Auto-antibody evaluation in idiopathic interstitial pneumonia and worse survival of patients with Ro52/TRIM21auto-antibody.

Some patients with interstitial pneumonia (IP) have auto-antibodies, but do not fit the criteria for specific connective tissue diseases. Examination of auto-antibodies is recommended for diagnosis idiopathic pulmonary fibrosis. A prospective cohort study was performed in 285 patients with IP. Eleven auto-antibodies were assessed and patients were followed for 2 years. All 285 patients underwent the myositis panel test (MPT) for 11 auto-antibodies. Among them, 23.5% (67/285) of the patients had a positive MPT and 14.7% (42/285) had connective tissue diseases. Among the 49 MPT positive patients without connective tissue diseases, 29 patients (59.2%) were positive for Ro52, including 17 patients with Ro52 mono-positivity. Among interstitial pneumonia patients without connective tissue diseases, the Ro52 mono-positive patients showed worse at 2-years survival than those who were Ro52 negative (p = 0.022, HR = 5.88, 95% CI 1.29-26.75). Most of the Ro52 positive patients also showed a low titer of anti-nucleolar antibody. About 20% of IP patients had auto-antibodies detectable by the MPT, and Ro52 positive patients accounted for more than half of the MPT positive patients without connective tissue diseases. Detection of Ro52 auto-antibodies may be useful for assessing the risk of progression in idiopathic interstitial pneumonia patients without connective tissue diseases and a low anti-nucleolar antibody titer.

Real-life effectiveness of fluticasone furoate/vilanterol after switching from fluticasone/salmeterol or budesonide/formoterol therapy in patients with symptomatic asthma: Relvar Ellipta for Real Asthma Control Study (RERACS study).

BACKGROUND: This study evaluated the efficacy of switching therapy from fluticasone propionate/salmeterol (FP/SM) or budesonide/formoterol (BD/FM) to fluticasone furoate and vilanterol (FF/VI) at the equivalent corticosteroid dose in a real-world setting. METHODS: A prospective, 3-month, open-label, parallel group, switching therapy trial was performed in symptomatic asthma patients under routine management. Patients using 1 puff of FP 250 µg/SM 50 µg b.i.d or 2 puffs of BD 160 µg/FM 4.5 µg b.i.d were switched to FF 100 µg/VI 25 µg once daily, while patients using 1 puff of FP 500 µg/SM 50 µg b.i.d or 4 puffs of BD 160/FM b.i.d was switched to FF 200 µg/VI 25 µg once daily. The primary outcome was improvement of the predicted forced expiratory volume in 1 second % (%FEV1), while secondary outcomes were improvement of asthma symptoms evaluated by the asthma control test (ACT) and fractional exhaled nitric oxide (FeNO). RESULTS: The %FEV1 was improved at 4 weeks after switching, and the improvement was maintained until 12 weeks. ACT also improved after switching. Patients with ACT <20 before switching showed greater improvement of symptoms at 4 weeks and 62% had an ACT score >20. FeNO decreased from 8 weeks. CONCLUSIONS: In symptomatic asthma patients showing insufficient control, improvement of asthma was obtained by switching to FF/VI at the equivalent corticosteroid dose accompanied with the improvement of biomarkers. FF/VI can be a useful option for better control of asthma because of its high efficacy, long duration of action, and delivery via a single-action device.

Comparison of inducible nitric oxide synthase mRNA expression in different airway portions and association with nitric oxide parameters from patients with asthma.

BACKGROUND: Fractional exhaled nitric oxide concentration (FeNO) is widely used to support diagnosis and monitoring of bronchial asthma (BA). Tsoukias and George proposed a two-compartment model (2CM) for assessing the alveolar concentration of NO, referred to as CANO(2CM), while Condorelli et al proposed a model based on the trumpet shape of the airway tree and axial diffusion (TMAD), referred to as CANO(TMAD). In addition, Högman et al proposed non-linear model, referred to as CANO(non-linear). OBJECTIVE: We examined associations between the expression of inducible nitric oxide synthase (iNOS) mRNA in airway cells (ACs) by bronchoscopy and NO-parameters calculated by the three methods and identified which of them accurately reflected expression of iNOS mRNA from different airway portions. METHODS: We retrospectively analysed data of 18 patients with stable, mild-moderate asthma, including 10 steroid-naïve BA (snBA) patients. Samples were obtained from airway brushings and bronchoalveolar lavage (BAL). Expressions of iNOS protein in tissue samples were evaluated by immunostaining. The iNOS mRNA in ACs was measured by qPCR. NO-parameters calculated by the three methods above and evaluated whether they were associated with iNOS mRNA in ACs derived from proximal (2nd carina), distal (10-15th) airways and alveolar regions. RESULTS: Immunostaining revealed expression of iNOS proteins mainly in epithelial cells in the airways, while it was mainly expressed in macrophages in the alveolar region in the snBA group. The iNOS mRNA expression was increased in both proximal and distal ACs in the snBA group compared with steroid-treated BA group (stBA). CANO(2CM) negatively associated with FEV1 (%predicted) and also associated with iNOS mRNA in distal ACs significantly. However, CANO(TMAD) and CANO(non-linear) showed no correlation with lung function nor iNOS mRNA expression in any portions of ACs. CONCLUSIONS: These results suggested that CANO(2CM) reflected distal airway inflammation in steroid-naïve asthma.

Expression of intelectin-1 in bronchial epithelial cells of asthma is correlated with T-helper 2 (Type-2) related parameters and its function.

BACKGROUND: Intelectin-1 (ITLN-1) is secreted by intestinal goblet cells and detectable in blood. Its expression is increased in IL-13-overexpressing mouse airways. However, its expression and function in human airways is poorly understood. METHODS: Distal and proximal bronchial epithelial cells (BECs) were isolated from bronchoscopic brushings of disease control (D-CON), COPD, inhaled corticosteroid-treated asthma (ST-Asthma) and inhaled corticosteroid-naïve asthma (SN-Asthma) patients. ITLN-1 mRNA expression in freshly isolated BECs, primary cultured BECs with or without IL-13 and inhibition effects of mometasone furoate (MF) were investigated by quantitative real-time PCR (qPCR). Correlations between ITLN-1 mRNA and Type-2 related parameters (e.g. FeNO, IgE, iNOS, CCL26, periostin and DPP4 mRNA) were analyzed. ITLN-1 protein distribution in asthmatic airway tissue was assessed by immunohistochemistry. Bronchial alveolar lavage (BAL) and serum ITLN-1 protein were measured by ELISA. The effect of recombinant human (rh) ITLN-1 on stimulated production of CXCL10 and phospho(p)-STAT1 expression examined in lung fibroblasts. RESULTS: ITLN-1 mRNA was expressed in freshly isolated BECs and was correlated with Type-2 related parameters. ITLN-1 protein was increased in goblet cells in SN-Asthmatics and increased in SN-Asthmatic BAL fluid. There were no any differences in serum ITLN-1 concentration between ST and SN-Asthma. IL-13 enhanced ITLN-1 expression and inhibited by MF from BECs in vitro, while rhITLN-1 inhibited CXCL10 production and p-STAT1 expression in HFL-1 cells. CONCLUSION: ITLN-1 is induced by IL-13 and expressed mainly in goblet cells in untreated asthma where its levels correlate with known Type-2 related parameters. Further, ITLN-1 inhibits Type-1 chemokine expression.

Changes of plasmalogen phospholipid levels during differentiation of induced pluripotent stem cells 409B2 to endothelial phenotype cells.

Endothelial cells (EC) are involved in regulating several aspects of lipid metabolism, with recent research revealing the clinicopathological significance of interactions between EC and lipids. Induced pluripotent stem cells (iPSC) have various possible medical uses, so understanding the metabolism of these cells is important. In this study, endothelial phenotype cells generated from human iPSC formed cell networks in co-culture with fibroblasts. Changes of plasmalogen lipids and sphingomyelins in endothelial phenotype cells generated from human iPSC were investigated by reverse-phase ultra-high-pressure liquid chromatography mass spectrometry (UHPLC-MS/MS) analysis. The levels of plasmalogen phosphatidylethanolamines (38:5) and (38:4) increased during differentiation of EC, while sphingomyelin levels decreased transiently. These changes of plasmalogen lipids and sphingomyelins may have physiological significance for EC and could be used as markers of differentiation.

Matrix-assisted laser desorption/ionization imaging mass spectrometry reveals changes of phospholipid distribution in induced pluripotent stem cell colony differentiation.

Induced pluripotent stem cells (iPSCs) are opening up new possibilities for medicine. Understanding the regulation of iPSC biology is important when attempting to apply these cells to disease models or therapy. Changes of lipid metabolism in iPSCs were investigated by matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF-IMS). Analysis revealed changes of the intensity and distribution of peaks at m/z 782.5 and 798.5 in iPSC colonies during spontaneous differentiation. Two phosphatidylcholines (PCs) were identified: C44H81NO8P, PC(36:4)[M+H]+ at m/z 782.5 and C42H82NO8P, PC(34:1)[M+K]+ at m/z 798.5. The intensity of PC(36:4) showed an inverse relation between undifferentiated and differentiated iPSC colonies. PC(34:1) displayed a diffuse distribution in undifferentiated iPSC colonies, while it showed a concentric distribution in differentiated iPSC colonies, and was localized at the border of the differentiated and undifferentiated areas or the border between undifferentiated iPSC and feeder cells. These findings suggested that the distribution of lipids changes during the growth and differentiation of iPSCs and that MALDI-TOF-IMS was useful for analyzing these changes. PC(36:4) might play a role in maintaining pluripotency, while PC(34:1) might play a role in the differentiation and spread of iPSCs. Graphical Abstract MALDI Imaging for phosphatidylcholine distribution changes during sponteneous differentiaton of induced pluiripotent stem cells colonies.

Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells.

BACKGROUND: Type 2 helper T-cell cytokines including IL-13 play a central role in the pathogenesis of bronchial asthma (BA). During the course of our research, our attention was drawn to dipeptidyl peptidase-4 (DPP4) as one of the molecules that were induced from bronchial epithelial cells (BECs) by IL-13 stimulation. DPP4 could become a new biomarker or therapeutic target. The aim of this study was to investigate the expression of DPP4 in the asthmatic airway, and its role in the pathophysiology of asthma. METHODS: BECs were isolated from patients with inhaled corticosteroid-treated asthma (stBA) and inhaled corticosteroid-naïve asthma (snBA) using bronchoscopy. DPP4 mRNA expression in freshly isolated BECs and primary cultured BECs with or without IL-13 stimulation was investigated by microarray analysis and quantitative real-time PCR (qPCR). The distribution of DPP4 protein was determined by immunostaining of transbronchial lung biopsy specimens from asthma patients. The effect of recombinant human (rh) DPP4 on the proliferation of lung fibroblasts (HFL-1) and bronchial smooth muscle cells (BSMCs) was examined, as well as its effect on the production of fibronectin (FN). RESULTS: DPP4 mRNA was strongly expressed in freshly isolated BECs in snBA, and its expression was significantly enhanced by IL-13 stimulation. DPP4 mRNA expression in BECs of snBA significantly correlated with exhaled nitric oxide. Biopsied tissues of the asthmatic airway revealed strong expression of DPP4 protein in BECs from snBA subjects. rhDPP4 stimulated the proliferation of HFL-1 and BSMCs, and it also enhanced production of FN from these airway cells. CONCLUSION: DPP4 may be involved in the pathologic features of asthmatic airway inflammation and cell proliferation and FN production.

Riluzole-induced lung injury in two patients with amyotrophic lateral sclerosis.

Riluzole has recently been proven as the first effective drug for the treatment of amyotrophic lateral sclerosis (ALS). We report two rare cases of lung injury caused by riluzole therapy in patients with ALS. Chest radiographs showed bilateral lower lobe, dorsal-dominant ground glass opacity, and/or consolidation. A drug lymphocyte stimulation test (DLST) of peripheral blood or bronchoalveolar lavage cells was positive for riluzole. Histopathological examination of lung biopsy specimens revealed lung injury without fungoid granuloma, vasculitis, or diffuse alveolar damage. To the best of our knowledge, this is the first report of riluzole-induced lung injury with positive DLST results.

Patients in whom active tuberculosis was diagnosed after admission to a Japanese university hospital from 2005 through 2007.

To identify problems in early diagnosis of tuberculosis and to design countermeasures against the disease, we examined the status of active tuberculosis among patients admitted to a university hospital that did not have an isolation ward for tuberculosis. Between 2005 and 2007, we analyzed demographic characteristics, disease type, chest radiologic findings, and the process leading to diagnosis. Active tuberculosis was diagnosed after admission in 55 patients (34 males and 21 females): pulmonary tuberculosis, 26; tuberculous pleuritis, 13; tuberculous meningitis, 6; miliary tuberculosis, 4; tuberculous pericarditis, 3; lymph-node tuberculosis, 2; and tracheal and bronchial tuberculosis, 1. Although radiographic examinations provided abundant information, chest radiography showed normal findings in 7 patients (12.7%). Computed tomographic scanning was useful for detailed evaluation of abnormalities. Twenty patients (36.4%) were given diagnoses at departments other than ours (Department of Pulmonary Medicine). Numbers of days between hospital admission and diagnosis of tuberculosis (50th percentile/80th percentile) were 8.0/37.8 for miliary tuberculosis, 8.0/8.0 for tracheal and bronchial tuberculosis, 7.5/17.8 for tuberculous pleuritis, 7.0/8.8 for tuberculous pericarditis, 6.0/15.6 for pulmonary tuberculosis, 3.5/4.4 for lymph-node tuberculosis, and 1/1 for tuberculous meningitis. Early diagnosis of tuberculosis requires adherence to the following precautions. Tuberculosis should be suspected in any patient with respiratory symptoms. Sputum tests for acid-fast bacteria should be performed at least three times initially. If findings on chest X-ray films are equivocal, high-resolution computed tomography should be performed to confirm details of shadows and to detect minimal pulmonary shadows or cavitary lesions. Physicians from all specialties should be repeatedly informed about the risk of tuberculosis and should include tuberculosis in the differential diagnosis in patients suspected to have pulmonary diseases.