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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 FEV 1 (%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.

Yellow nail syndrome (YNS) pleurisy is often difficult to control, and pathological examinations have rarely been reported. We herein report a case of bucillamine-induced YNS in which histopathology of the parietal pleura revealed hyperplasia of the lymphoid follicles and lymphangiectasia. Even after the discontinuation of bucillamine, the pleurisy and lymphedema showed no change. Based on the histopathological findings showing similarity to rheumatoid pleurisy, we administered corticosteroid treatments, and both the pleurisy and lymphedema improved. The findings in the present case suggest that, in bucillamine-induced YNS, pleurisy may be related to inflammation caused by rheumatoid arthritis in addition to abnormalities in lymphatic vessels.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.

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. Electronic supplementary material The online version of this article (doi:10.1186/s13223-017-0207-8) contains supplementary material, which is available to authorized users.

To clarify the clinical features of organizing pneumonia (OP) associated with rheumatoid arthritis (RA) and to determine whether development of OP is related to RA activity.A cross-sectional study was conducted, in which medical records of 499 consecutive RA patients who visited our hospital during one month were reviewed. OP was diagnosed by pathological findings by trans-bronchial biopsy or by clinical features (typical computed tomography findings, no causative agents, good response to glucocorticoids, and lack of response to antibiotics).Among 499 patients, OP was found in 19 patients and the estimated prevalence was 1.9-4.8%. No differences in clinical features were noted between the OP and non-OP groups. The mean age of OP development was 57.2 years and the period from the onset of RA to OP ranged from -4 to +34 years. Although 14 patients presented OP after the onset of RA, two developed OP before RA and three developed OP simultaneously with RA. Patients receiving tumor necrosis factor inhibitors also developed OP. RA disease activity just before onset of OP was low in 8 of 14 RA cases. At the onset of OP, only two patients showed exacerbations of arthritis, whereas most patients presented with fever and serum C-reactive protein (CRP) elevations. Glucocorticoids were effective for OP in all patients who received them. Relapse occurred in 4 of 19 cases.OP develops in approximately 4% of RA patients, which occurs independently from arthritis activity and at any time in RA patients.

We studied the subsets of peripheral blood dendritic cells (DCs) and lipid accumulation in DCs to investigate the involvement of DCs in the decreased anticancer immunity of advanced lung cancer patients. We analyzed the population of DC subsets in peripheral blood using flow cytometry. We then determined lipid accumulation in the DCs using BODIPY 650/665, a fluorophore with an affinity for lipids. Compared with healthy controls, the number of DCs in the peripheral blood of treatment-naive cancer patients was significantly reduced. In patients with stage III + IV disease, the numbers of myeloid DCs (mDCs) and plasmacytoid DCs were also significantly reduced. Lipid accumulation in DCs evaluated based on the fluorescence intensity of BODIPY 650/665 was significantly higher in stage III + IV lung cancer patients than in the controls. In the subset analysis, the fluorescence was highest for mDCs. The intracellularly accumulated lipids were identified as triglycerides. A decreased mixed leukocyte reaction was observed in the mDCs from lung cancer patients compared with those from controls. Taken together, the results show that lung cancer patients have a notably decreased number of peripheral blood DCs and their function as antigen-presenting cells is decreased due to their high intracellular lipid accumulation. Thereby, anticancer immunity is suppressed.

Co-infection with cryptococcus and tuberculosis has rarely been reported. We herein report a case of an 80-year-old man with cryptococcal pleuritis concurrent with pulmonary tuberculosis. He was admitted for progression of left pleural effusion and consolidation in the left upper lobe. Culture for Mycobacterium tuberculosis was positive in sputum, and analyses of pleural effusion revealed lymphocyte-predominant high levels of adenosine deaminase (ADA). Medical thoracoscopy revealed massive infiltration of Cryptococcus neoformans in pleura without granuloma. This is the first case report of cryptococcal pleuritis coincident with pulmonary tuberculosis. Cryptococcal pleuritis should be ruled out when the adenosine deaminase levels are elevated in pleural effusion.

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.

Background: Forestry and field workers who work outdoors are at high risk for Hymenoptera stings and may develop occupation-related allergies from being stung. However, clinical and immunological surveys of Hymenoptera stings in the occupational setting have rarely been reported. We surveyed the natural history of Hymenoptera stings in Japanese forestry workers (FWs) and electrical facility field workers (EFFWs), and we assessed the utility of measuring specific (s)IgE Ab to Hymenptera venom. Methods: Questionnaires on hornet and paper wasp stings were completed by 999 FWs, 354 EFFWs, and 365 office workers as controls between July and November 2009. Sera from these participants were tested for sIgE Ab levels to Hymenptera venom with a CAP system using a fluoroenzyme immunoassay. Results: Of the participants who had experienced Hymenoptera stings, 914 (91.5%) were FWs, 293 (82.8%) were EFFWs, and 295 (80.8%) were controls. Of the participants who had experienced systemic reactions, 210 (21.0%) were FWs, 51 (14.4%) were EFFWs, and 39 (10.7%) were controls. sIgE Ab in response to hornet and wasp venom was positive (≥ class 2) in 42.4% and 41.4% of FWs, 30.1% and 31.4% of EFFWs, and 15.1% and 18.1% of controls, respectively. The likelihood of being sIgE-positive to wasp and hornet venom was significantly higher in FWs and EFFWs than in controls (P Conclusions: 21% of FWs and 14% of EFFWs had experienced systemic reactions to Hymenoptera stings with a higher frequency compared with office workers in the same area. 40% of FWs and 30% of EFFWs had sera that were sIgE positive to Hymenoptera venom.

Contains fulltext : 177447.pdf (Publisher’s version ) (Closed access) Nontuberculous mycobacteria (NTM) infections involving anti-interferon-gamma (IFN-gamma)-neutralizing autoantibodies have been described in previously immunocompetent adults. To investigate the factors underlying various disease manifestations, we reviewed 35 articles published between January 2004 and November 2016 and identified 111 NTM patients with anti-IFN-gamma autoantibodies. Rapidly growing mycobacteria (RGM) accounted for 53% of the isolated species. RGM were predominant among the NTM species isolated from Thai (73%), Chinese (58%) and Filipino (56%) patients, whereas M. avium complex (MAC) was predominant among Japanese (58%) and non-Asian (80%) patients. The commonly involved organs included the lymph nodes (79%), bones/joints (34%) and lungs (32%). Compared with the patients with MAC, the patients with RGM had a higher incidence of lymph node lesions (P

We herein report a case of atypical drug-induced hypersensitivity syndrome (DIHS) involving serological reactivation of cytomegalovirus induced by carbamazepine with pulmonary and skin manifestations. These lesions were not present on admission, but developed on virus reactivation as indicated by the presence of inclusion bodies and multinucleated giant cells in alveolar cells with CD8(+) T lymphocyte infiltration on a transbronchial lung biopsy. Although the precise mechanism of DIHS remains unknown, this case suggests the crucial role of viral reactivation in pulmonary lesions in DIHS.

Background The epidermal growth factor receptor (EGFR) T790M mutation is considered the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations. Although chemotherapy is commonly used for those patients under the condition without T790M-targeted therapy, the clinical outcomes are poorly defined. Therefore, we aimed to reveal the treatment patterns and clinical outcomes in patients with T790M-positive NSCLC. Methods We conducted a retrospective observational study at 23 sites in Japan, and 141 patients with T790M-positive advanced/recurrent NSCLC were identified from January 2008 to December 2014. Their records were studied to understand treatment patterns after detection of a T790M mutation and to assess the objective response rate (ORR) and median survival time (MST) to specific treatment modalities. Results Of 141 patients, 24 had de novo T790M-positive tumors and 117 had acquired T790M-positive tumors, with MSTs (95% CI) of 21.4 (12.4-36.7) and 9.1 (6.4-13.9) months, respectively. The most common regimen was platinum-based doublet chemotherapy ± bevacizumab, which was associated with an ORR/MST of 25.0%/29.1 months, respectively, in patients with de novo T790M mutations, and 22.2%/15.3 months, respectively, in patients with acquired T790M mutations. Conclusions This study reveals the treatment patterns and outcomes of NSCLC patients in Japan after detection of the T790M mutation. The most common treatment following detection of the T790M mutation was platinum-based doublet chemotherapy ± bevacizumab. Platinum-based doublet chemotherapy ± bevacizumab was moderately effective, indicating the need for targeted therapies for patients with T790M mutation-positive NSCLC.

Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis; however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor (TGF)-β1, in this study. To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation. In the bleomycin-induced early-stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-β1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF-β1 levels and relative changes of TGF-β1 mRNA expression, however, were not decreased significantly by sivelestat. These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-β activation and inflammatory cell recruitment in the lung.

[Purpose] This study examined the influence of signals from ankle joint afferent fibers on the reflexive plantae muscle activity during standing subjects. [Subject] Ten male healthy adults participated in this study. [Methods] The subjects stood with their eyes closed on a movable platform that was moved backward. Vibrators (about 90 Hz) were applied to the medial and lateral malleolus of both legs. The vibrators were turned off in the control condition. In the malleolus vibration (MV) condition, vibration stimulus was applied for one minute before the beginning of trials and was continued during the trials (about six minutes). The short (SLR) and medium latency reflex (MLR) of the flexor digitorum brevis muscle (FDB) electromyogram (EMG) responses of the left leg during the platform translations were measured under the control and MV conditions. [Results] The latencies of the FDB SLR and MLR during MV condition were observed to increase significantly in comparison to the control. The integration EMG response values (iEMG) of the SLR and MLR significantly decreased during MV condition. [Conclusion] Excessive afferent signals from the ankle articular mechanoreceptors may participate in the reduction of the reflexive FDB SLR and MLR activities during standing postural perturbation due to changes in the excitability of inhibitory interneurons.

背景．進行・再発肺癌に対する薬物治療法としてEGFR遺伝子変異陽性例についてはゲフィチニブの使用が推奨されているが，いずれ獲得耐性化することが多い．症例．65歳，女性．背部痛を主訴に受診．胸椎腫瘍を認め可及的切除術を施行された．胸部CTでは左下葉に結節影を認めた．病理組織所見から肺腺癌の胸椎転移と診断された（cT1N0M1，c-stage IV）．CBDCA+PTX 2コース施行後，ゲフィチニブを導入，肺腫瘍の縮小が得られたが6年のあいだに腫瘍は緩徐ながら再増大傾向を示した．気管支鏡下肺生検を施行し腺癌が検出され，EGFR遺伝子検査にてT790M耐性遺伝子を認めた．遠隔転移巣は制御されている一方，原発巣がゲフィチニブ耐性化したものと判断し左下葉切除術を施行した．術後1年8か月現在無再発生存中である．結論．胸椎転移巣の手術後，ゲフィチニブにより長期制御が得られたが耐性獲得化したため，サルベージ手術を施行し良好な結果を得たIV期肺癌の1例を経験した．獲得耐性部位が原発巣のみに限局している場合には，IV期進行肺癌であっても外科療法を考慮すべき余地があると考える．

An 83-year-old woman presented with dyspnoea. Chest X-ray showed right-sided pleural effusion, which was confirmed by chest CT scans on admission. A nodular shadow was also visualised in the front part of the chest ([figure 1][1]). 18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET)

Objective Physicians have provided care to only 0.2 million of the 5.3 million Japanese over the age of 40 years old who have chronic obstructive pulmonary disease (COPD). Among such individuals, many patients with respiratory symptoms diagnosed as chronic bronchitis (CB) are prescribed mainly expectorants. To determine the current status of COPD subjects diagnosed with and treated for CB, we investigated the prevalence of airflow limitation (AFL) in CB patients diagnosed by general practitioners (GPs) and the therapies administered to them. Methods Patients receiving treatment by GPs as CB completed a questionnaire and the FEV1/FEV6 ratio was measured by their GPs with a Piko-6. The prevalence of AFL (FEV1/FEV6

A 56-year-old woman was referred to our hospital because of dyspnea, wheezing, and a productive cough. Eight years before presentation, bronchial asthma was diagnosed and the patient received inhaled corticosteroids plus antiasthmatic agents (a long-acting inhaled p2-agonist, leukotriene modifiers, and theophylline). Chest radiography showed small diffuse nodular shadows, and a computed tomographic scan showed thickening of the bronchi and bronchioles, with diffuse centrilobular nodules in both lung fields. A blood test and microscopic examination of the bronchoalveolar fluid revealed marked eosinophilia. Transbronchial lung biopsy and transbronchial biopsy showed eosinophilic bronchitis and bronchiolitis. After treatment with oral prednisolone (40 mg daily) and inhaled corticosteroids, the symptoms, blood eosinophilia, and radiographic findings improved. Recently, several similar cases of eosinophilic bronchiolitis have been reported. Studies of further cases and elucidation of the pathophysiology of eosinophilic bronchiolitis are necessary to establish a concept for this disease and to determine whether it should be classified as a subtype of bronchial asthma or as a distinct entity.

Objective To examine the relation between annual trends in the antimicrobial susceptibility of Pseudomonas aeruginosa and drug usage, we compared annual changes in the susceptibility rates of P. aeruginosa clinical isolates during a 4-year period and annual trends in the overall usage of antimicrobials during the same period. Methods We studied annual trends in MIC(90)/MIC(50), antimicrobial use density (AUD), and antimicrobial susceptibility rates based on clinical breakpoints for 150 strains of P. aeruginosa isolated from respiratory specimens at Dokkyo Medical University Hospital from 2005 through 2008. Results The MIC(90)/MIC(50) of antimicrobials effective against P. aeruginosa in years 2005, 2006, 2007, and 2008 were as follows: imipenem, 32/2, 32/1, 8/2, and 16/1 microg/mL; meropenem, 8/1, 8/1, 4/0.5, and 4/0.5 microg/mL; and biapenem, 16/1, 32/0.5, 4/0.5, and 8/0.5 microg/mL, indicating that susceptibility to carbapenems increased slightly. The MIC(90)/MIC(50) was 4/0.25, 2/0.125, 1/0.125, and 2/0.25 microg/mL for ciprofloxacin, 8/4, 8/4, 4/4, and 8/4 microg/mL for amikacin, 64/16, 64/16, 64/16, and 64/16 microg/mL for sulbactam/cefoperazone, 8/2, 16/2, 32/2, and 8/2 microg/mL for ceftazidime, indicating little change. The AUDs of fourth-generation cephalosporins increased from 2005 to 2008 (16.2, 18.4, 28.0, and 23.0), while the AUDs of carbapenems decreased (25.7, 23.7, 10.9, and 12.5). Conclusion The decrease in the AUDs of carbapenems was associated with increased susceptibility rates of P. aeruginosa to carbapenem derivatives. A continuous understanding of trends in the resistance of P. aeruginosa and various other pathogens is essential for designing countermeasures against nosocomial infections, including the proper and effective use of antimicrobials.

The information conveyed from dendritic cells (DCs) to naïve CD4(+) T cells has crucial influence on their differentiation toward effector T cells. In an effort to identify DC-derived molecules directly contributing to T cell differentiation, we searched for molecules distinctively expressed between two DC subtypes, which were differentiated from peripheral monocytes by cultivation with GM-CSF (for DC1) or IL-3 (for DC2) in the presence of IL-4 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells, respectively. As the first step to address this issue, we subtracted DC1 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2, whose products are known to reside in other than the nucleus. Intriguingly, many of them were molecules involved in Th2-skewed disease pathologies, such as FN1, ITGAE, GPNMB, PLAUR, FPRL2, LILRB4, SERPINE1, ALOX15, TBXAS1, NCF2, CCL3, IL1RN, SPARC, and STAB1, suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations. We also found that expressions of CYP27A1, PPAP2B, RSAD2, and ABCC3 were up-regulated in DC2, implying their significant function in Th2-deviated states. The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC-derived key molecules for T cell differentiation.

Background and objective: Leucocytes, especially lymphocytes and neutrophils, as well as alveolar macrophages, that infiltrate into the lung are involved in the development of pulmonary fibrosis. However, the role of T helper (Th)2-type inflammation, mediated by Th2 cells and eosinophils, in fibrosis remains unknown. Transgenic mice deficient in the transcriptional repressor, Bcl6, display an attenuation of Th2 cytokine production. We studied the effects of Th2-type pulmonary inflammation on bleomycin-induced pulmonary fibrosis using Bcl6 transgenic mice. Methods: Bleomycin was administered to ovalbumin (OVA)-sensitized Bcl6 transgenic and wild-type mice by intratracheal instillation during sequential OVA antigen challenge. Concentrations of transforming growth factor-β1 in the BAL fluid were measured 2 weeks after bleomycin administration. At the same time lung tissue was examined histopathologically, and homogenized to assess collagen levels and Th1/Th2 cytokine mRNA expression. Results: Although OVA-sensitized, bleomycin-treated Bcl6 transgenic mice had markedly lower numbers of eosinophils in both BAL and lung tissue compared with OVA-sensitized, bleomycin-treated wild-type mice, the development of pulmonary fibrosis in response to bleomycin was similar in Bcl6 transgenic mice and wild-type mice. Conclusion: These results suggest that Th2-dominant inflammation in the lung is not essential for the development of bleomycin-induced pulmonary fibrosis.

廃用性萎縮筋における毛細血管，及び血管増殖因子の変化をラット後肢懸垂モデルで検証した。2週間の後肢懸垂後のヒラメ筋は，正常筋に比較して，筋湿重量は61％，筋線維横断面積は47％に減少し，廃用性萎縮を示した。毛細血管・筋線維比も，廃用性萎縮筋では23％の減少を示した。骨格筋細胞における酸化的リン酸化反応を示すコハク酸脱水素酵素活性は，廃用性萎縮筋で低下し，骨格筋細胞の代謝活性が低下していることを示唆した。また，低酸素で誘導されるHIF1- αmRNAは廃用性萎縮筋では変化せず，血管増殖因子VEGF mRNAやVEGFタンパク質は有意に低下を示した。これらの結果から，廃用に伴う不活動は骨格筋細胞の酸化系酵素活性を低下させると共に，毛細血管の退行的なリモデリングを発生させ，血管増殖因子の減少が関与することを明確にした。

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrosing disease. Acute exacerbation of IPF (AE-IPF) is an abrupt and rapid deterioration by unidentifiable causes which occurs during chronic clinical course of IPF. The estimated incidence is 5–15 % per year in IPF patients. Moreover, AE-IPF is not only associated with a very high mortality rate (over 70 %), but it is also an important determinant of overall prognosis in patients with IPF. Pathologically, AE-IPF is characterized by acute diffuse alveolar damage (DAD) lesion that develops close to the chronic progressive usual interstitial pneumonia (UIP) lesion. Because DAD is also a common pathological feature observed in acute respiratory distress syndrome (ARDS), acute interstitial pneumonia (AIP), and AE-IPF, it is possible to regard AE-IPF as ARDS developed due to IPF. Although the trigger factors for AE-IPF are often unclear, sometimes the triggers such as surgery, corticosteroid dose reduction, or viral infection are evident. Evidence-based and effective therapies are lacking for AE-IPF, with the current management guidelines recommending only supportive care and corticosteroid use. Novel treatments for AE-IPF that have been investigated in small-scale studies, including the use of polymyxin B-immobilized fiber column (PMX) hemoperfusion, may be promising. When AE with DAD pathology develops once, treatment is extremely difficult; therefore, development of effective prevention methods is required. To this date, there is emerging evidence from clinical trials of investigational treatments for chronic phase of IPF which may reduce the incidence of AE-IPF.

Transforming growth factor-alpha and epidermal growth factor (EGF), the ligands for EGF receptor (EGFR), stimulate fibroblast proliferation and play an important role in the pathogenesis of pulmonary fibrosis. Therefore, inhibition of the EGFR signal by an EGFR tyrosine kinase inhibitor (EGFR-TKI) may prevent pulmonary fibrosis. However, there is a possibility that blocking the EGFR signal may inhibit epithelial cell repair, thereby exaggerating lung fibrosis.To investigate the effect of EGFR-TK inhibition on lung fibrosis.We looked at the effects of the EGFR-TKIs gefitinib (20, 90, 200 mg/kg) and AG1478 (12 mg/kg) on a bleomycin-induced lung fibrosis model in mice.Gefitinib prevented lung fibrosis at all three doses. Furthermore, in those mice that did not receive bleomycin treatment, gefitinib at 200 mg/kg did not induce lung fibrosis. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited by gefitinib. AG1478 also attenuated the lung fibrosis. In vitro studies further demonstrated that the addition of gefitinib or AG1478 suppressed the EGFR ligand-induced proliferation of lung fibroblasts.These findings suggest that, in the preclinical setting, EGFR-TKIs may have a protective effect on lung fibrosis induced by bleomycin. Because these molecular targeted drugs may have differing effects depending on species and individuals, a cautious interpretation is warranted.

The physiological and pharmacological properties of contraction and the ultrastructure of buccal mass retractor muscle (I4) and gill-pinnule closure muscle (GPCM) in Aplysia kurodai were studied to learn more about the sources of activator Ca2+ in molluscan smooth muscle. Acetylcholine (ACh) and high K+-induced contractions were reduced by lowering the external Ca2+ concentration, and eliminated by the removal of extracellular Ca2+. Nifedipine appreciably reduced ACh- and high K+-induced contractions, while amiloride decreased only ACh-induced contractions and had no significant effect on high K+-induced contractions. When nifedipine and amiloride were applied together, either type of contraction was still appreciable. Serotonin (5-HT) could potentiate subsequent ACh- and high K+-induced contractions in I4; potentiated tension was significantly reduced by nifedipine and amiloride, whereas 5-HT inhibited ACh-and high K+-induced contractions in GPCM. The potentiating effects of 5-HT may be mediated by the activation of the Ca2+-channel to increase the influx from extracellular Ca2+. Caffeine caused contractions in Ca2+-free solution in both muscles. Electron microscopy revealed sarcolemmal vesicles underneath the plasma membrane in both muscle fibers. Electron microscopical cytochemistry demonstrated that pyroantimonate precipitates were localized in the sarcolemmal vesicles and in the inner surface of plasma membranes in the resting fibers. Present results indicate that the contractions of I4 and GPCM fibers are caused not only by Ca2+-influx but also by Ca2+ release from the intracellular storage sites, such as the sarcolemmal vesicles and the inner surface of plasma membranes.

A small GTPase, Rho, plays key roles in cell adhesion, motility, and contraction after stimulation. Among Rho effectors isolated, the family of Rho-associated coiled-coil-forming protein kinases (ROCK) is implicated in Rho-mediated cell adhesion and smooth muscle contraction. The effect of a specific inhibitor of ROCK, Y-27632, was evaluated in a murine model of acute lung injury induced by intravenous injection of Escherichia coli endotoxin (lipopolysaccharide [LPS]). Lung edema was evaluated by measuring extravascular leakage of radio-labeled serum albumin, and neutrophil emigration into the lung parenchyma by morphometric observation and measuring myeloperoxidase activity. Pretreatment with Y-27632 attenuated both lung edema and neutrophil emigration after LPS. We also measured albumin transfer through cultured endothelial cell monolayers on a porous filter. Tumor necrosis factor-alpha significantly increased albumin transfer, which was attenuated by pretreatment with Y-27632. Fluorescence microscopy revealed that morphologic changes in endothelial cells induced by tumor necrosis factor-alpha were inhibited by Y-27632. In contrast, the increased fraction of neutrophils with polymerized actin after formyl-methionyl-leucyl-phenylalanine was not altered by Y-27632. These data suggest that ROCK may play an important role in the pathogenesis of LPS-induced lung injury and that ROCK inhibition could attenuate cytoskeletal rearrangement of endothelial cells, leading to decreased neutrophil emigration into the lung parenchyma.

目的. 肺癌の骨転移において18F-fluorodexyglucose positron emission tomography (18FDG-PET) を99mTc骨シンチと比較し, その有用性を検討した. 対象及び方法. 2003年4月から2004年10月まで骨シンチとPETとを同時期に施行した肺癌症例を対象とした. 骨転移の最終診断は両検査に加え, 骨単純X線, CT, MRI及び臨床経過にて判定した. 症例は29例で, 男性20名, 女性9名, 平均年齢66.7歳, 組織型は扁平上皮癌9例, 腺癌13例, 腺扁平上皮癌1例, 小細胞癌3例, 肺胞上皮癌2例, 未分化癌1例. 病期はIA期6例, IB期1例, IIB期1例, IIIA期6例, IIIB期5例, IV期10例であり, IV期のうち7例に骨転移を認めた. 結果. 骨シンチでは感度100%, 特異度81.8%であり, 偽陽性4例あった. PETでは感度100%, 特異度86.3%であり, 偽陽性3例あった. 両検査方法の偽陽性・偽陰性の原因として, (1) PETでは骨周辺部位の病変と骨転移との鑑別が困難な場合があること, (2) 骨折病変への取り込みは骨シンチに比較し, PETでは早期に陰性化することなどが挙げられた. 結論. PETは骨シンチと同等以上の診断能を有しており, 同時に他臓器への転移診断が可能な点を考慮すれば, 今後, 骨シンチに代わる検査と考えられる.

Background Airway remodeling has an important role in the pathogenesis of bronchial asthma. Many mediators that influence the pathophysiology of bronchial asthma, especially cysteinyl leukotrienes (CysLTs) and TGF-β 1 , are involved in airway remodeling. Objective To know whether TGF-β 1 alters fibroblast responsiveness to CysLTs, we examined the effects of leukotriene (LT) D 4 on collagen production from fibroblasts and from myofibroblasts transformed by TGF-β 1 . We also examined whether TGF-β 1 upregulates CysLT1 receptor (CysLT1R) expression in fibroblasts. Methods Concentrations of procollagen in the human fetal lung fibroblast (HFL) 1 cell supernatant were measured by using an enzyme immunoassay kit in the presence or absence of various concentrations of LTD 4 , TGF-β 1 , CysLT1R antagonist, or some combination of these. The mRNA expression of CysLT1R and α-smooth muscle actin as a marker of myofibroblasts was measured by means of real-time PCR. Furthermore, protein expression of CysLT1R on fibroblasts was measured by means of flow cytometric analysis. Results TGF-β 1 stimulated collagen production from HFL-1 cells, but LTD 4 alone did not. LTD 4 in combination with TGF-β 1 increased collagen production compared with TGF-β 1 alone. Real-time PCR showed that stimulation with TGF-β 1 significantly upregulated CysLT1R and α-smooth muscle actin mRNA expression in HFL-1 cells. Conclusions LTD 4 increased collagen production by upregulating CysLT1R induced by TGF-β 1 . In the TGF-β–rich milieu, activated myofibroblasts expressing CysLT1R can respond to CysLTs and produce large amounts of extracellular matrix, thereby contributing to airway remodeling. These data suggest that treatment with leukotriene receptor antagonists might prevent airway remodeling in patients with asthma.

Item does not contain fulltext A case of disseminated nontuberculous mycobacteria(l) (NTM) infection in a patient with positive neutralizing anti-interferon-gamma (IFN-gamma) autoantibodies involving bone, bronchus, systemic lymph nodes, and skin is reported. The causative NTMs were two different strains: Mycobacterium gordonae, which rarely causes true disease, and Mycobacterium mantenii, which is extremely rare. Anti-mycobacterial treatment successfully ameliorated all disseminated lesions. Although the concentration of anti-IFN-gamma autoantibodies increased during the pre-treatment period, it gradually decreased after anti-mycobacterial treatment was started.

Numerous in vitro and in vivo studies in both animals and patients with asthma have shown that interleukin (IL)-9 is an important inflammatory mediator in asthma. To examine the effects of IL-9 antagonism on airway inflammation, ovalbumin-sensitized BALB/c mice were intravenously given anti-IL-9 antibody or an isotype-matched control antibody 30 minutes before challenge with aerosolized ovalbumin. Airway response to methacholine was measured, and samples of bronchoalveolar lavage fluid (BALF) were obtained 24 hours after the last antigen challenge. Lung tissue was harvested and examined histopathologically. After ovalbumin challenge, there were significant increases in airway hyperreactivity, the numbers of inflammatory cells in lung, and IL-4, IL-5, and IL-13 production in BALF. Treatment with anti-IL-9 antibody significantly prevented airway hyperreactivity in response to methacholine inhalation. Blockade of IL-9 reduced the numbers of eosinophils (0.3 +/- 0.1 x 10(5) and 23.6 +/- 0.5 x 10(5)/ml, anti-IL-9 antibody/control immunoglobulin G) and lymphocytes (0.2 +/- 0.2 x 10(5) and 0.8 +/- 0.1 x 10(5)/ml) in BALF. Anti-IL-9 antibody treatment also reduced the concentrations of IL-4 (from 70.6 +/- 4.6 to 30.8 +/- 5.2 pg/ml), IL-5 (from 106.4 +/- 12 to 54.4 +/- 6.6 pg/ml), and IL-13 (from 44.2 +/- 7.6 to 30.1 +/- 5.5 pg/ml) in BALF. Macrophage-derived cytokine expression in the airways was also decreased by IL-9 blockade. Taken together, our findings emphasize the importance of IL-9 in the pathogenesis of asthma and suggest that blockade of IL-9 may be a new therapeutic strategy for bronchial asthma.

Background: Ves v 5 and Pol d 5, which constitute antigen 5, are recognized as the major, most potent allergens of family Vespidae. Several studies have reported the diagnostic sensitivity of the novel recombinant (r)Ves v 5 and rPol d 5 allergens in routine clinical laboratory settings by analyzing a group of Vespula and Polistes venom-allergic patients. In this study, we analyzed the sensitivity to venom specific (s)IgE by spiking with rVes v 5 and rPol d 5 in Japanese patients suspected of Hymenoptera venom allergy. Methods: Subjects were 41 patients who had experienced systemic reactions to hornet and/or paper wasp stings. Levels of serum sIgE against hornet and paper wasp venom by spiking with rVes v 5 and rPold d 5, respectively, as improvement testing, compared with hornet and paper wasp venom, as conventional testing, were measured by ImmunoCAP. Results: Of the 41 patients, 33 (80.5%) were positive (≥0.35 UA/ml) for hornet and/or paper wasp venom in conventional sIgE testing. sIgE levels correlated significantly (P

Objectives Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are particularly effective in non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. However, some studies have reported survival benefits in NSCLC patients with wild-type EGFR upon erlotinib treatment. This trial was conducted to evaluate the efficacy of erlotinib monotherapy and investigate the predictive values of several biomarkers. Patients and methods Patients with previously treated NSCLC but without EGFR gene mutations that had never or light smoked were eligible for this study. Gene status screening was performed using the PNA-LNA PCR clamp method. Erlotinib was administered until disease progression or unacceptable toxicities occurred. EGFR gene status was re-evaluated using the fragment method to detect exon 19 deletions and the Cycleave-PCR method to detect point mutations. Expression of hepatocyte growth factor (HGF), Met, and thymidylate synthase (TS) were evaluated using immunohistochemistry. Results Forty-seven patients were enrolled in the study between March 2010 and November 2011. Objective response rate (ORR) and disease control rate (DCR) were 15.2% and 41.3%. Re-evaluations for EGFR gene were performed in 32 tumor samples. EGFR gene mutations were found in eight samples (5:exon 19 deletion, 2:G719X, 1:L858R). Six patients had PR and two had SD among these eight patients. A total of 24 patients were confirmed as wild-type EGFR using different methods. ORR and DCR were 4.2% and 41.7%. The median progression free survival (PFS) and median survival times were 2.0 and 6.0 months, respectively. Patients with tumors expressing HGF showed shorter PFS but not MET or TS. Conclusions Re-examination of EGFR gene status using different detecting method or different sample should be considered to grasp a chance of erlotinib treatment after first line treatment. In confirmed EGFR wild NSCLC, negative HGF staining could be a biomarker for longer PFS by erlotonib treatment.

The melanophores in the dermis on scales in the bitterling, Acheilognathus lanceolatus were studies to obtain information about the control mechanism of aggregation and dispersion using intact, membrane-permeabilized and cultured cells. The cultured melanophores showed supersensitivity, namely, they responded to norepinephrine with much higher sensitivity than intact cells. The cultured melanophores failed to respond to high KCl. Melatonin aggregated and adenosine dispersed melanosomes within a cell. Digitonin permeabilized cells showed aggregation with Ca ions and dispersion by cyclic adenosine 3',5'-monophosphate (cAMP) in the presence of ATP. Movement of melanosomes was observed under the high magnification of light microscope and the tracks of each pigment granule were followed. The granules moved fast and linearly during aggregation, whereas they showed to-and-fro movement during dispersion.

Reactive oxygen species (ROS) play an important role in the pathogenesis of pulmonary fibrosis. We previously demonstrated that N-acetylcysteine (NAC), an antioxidant, inhibited adhesion molecule expression and cytokine production in lung cells. When NAC is inhaled into the alveolar space, it is expected to directly interact with inflammatory cells and to elevate glutathione levels in the epithelial lining fluids. We therefore examined whether inhaled NAC inhibits lung fibrosis induced by bleomycin (BLM). Male ICR mice were given a single intravenous injection of BLM (150 mg/ kg). Thirty milliliters of NAC (70 mg/ml) or saline were inhaled twice a day for 28 d using an ultrasonic nebulizer. In the inflammatory phase (Day 7), NAC administration attenuated the cellular infiltration in both bronchoalveolar lavage fluid (BALF) and alveolar tissues. At Day 28, the fibrotic changes estimated by Aschroft's criteria and hydroxyproline content in the NAC inhalation group were significantly decreased compared with the BLM-only group (p < 0.05). CXC chemokines, macrophage inflammatory protein-2 (MIP-2), cytokine-induced neutrophil chemoattractant (KC), and CC chemokines, macrophage inflammatory protein-1alpha (MIP-1alpha), in BALF were mostly elevated on Day 7 in the BLM-only group; however, these elevations were significantly repressed by NAC inhalation (p < 0.05). Lipid hydroperoxide (LPO) was also quantified in BALF. LPO was markedly increased on Day 3 in the BLM-only group, and this increase was significantly decreased by NAC inhalation (p < 0.05). These results revealed that aerosolized NAC ameliorated acute pulmonary inflammation induced by BLM injection via the repression of chemokines and LPO production, resulting in the attenuation of subsequent lung fibrosis. These findings are limited to the BLM-induced lung fibrosis animal model. However, NAC inhalation will be expected to be a potential therapy for patients with other interstitial pneumonias because ROS are involved in the pathogenesis of lung injury in most interstitial pneumonia.

Although sarcoidosis and lung cancer are both frequently encountered conditions, their simultaneous occurrence in the same patient is unusual. In this report, we describe 4 cases of their concurrence and discuss the possible pathogenic mechanisms of their concurrent appearance. In particular, in 2 of the cases, both diseases had coexisted for a long period (more than 6 and 4 years, respectively), showing a surprisingly slow growth of cancers. Although the chest computed tomography showed hilar and mediastinal lymphadenopathy, the histopathological findings of the excised lymph nodes of both cases revealed no metastasis. The causal relationship between sarcoidosis and lung cancer remains uncertain, but cases such as these may be helpful in elucidating its precise nature.

New quinolone (NQ) antimicrobials have strong bactericidal effects and a broad spectrum of antimicrobial activities. In this study, we investigated the in vitro effects of grepafloxacin (GPFX), a newly developed fluoroquinolone, on neutrophil functions. Superoxide production by neutrophils was measured using the ferricytochrome reduction assay. Enhancement of Superoxide production was observed in the presence of more than 10μg/ml of GPFX when stimulated with formyl-methionyl-leucyl-phenylalanine (FMLP) and more than 3μg/ml when stimulated with phorbol myristate acetate (PMA) . Neutrophils pretreated with more than 30μg/ml of GPFX also showed enhancement of superoxide production in response to both of the two stimuli. On the other hand, GPFX had no effect on FMLP-induced neutrophil chemotaxis at any of the concentrations (1 to 100μg/ml) . These results suggest that GPFX facilitates the improvement of bacterial infections with the combination of its bactericidal effect and the activation of neutrophils in vivo.

To clarify the bronchoscopic findings in metastatic spread to the bronchi, we analyzed the records of 65 cases of metastatic pulmonary disease in which fiberoptic bronchoscopy had been done. Forty-five patients (69.2%) had abnormal bronchoscopic findings. These patients could be divided into three groups, according to bronchoscopic findings and route of metastatic spread to the bronchi: endobronchial metastasis (n=15), bronchial involvement (that is, direct extension to the bronchi from adjacent metastatic foci, n=15), and lymphangitis carcinomatosa (n=15). Breast cancer and colon cancer were common in cases of endobronchial metastasis, and the bronchial tumor often presented as a polypoid or nodular lesion covered with necrotic material. Submucosal swelling with an irregular margin and narrowing of the bronchial lumen were seen in cases of bronchial involvement. In conclusion, each type of primary extrapulmonary tumor is associated with characteristic endobronchial findings of pulmonary metastases such as endobronchial metastasis and bronchial involvement, which should be discriminated if possible, because of their different metastatic process.

Recent studies suggest that nitric oxide (NO) may play an important role in the pathophysiology of pulmonary hypertension. Nitroglycerin is metabolized to NO, which is a potent vascular smooth muscle relaxant. The aim of the present study was to compare the effects of inhaled and infused nitroglycerin on pulmonary hemodynamics and gas exchange in anesthetized, artificially ventilated dogs. Nitroglycerin was administrated either by inhalation or by infusion. Systemic blood pressure (SBP), pulmonary arterial pressure (PAP), and pulmonary capillary wedge pressure (PCWP) were measured, and cardiac output was estimated by an electromagnetic flowmeter. Blood gas measurements were performed during hypoxic gas exposure (FiO2; 0.1) with a continuous inhalation or infusion of nitroglycerin (1, 2.5 µg/kg/min). Inhaled (n = 4) and infused (n = 4) nitroglycerin (1 µg/kg/min) did not produce any detectable effects on the hemodynamics. Inhaled nitroglycerin (2.5 µg/kg/min) reduced SBP, PAP and calculated pulmonary vascular resistance (PVR) in all dogs. Cardiac output did not change. In addition, inhaled nitroglycerin increased PaO2. In contrast, the continuous infusion of nitroglycerin (2.5 µg/kg/min) did not change in PAP, whereas infused nitroglycerin decreased the mean SBP. Infused nitroglycerin did not alter cardiac output and calculated PVR. A decreased PaO2 was noted in 2 dogs on nitroglycerin infusion. These findings indicate that inhaled nitroglycerin effects the pulmonary circulation relatively more than infused nitroglycerin, which tends to have more of a general effect on the systemic circulation. The effects of inhaled nitroglycerin may thus be comparable to the effects of NO inhalation.

To elucidate the role of major chemotactic factors, cytokine-induced neutrophil chemoattractant (CINC), leukotriene B4 (LTB4) and C5a in lipopolysaccharide (LPS)-induced acute lung injury in rat, we employed three reagents: anti-CINC-1 antibody, an LTB4 receptor antagonist (ONO-4057) and an anti-complementary agent (K-76COONa). Rats were divided into five groups: (1)control group; (2) LPS group, which received intratracheal instillation of LPS (100 microg/kg); (3) Anti-CINC group, which received intratracheal coinstillation of LPS with anti-CINC-1 antibody (1 mg/kg); (4) LTB4-Ra group, which received intravenous ONO-4057 (10 mg/kg) prior to intratracheal LPS; (5) Anti-C5a group, which received intravenous K-76COONa (100 mg/kg) prior to intratracheal LPS. The number of neutrophils in bronchoalveolar lavage (BAL) fluids 6 h after LPS instillation was significantly reduced in the Anti-CINC group, however, no reduction was found in either the LTB4-Ra group or Anti-C5a group. The levels of CINC-1, CINC-2alpha and CINC-3 in BAL fluids were significantly higher in the LPS group than in the saline-instilled control group. In vitro, the production of CINC-1 and CINC-3 from LPS-stimulated macrophages was significantly elevated compared to unstimulated macrophages 6 h later. The increase in CINC-2alpha production was markedly less than that of CINC-1 or CINC-3. These results indicate that CINCs, especially CINC-1 and CINC-3 play an important role in the recruitment of neutrophils to the lung in LPS-induced acute lung injury.