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Rie Tanaka,1 Akira Koarai,1 Mitsuhiro Yamada,1 Naoya Fujino,1 Tomohiro Ichikawa,1 Tadahisa Numakura,1 Katsuhiro Onodera,2 Yorihiko Kyogoku,1 Tsutomu Tamada,1 Motohiko Miura,3 Yoshiaki Minakata,4 Masakazu Ichinose,5 Hisatoshi Sugiura1 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Mizusawa Hospital, Oshu, Japan; 3Department of Respiratory Medicine, Tohoku Rosai Hospital, Sendai, Japan; 4Department of Respiratory Medicine, National Hospital Organization Wakayama Hospital, Wakayama, Japan; 5Academic Center, Osaki Citizen Hospital, Osaki, JapanCorrespondence: Akira KoaraiDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8539Fax +81-22-717-8549Email koarai@rm.med.tohoku.ac.jpBackground: Daily physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD) and a reduced level of physical activity has been shown to be an important predictor for the prognosis, such as increased risk of exacerbation and mortality. However, there has not yet been a useful biomarker of the physical activity. In our previous cross-sectional study, we showed that the level of one of the possible myokines, which is an anti-aging factor, growth differentiation factor 11 (GDF11), was decreased in the plasma from patients with COPD and correlated with the physical activity. To clarify this relationship, we conducted a longitudinal evaluation of such factors.Patients and Methods: Twenty-four COPD patients were enrolled and prospectively followed. We measured the levels of plasma GDF11 and systemic inflammatory markers with immunoblotting or ELISA, respectively. We also evaluated lung function and daily physical activity using a triaxial accelerometer and the incidence of exacerbation.Results: The change in the plasma level of GDF11, but not systemic inflammatory markers, was positively correlated with the change in the physical activity in an intensity-dependent manner (between the change in the number of steps and GDF11; r = 0.41, p = 0.047). In the multiple regression analysis, the relationship was confirmed (β = 0.93, p < 0.001). In addition, patients who maintained their plasma level of GDF11 showed a significantly lower incidence in exacerbations of COPD than those with decreased levels of GDF11 (p = 0.041).Conclusion: The longitudinal change in the plasma level of GDF11 was positively correlated with the change in the daily physical activity in COPD. GDF11 could be a useful humoral factor that reflects the physical activity in COPD.Keywords: chronic obstructive pulmonary disease, physical activity, growth differentiation factor 11, exacerbation, longitudinal study

Additional file 1. Supporting information.

Background The airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens. Methods BEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated. Results The amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin. Conclusions The current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.

Rationale Cellular senescence is observed in the lungs of patients with COPD and may contribute to the disease pathogenesis. Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor β superfamily and was recently reported to be a circulating protein that may have rejuvenating effects in mice. We aimed to investigate the amounts of GDF11 in the plasma and the lungs of patients with COPD and elucidate the possible roles of GDF11 in cellular senescence. Methods The plasma levels of GDF11 were investigated in two separate cohorts by western blotting. The localisation and expression of GDF11 in the lungs were investigated by immunohistochemistry and quantitative reverse transcription PCR, respectively. The effects of GDF11 on both cigarette smoke extract (CSE)-induced cellular senescence in vitro and on elastase-induced cellular senescence in vivo were investigated. Results The levels of plasma GDF11 in the COPD group were decreased compared with the control groups in the two independent cohorts. The levels of plasma GDF11 were significantly positively correlated with pulmonary function data. The mRNA expression of GDF11 in mesenchymal cells from the COPD group was decreased. Chronic exposure to CSE decreased the production of GDF11. Treatment with GDF11 significantly inhibited CSE-induced cellular senescence and upregulation of inflammatory mediators, partly through Smad2/3 signalling in vitro. Daily GDF11 treatment attenuated cellular senescence and airspace enlargement in an elastase-induced mouse model of emphysema. Conclusions The decrease in GDF11 may be involved in the cellular senescence observed in COPD.

Rationale: Reactive sulfer species have been recently identified as much stronger antioxidants than glutathione and we have demonstrated that the levels of reactive persulfides/polysulfides are decreased in the lungs of COPD. However, the roles of reactive persulfides/polysulfides in the pathogenesis of COPD remain unclear. The aim of this study was to investigate the role of reactive sulfer species in cigarette smoke (CS)-induced premature senescence in lung resident cells. Methods: Human fetal lung fibroblasts (HFL-1) transfected with siRNA for the novel synthetase of reactive sulfer species were exposed to cigarette smoke extract (CSE). The amount of reactive persulfides/polysulfides was measured using sulfane sulfur probe-4 (SSP-4), a specific probe for reactive sulfer species. The expressions of p53 and p21, markers for senescence, in the cells were analyzed by western blotting. Senescence associated beta galactosidase (SA-β gal) activity was measured using a commercial kit. The release of IL-6 and IL-8, cytokines associated with senescence, were quantified by ELISA. Results: The expression of the synthetase and the SSP-4 level were reduced in the CSE-treated cells. The productions of markers and cytokines associated with senescence were potentiated in the synthetase knockdown CSE-exposed cells compared to the control-siRNA transfected CSE-exposed cells. The SA-β gal activities were significantly augmented in the synthetase knockdown CSE-exposed cells compared to the control-siRNA transfected CSE-exposed cells. Conclusions: The current study suggests that the reduction in reactive sulfer species might be related to CS-induced cellular senescence.

Axl receptor tyrosine kinase is involved in the growth and metastasis and is an indicator of poor prognosis in several cancers including lung cancers. Although a mitogen-activated protein kinase (MAPK) pathway and an epithelial-to-mesenchymal transition (EMT) program are critical, molecular mechanisms underlying the Axl-driven cancer progression have not been fully elucidated. We aimed to identify molecules up-regulated by Axl kinase in lung adenocarcinomas. Through the global gene expression analysis and the functional annotation clustering, we found that AXL expression positively correlated with mRNA expressions of immune checkpoint molecules and chemokine receptors in non-small-cell lung cancers. Validation cohorts including our biobank confirmed that the AXL expression significantly correlated with expression of genes encoding programmed death-ligand1 (PD-L1) and CXC chemokine receptor 6 (CXCR6) in lung adenocarcinoma, especially in epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma. Pharmacological inhibition of Axl kinase activity decreased mRNA expressions of PD-L1 and CXCR6 in EGFR mutation-positive cell lines. Our data indicates the novel role of Axl kinase as a driver of immune checkpoint molecules and chemokine signalling pathways in the progression of lung adenocarcinomas. This study also highlights the necessity of clinical trials in order to test the efficacy of Axl kinase inhibition in the Axl-highly expressing subset of lung adenocarcinomas. Electronic supplementary material The online version of this article (10.1186/s12943-019-0953-y) contains supplementary material, which is available to authorized users.

Materials and Methods. (DOCX 37 kb)

Figure S1. A dose-dependent decrease in phosphorylation of Axl in PC9 cells by the Axl kinase inhibitor. Figure S2. Knockdown of Axl decreases mRNA expression of PD-L1, PD-L2 and CXCR6 in vitro. Figure S3. Immunoblots indicating decreases in phosphorylation of ERK1/2 and AKT by the Axl kinase inhibitor. Figure S4. A selective MEK1/2 inhibitor or an AKT inhibitor reduces PD-L1 mRNA expression in vitro. Figure S5. Diverse downstream pathways driven by Axl receptor tyrosine kinase in non-small-cell lung cancer. (DOCX 2506 kb)

A 49-year-old male Japanese patient was admitted to our hospital under the diagnosis of COVID-19 pneumonia. For 5 days before admission, he had experienced various symptoms, including high fever, watery diarrhea, dyspnea, and cough, and he tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid. The patient is a smoker who was on medication for hypertension. A chest computed tomography scan showed bilateral multiple patchy ground-glass opacities. Despite being treated with several therapeutic agents, he still exhibited dyspnea (oxygen saturation [SpO2] in ambient air: 88%), a high fever (axillary temperature: 39 °C), and high blood pressure (148/98 mmHg). Because laboratory data revealed high levels of C-reactive protein (CRP; 2.10 mg/dL) and urinary β2-microglobulin (B2M; 33,683 µg/mL), the anti-interleukin-6 receptor antibody tocilizumab (TCZ; 400 mg) was administered intravenously. One day after injection, he was afebrile. Four days after the TCZ injection, his CRP level dropped to 0.27 mg/dL, B2M level decreased to 3817 µg/mL, and viral load became low. No adverse drug reaction due to TCZ was observed. The patient was discharged 15 days after admission. The early administration of TCZ in this patient prevented the pneumonia and kidney injury caused by COVID-19 from progressing to hyperinflammation syndrome.

Background Asthma–chronic obstructive pulmonary disease overlap (ACO) has frequent exacerbations and a poor quality of life and prognosis compared with those of chronic obstructive pulmonary disease alone. However, the pathogenesis of ACO has not been fully elucidated yet. Objectives The aim of this study was to investigate nitrosative stress, which causes a redox imbalance and tissue inflammation in the airways of patients with ACO, and to evaluate the relationship between nitrosative stress and the clinical course in study subjects. Methods Thirty healthy subjects and 56 asthmatic patients participated in this study. The asthmatic patients were divided into 33 asthmatic patients and 23 patients with ACO. The study subjects had been followed prospectively for 2 years to evaluate the clinical course. Nitrosative stress was evaluated based on the production of 3-nitrotyrosine (3-NT) in sputum cells. Results Production of 3-NT was significantly enhanced in patients with ACO compared with that in asthmatic patients. Amounts of reactive persulfides and polysulfides, newly identified powerful antioxidants, were significantly decreased in the ACO group. Baseline levels of 3-NT were significantly correlated with the frequency of exacerbations and decrease in FEV1 adjusted by age, smoking history, and blood eosinophil count. The 3-NT–positive cells were also significantly correlated with amounts of proinflammatory chemokines and cytokines. Conclusions These findings suggested that greater nitrosative stress occurred in the airways of patients with ACO, and the degree of nitrosative stress was correlated with an impairment in the clinical course. Nitrosative stress might be related to the pathogenesis of ACO.

Rie Tanaka,1 Hisatoshi Sugiura,1 Mitsuhiro Yamada,1 Tomohiro Ichikawa,1 Akira Koarai,1 Naoya Fujino,1 Satoru Yanagisawa,1 Katsuhiro Onodera,1 Tadahisa Numakura,1 Kei Sato,1 Yorihiko Kyogoku,1 Hirohito Sano,1 Shun Yamanaka,1 Tatsuma Okazaki,1 Tsutomu Tamada,1 Motohiko Miura,2 Tsuneyuki Takahashi,3 Masakazu Ichinose1 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan; 2Department of Respiratory Medicine, Tohoku Rosai Hospital, Aoba-ku, Sendai, Japan; 3Department of Internal Medicine, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Wakabayashi-ku, Sendai, Japan Background: Growth differentiation factor 11 (GDF11) is reported to possess anti-aging and rejuvenating effects, including muscle regeneration and to be highly expressed in skeletal muscle. Recently, we demonstrated that the levels of plasma GDF11 were decreased in COPD. However, the effect of decreased circulating GDF11 in the pathophysiology of COPD remains unknown. The aim of this study is to investigate the association between the plasma GDF11 levels and various clinical parameters in patients with COPD. Patients and methods: Eighteen ex-smokers as control subjects and 70 COPD patients participated in the current study. We measured the levels of plasma GDF11 using immunoblotting, lung function, physical activity using a triaxial accelerometer, quadriceps strength, exercise capacity, and systemic inflammatory markers. We investigated the association between the levels of plasma GDF11 and these clinical parameters. Results: The levels of plasma GDF11 in the COPD patients had significant positive correlations with the data of lung function. Furthermore, the levels of plasma GDF11 were significantly correlated with the physical activity, quadriceps strength, and exercise capacity. Moreover, the levels of plasma GDF11 were significantly correlated with the data of inflammatory markers. Although various factors were related to GDF11, the multiple regression analysis showed that physical activity was significantly associated with the levels of plasma GDF11. Conclusion: Physical inactivity was significantly related to the decreased GDF11 levels in COPD, which might be useful for understanding the pathogenesis of COPD. Clarifying the relationships between the physical inactivity and GDF11 may reveal a potentially attractive therapeutic approach in COPD via increasing the plasma levels of GDF11. Keywords: physical activity, muscle strength, rejuvenating factor, COPD