of hospitalization due to worsening of asthma symptoms. This will provide more information to the relevant authorities to allocate appropriate medical resources as per the weather conditions in Qingdao, China. Methods: All adult patients admitted for asthma exacerbation from 1 January, 2017 to 31 December, 2019 were enrolled from 13 main hospitals of Qingdao. The clinical data, including age, sex, smoking history, etc., were collected from the electronic medical record (EMR) systems. The hourly air quality of Qingdao from 2017-2019, including the air quality index (AQI), PM2.5 and PM10, was obtained from the China National Environmental Monitoring Centre. All these parameters during 2017-2019 were compared monthly. For meteorological data, the monthly horizontal wind at 850 hPa and vertical velocity at 500 hPa during 1960-2020 were obtained from National Center for Environmental Prediction (NCEP) and the National Center for Atmospheric Research (NCAR) global reanalysis dataset. The correlation analysis was applied to determine the association between asthma hospitalizations and the environmental factors, including atmospheric pressure, humidity, vertical visibility, and etc., monthly. Results: In all, 10,549 asthmatic inpatients (45.7% males, 54.3% females) were included in the study. The inpatients number for asthma exacerbation had a plateau lasting from March to June of 2019, accompanied with high PM2.5 and PM10, as well as bad air quality from January to March of 2019, potentially governed by the El Niño event in 2018. However, there was no significance correlation between the number of asthma hospitalizations and the average value of all environmental factors. Conclusions: The high rate of hospitalization for asthma exacerbation in Qingdao during the spring of 2019 was associated with the unfavorable weather conditions, which might be linked to the atmospheric circulation in East Asia.

Metabolic changes induced by TGF-ß1 via reduced expression of phosphatidylserine decarboxylase during myofibroblast transition.

Metabolic alteration is increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types, and metabolically targeted therapies could become important strategies for reducing fibrosis. In present study, target enzymes that are involved in changes in phospholipid metabolism during fibroblast-to-myofibroblast transition induced by transforming growth factor beta 1 (TGF-ß1) were examined. Different amounts of phospholipids were found in the 2 groups. In response to TGF-ß1 stimulation, 17 lipids decreased and 17 increased. The latter included the phospholipids phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE). Furthermore, among the rate-limiting enzymes that regulate these phospholipids, phosphatidylserine decarboxylase (PISD), which controls conversion of PS to PE and is localized in mitochondria, decreased in response to TGF-ß1. Knockdown of PISD alone without TGF-ß1 stimulation increased expression of α-smooth muscle actin mRNA and production of total collagen. Taken together, these results indicate that PISD is involved in the mechanism of fibrogenesis by regulating phospholipid metabolism.

REST Inactivation and Coexpression of ASCL1 and POU3F4 Are Necessary for the Complete Transformation of RB1/TP53-Inactivated Lung Adenocarcinoma into Neuroendocrine Carcinoma.

Although recent reports have revealed the importance of the inactivation of both RB1 and TP53 in the transformation from lung adenocarcinoma into neuroendocrine carcinoma (NEC), the requirements for complete transformation into NEC have not been elucidated. To investigate alterations in the characteristics associated with the inactivation of RB1/TP53 and define the requirements for transformation into NEC cells, RB1/TP53 double-knockout A549 lung adenocarcinoma cells were established, and additional knockout of REST and transfection of ASCL1 and POU class 3 homeobox transcription factors (TFs) was conducted. More than 60 genes that are abundantly expressed in neural cells and several genes associated with epithelial-to-mesenchymal transition were up-regulated in RB1/TP53 double-knockout A549 cells. Although the expression of chromogranin A and synaptophysin was induced by additional knockout of REST (which mimics the status of most NECs), the expression of another neuroendocrine marker, CD56, and proneural TFs was not induced. However, coexpression of ASCL1 and POU3F4 in RB1/TP53/REST triple-knockout A549 cells induced the expression of not only CD56 but also other proneural TFs (NEUROD1 and insulinoma-associated 1) and induced NEC-like morphology. These findings suggest that the inactivation of RB1 and TP53 induces a state necessary for the transformation of lung adenocarcinoma into NEC and that further inactivation of REST and coexpression of ASCL1 and POU3F4 are the triggers for complete transformation into NEC.