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Cells communicate with each other to coordinate their gene activities at the population level through signaling pathways. It has been shown that many gene activities are oscillatory and that the frequency and phase of oscillatory gene expression encode various types of information. However, whether or how such oscillatory information is transmitted from cell to cell remains unknown. Here, we developed an integrated approach that combines optogenetic perturbations and single-cell bioluminescence imaging to visualize and reconstitute synchronized oscillatory gene expression in signal-sending and signal-receiving processes. We found that intracellular and intercellular periodic inputs of Notch signaling entrain intrinsic oscillations by frequency tuning and phase shifting at the single-cell level. In this way, the oscillation dynamics are transmitted through Notch signaling, thereby synchronizing the population of oscillators. Thus, this approach enabled us to control and monitor dynamic cell-to-cell transfer of oscillatory information to coordinate gene expression patterns at the population level., (© 2017 Isomura et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Early postpartum women are more likely to develop tuberculosis than nonpregnant women mainly due to immune reconstitution after delivery. Paradoxical response (PR) during antituberculosis treatment also arises via recovery from immunosuppression. However, no study focused on PR during antituberculosis treatment in a postpartum patient has been reported., Case Presentation: We present two sequential cases (Patient 1: 26-year-old; Patient 2: 29-year-old) of postpartum tuberculosis with pulmonary and extrapulmonary lesions (Patient 1: peritonitis; Patient 2: psoas abscess secondary to spondylitis). Both cases progressed to PR (worsening of pre-existing lung infiltrations (Patients 1, 2) and new contralateral effusion (Patient 2)) in a relatively short time after initiation of treatment (Patient 1: 1 week; Patient 2: 3 weeks), suggesting that immune modulations during pregnancy and delivery may contribute to the pathogenesis of both disseminated tuberculosis and its PR. The pulmonary lesions and effusion of both cases gradually improved without change of chemotherapy regimen., Conclusion: Physicians should recognize PR in tuberculosis patients with postpartum and then evaluate treatment efficacy.

Background: Mycobacterium xenopi-infected patients have a high prevalence of pulmonary cavities and nodules. However, the clinical course for patients with miliary nodules due to M. xenopi has not yet been reported., Case Presentation: We encountered a case of miliary nodules with gradually worsening coughing and sputum production in a 44-year-old male who had renal dysfunction due to glomerulosclerosis with a decade-long history of steroid therapy. Although we started anti-tuberculosis treatment on clinical suspicion of miliary tuberculosis, cultures of sputum and bronchial lavage were both positive for M. xenopi. The patient was successfully treated with rifampin, ethambutol and clarithromycin, without fibrosis. It was unclear whether the miliary pattern was induced by hematogenous or endobronchial spread of the M. xenopi infection., Conclusion: Even when clinical and radiological disease manifestations are similar to those of miliary tuberculosis, M. xenopi infection should be considered in the differential diagnosis of miliary nodules.

Aim: The present study aimed to evaluate the effectiveness and safety of weekly paclitaxel (PTX) combined with carboplatin (CBDCA) plus bevacizumab (BEV), followed by maintenance BEV in patients with advanced NSCLC., Patients and Methods: Patients with unresectable stage IIIB and IV NSCLC (n=43) were treated with CBDCA (AUC 6, day 1), BEV (15 mg/kg, day 1), and PTX (70 mg/m(2), days 1, 8, 15) intravenously every 4 weeks, for 3 to 6 cycles, followed by maintenance BEV (15 mg/kg) every 3 weeks., Results: The objective response rate and disease control rate were 67.4% and 90.7%, respectively. The median progression-free survival was 7.6 months. The median overall survival was 17.7 months. Common adverse events were tolerable bone marrow suppression, fatigue, hypertension, and nasal bleeding., Conclusion: Weekly administration of PTX combined with CBDCA plus BEV therapy was effective, and well-tolerated by advanced NSCLC patients., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare entity of unknown etiology in young adults that is typically characterized by cervical lymphadenopathy and persistent fever. The pathogenesis of KFD has been suggested to be an abnormal immune response, and infections or autoimmune diseases are considered to be involved in KFD. However, KFD associated with community acquired pneumonia (CAP) has not been reported., Case Description: A 35-year-old male was admitted due to high fever, diffuse air-space consolidation in the right lung with ipsilateral pleural effusion and massive mediastinal and hilar lymphadenopathy without cervical lesions. On clinical suspicion of malignant lymphoma complicated with pneumonia, we performed a video-assisted thoracoscopic lymph node biopsy, and the diagnosis of KFD was established. Complete cure of the intrathoratic lesions was observed by administration of β-lactam antibiotics alone without steroid therapy., Discussion and Evaluation: Previous large case series have identified no pathogenic relationship between KFD and pneumonia. The hilar adenopathy could have caused airway compression leading to pneumonia., Conclusions: KFD should be considered in the differential diagnosis of massive mediastinal and hilar lymphadenopathy, even when there are no superficial lesions. In addition, we need to bear in mind that unexpected disorders occasionally coexist with common diseases.

Background: Central airway obstruction (CAO) may be caused by various etiologies. However, conventional chest X-rays are rarely diagnostic for patients with CAO., Case Presentation: We here described a 64-year-old asymptomatic female with tracheal mucosa-associated lymphoid tissue lymphoma discovered on spirometric findings during a complete physical examination. The plateau of forced expiratory flow was consistent with CAO. A decreased peak expiratory flow rate was noted at least 3 years before the diagnosis, and was attributed to an insufficient effort by the patient. Impulse oscillometric measurements, which were taken during quiet breathing and were effort-independent, suggested elevated respiratory resistance. These abnormalities completely disappeared after radiation therapy., Conclusion: The addition of impulse oscillometry to spirometry may be useful for screening CAO in routine health examinations.

A 51-year-old man was admitted to our hospital because of fever and diarrhea. Chest X-ray revealed consolidation in the left lower lung field. Ceftriaxone and minocycline were given empirically, under the suspicion of bacterial or atypical pneumonia. In spite of treatment with antibiotics, the disease rapidly progressed to systemic inflammatory response syndrome. The diagnosis of acute respiratory distress syndrome (ARDS) accompanied with influenza (H1N1) 2009 was made because of positive findings of real-time polymerase chain reaction. While multidisciplinary treatment was performed, his condition was further deteriorated suggesting the excessive pro-inflammatory mediators. To remove them, we conducted polymyxin-B immobilized column-direct hemoperfusion (PMX-DHP), and his general condition recovered successfully. PMX-DHP may be a useful treatment choice for ARDS accompanied with influenza.

A case of primary gingival tuberculosis in a 71-year-old Japanese woman is herein presented. A serous saliva culture was positive for tuberculosis, and we recognized that the origin of the tuberculosis infection was the gingiva based on the genetic identification in gingival biopsy tissue. The definitive diagnosis was facilitated by the genetic identification, a useful modern tool for diagnosing infectious diseases. The location and clinical presentation of this lesion were unusual, which underlines the importance of considering tuberculosis in the differential diagnosis of oral lesions that affect the gingiva.

Interstitial lung disease (ILD) has a heterogeneous clinical presentation and establishing prognosis for these patients is challenging. We investigated the clinical characteristics and outcome of patients with idiopathic interstitial pneumonias (IIPs) and patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). We conducted a multicenter prospective study on 104 patients diagnosed with IIPs and 29 patients diagnosed with CTD-ILD, which were newly diagnosed and treated with corticosteroids initially. We compared the clinical characteristics, high-resolution computed tomography (HRCT) imaging date, and outcomes. Cox proportional hazard regression analysis was used to identify variables with increased risk of death. Survival was analyzed according to the Kaplan-Meier method and was assessed with the log-rank test. Of 133 patients with IIPs (n = 104) or CTD-ILD (n = 29), 44 patients died during the follow-up period (mean: 1.6 ± 0.78 years). Patients with IIPs seemed to be associated with worse survival compared with those with CTD-ILD; however, this difference was not significant (log-rank test, P = 0.084). Significant predictors for mortality in patients with IIPs at baseline were lower for performance status and definite usual interstitial pattern (UIP) on HRCT. Patients with UIP experienced worse survival than those with non-UIP. A definite UIP on HRCT and lower baseline performance status have important prognostic implications in patients with IIPs.

Background: Pneumonitis is a rare complication of bacillus Calmette-Guerin (BCG) immunotherapy seen in patients with urothelial cancer following the repeated administration of BCG. However, no case of BCG-induced pleurisy has been reported., Case Presentation: We here report the first case of pneumonitis with lymphocytic pleurisy following bacillus Calmette-Guerin (BCG) immunotherapy. Although marked T helper cell alveolitis was found by bronchoalveolar lavage and transbronchial biopsies, no acid-fast bacillus could be identified in recovered BALF or pleural effusion. The lymphocyte stimulation test of BCG was strongly positive. However, levels of serum and bronchoalveolar lavage fluid KL-6, a useful marker for hypersensitivity pneumonitis (HP), were within normal ranges., Conclusion: We speculate that the pathogenesis of our case may be a hypersensitive reaction to the proteic component of BCG entering the lung and pleural space, which is different from the etiology of the common type of HP.

Background/aims: The Japanese National Hospital Organization evidence-based medicine (EBM) Study group for Adverse effects of Corticosteroid therapy (J-NHOSAC) is a Japanese hospital-based cohort study investigating the safety of the initial use of glucocorticoids (GCs) in patients with newly diagnosed autoimmune diseases. Using the J-NHOSAC registry, the purpose of this observational study is to analyse the rates, characteristics and associated risk factors of intracellular infections in patients with newly diagnosed autoimmune diseases who were initially treated with GCs., Methodology/principal Findings: A total 604 patients with newly diagnosed autoimmune diseases treated with GCs were enrolled in this registry between April 2007 and March 2009. Cox proportional-hazards regression was used to determine independent risk factors for serious intracellular infections with covariates including sex, age, co-morbidity, laboratory data, use of immunosuppressants and dose of GCs. Survival was analysed according to the Kaplan-Meier method and was assessed by the log-rank test. There were 127 serious infections, including 43 intracellular infections, during 1105.8 patient-years of follow-up. The 43 serious intracellular infections resulted in 8 deaths. After adjustment for covariates, diabetes (Odds ratio [OR]: 2.5, 95% confidence interval [95% CI] 1.1-5.9), lymphocytopenia (≦1000/μl, OR: 2.5, 95% CI 1.2-5.2) and use of high-dose (≧30 mg/day) GCs (OR: 2.4, 95% CI 1.1-5.3) increased the risk of intracellular infections. Survival curves showed lower intracellular infection-free survival rate in patients with diabetes, lymphocytopaenia and high-dose GCs treatments., Conclusions/significance: Patients with newly diagnosed autoimmune diseases were at high risk of developing intracellular infection during initial treatment with GCs. Our findings provide background data on the risk of intracellular infections of patients with autoimmune diseases. Clinicians showed remain vigilant for intracellular infections in patients with autoimmune diseases who are treated with GCs.

Bronchopleural fistula (BPF) is a potentially fatal complication of lung cancer resection surgery that occurs during the healing process of the bronchial stump. However, the vulnerability of the healed surgical wound to overlapping acquired airway destruction has not yet been determined in detail. We herein present a case of fatal BPF following Mycobacterium abscessus (M. abscessus) infection, which occurred 11 years after right upper lobectomy for lung cancer. The findings of the present study suggest that patients with M. abscessus pulmonary disease in which airway destruction is progressing towards the bronchial stump of previous lobectomy should be considered for early completion pneumonectomy to prevent fatal BPF.

Aim: Assessment of the efficacy of docetaxel plus carboplatin vs. paclitaxel plus carboplatin in Japanese patients with advanced non-small cell lung cancer (NSCLC)., Patients and Methods: Chemotherapy-naïve patients were randomly assigned at a ratio of 2 to 1 to receive six cycles of either docetaxel (60 mg/m(2)) plus carboplatin [area under the curve (AUC)=6 mg/ml min] or paclitaxel (200 mg/m(2)) plus carboplatin (same dose), on day 1 every 21 days. The primary end-point was progression-free survival (PFS)., Results: A total of 90 patients were enrolled. Overall response rate, median PFS and median survival time in the docetaxel-plus-carboplatin group and the paclitaxel-plus-carboplatin group were 23% vs. 33%, 4.8 months vs. 5.1 months, and 17.6 months vs. 15.6 months, respectively. The docetaxel-plus-carboplatin group had a higher incidence of grade 3 or 4 neutropenia (88% vs. 60%)., Conclusion: Both regimens were similarly effective in Japanese patients with advanced NSCLC.

Background: The pathogenesis of primary tuberculous pleurisy is a delayed-type hypersensitivity immunogenic reaction to a few mycobacterial antigens entering the pleural space rather than direct tissue destruction by mycobacterial proliferation. Although it has been shown that pulmonary tuberculosis induces 18-fluorodeoxyglucose (FDG) uptake in active lesions, little is known about the application of FDG positron emission/computed tomography (FDG PET/CT) to the management of primary tuberculous pleurisy., Case Presentation: We report a case of asymptomatic primary tuberculous pleurisy presenting with diffuse nodular pleural thickening without distinct pleural effusion and parenchymal lung lesions mimicking malignant mesothelioma. An initial FDG PET/CT scan demonstrated multiple lesions of intense FDG uptake in the right pleura and thoracoscopic biopsy of pleural tissue revealed caseous granulomatous inflammation. The patient received antituberculous therapy for 6 months, with clearly decreased positive signals on a repeated FDG PET/CT scan., Conclusion: FDG PET/CT imaging may be useful for evaluating disease activity in tuberculous pleurisy patients with an unknown time of onset.

All-atom molecular dynamics (MD) simulation has become a powerful research tool to investigate structural and dynamical properties of biological membranes and membrane proteins. The lipid structures of simple membrane systems in recent MD simulations are in good agreement with those obtained by experiments. However, for protein-membrane systems, the complexity of protein-lipid interactions makes investigation of lipid structure difficult. Although the area per lipid is one of the essential structural properties in membrane systems, the area in protein-membrane systems cannot be computed easily by conventional approaches like the Voronoi tessellation method. To overcome this limitation, we propose a new method combining the two-dimensional Voronoi tessellation and Monte Carlo integration methods. This approach computes individual surface areas of lipid molecules not only in bulk lipids but also in proximity to membrane proteins. We apply the method to all-atom MD trajectories of the sarcoplasmic reticulum Ca(2+)-pump and the SecY protein-conducting channel. The calculated lipid surface area is in agreement with experimental values and consistent with other structural parameters of lipid bilayers. We also observe changes in the average area per lipid induced by the conformational transition of the SecY channel. Our method is particularly useful for examining equilibration of lipids around membrane proteins and for analyzing the time course of protein-lipid interactions., (Copyright © 2011 Wiley Periodicals, Inc.)

An 83-year-old woman was admitted to our hospital with abdominal pain. Examination revealed mediastinal lymphoadenopathy, hepatosplenomegaly, and infiltration of abnormal cells into the bone marrow with hemophagocytosis, and CD5-positive diffuse large B cell lymphoma was diagnosed. Chemotherapy was administered and progressive weakness of the limbs, resembling a Guillain-Barré-like syndrome, subsequently appeared. Cerebrospinal fluid examination indicated lymphoma cell infiltration. Although immune globulin and steroid therapies were not effective, intrathecal injection of methotrexate, predonisolone, and cytarabine improved these symptoms. Subsequent to chemotherapy, cell surface antigen changes were observed in the cerebrospinal fluid relative to those in bone marrow.

A 47-year-old woman was transported to our hospital because of vomiting and syncope after breakfast. Physical examination revealed icterus and anemia of bulbar conjunctivas, and abnormal neurological findings were detected. Laboratory data indicated marked anemia and thrombocytopenia (Hb 5.2 g/dl, Plt. 0.6×10(4)/μl), but no leukocyte abnormalities were found. Transaminase was slightly elevated, and serum indirect bilirubin in was also elevated. Based on these data, we initially suspected Evan's syndrome, which involves idiopathic thrombocytopenic purpura with autoimmune hemolytic anemia. So we transfused red blood cells, performed platelet transfusion, and administered steroids, but there was no response to these therapies. On the 4th day of admission, she developed a stroke followed by coma. After the stroke, we diagnosed the case as thrombotic thrombocytopenic purpura (TTP) because laboratory findings showed diminished activity of ADAMTS 13 (a disintegrin-like metalloproteinase with thrombospondin type 1 motifs 13) and ADAMTS 13 antigen. It is important to suspect TTP when hemolytic anemia with thrombocytopenia is observed, and to check the activity and antigen of ADAMTS13 immediately for the diagnosis. Platelet transfusion should be done cautiously in these cases.

A 65-year-old woman whose rheumatoid arthritis was treated with tocilizumab (TCZ) was found in chest radiography to have a new consolidation in the right lower lung field. Positive Mycobacterium intracellulare and Mycobacterium avium cultures in sputum and bronchial secretions yielded a diagnosis of pulmonary nontuberculous mycobacteriosis. The most common adverse TCZ effect is infection. This case highlights the fact that those treated with TCZ should be considered at elevated risk for developing nontuberculous mycobacteriosis.

We encountered 2 cases of drug-induced intrathoracic lesions caused by allergic reactions to mesalazine in patients with ulcerative colitis. Case 1: A 26-year-old man had a fever, cough and exertional dyspnea after 1 month of mesalazine treatment. He was hospitalized because of bilateral pulmonary infiltrates on a chest X-ray film. Case 2: A 27-year-old woman complained of fever and left back pain that exacerbated after 2 weeks of mesalazine treatment. She was hospitalized because of bilateral pulmonary effusions on chest CT. Both patients showed a positive reaction to a drug lymphocyte stimulation tests (DLST) for mesalazine. The first case was given a diagnosis of eosinophilic pneumonia by bronchoscopic examination, and responded to steroid therapy after discontinuation of mesalazine. The second case was given a diagnosis of pleuritis and improved on cessation of Mesalazine treatment.

S-1 is an oral anticancer fluoropyrimidine agent designed to elevate anticancer activity with a decrease in gastrointestinal toxicity. We conducted a phase II study to evaluate the efficacy and safety of combination chemotherapy with S-1 plus cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients were treated with S-1 administered orally at 40 mg/m(2) twice a day for 21 consecutive days, and cisplatin (60 mg/m(2)) infused intravenously on day 8, repeated every 5 weeks. Of the 44 patients enrolled in the study, 40 were assessable for efficacy and safety. The median number of cycles administered was 3 (range 1-9 cycles). Among the 40 assessable patients, 7 partial responses were observed, with an overall response rate (RR) of 17.5% [95% confidence interval (CI), 5.2-29.8]. Patients with squamous cell carcinoma showed a significantly higher RR (55.5%) than those with adenocarcinoma (9.1%) or other types of NSCLC (0%). The median progression-free survival was 4.3 months (95% CI, 3.4-4.9), the median survival time was 17.9 months (95% CI, 15.0-20.8), and the 1- and 2-year survival rates were 63.3 and 27.3%, respectively. Major grade 3-4 hematologic toxicities were leukocytopenia (7.5%), neutropenia (5.0%), anemia (15.0%) and thrombocytopenia (2.5%). No grade 4 non-hematologic toxicity or treatment-related death occurred. These results suggest that combination chemotherapy with S-1 plus cisplatin is a promising therapeutic candidate for patients with advanced NSCLC, particularly squamous cell carcinoma.

Chylothorax, the accumulation of fatty fluid within the chest cavity, is associated with multiple etiologies including surgical injuries. A rare complication of acupuncture in a 37-year-old woman who developed left pneumothorax and pleural fluid collection after acupuncture was performed on the neck and upper back is described. Chest tube drainage resulted in complete lung expansion, and analysis of the milky fluid revealed chyle leakage. Conservative treatment with a diet low in lipids and rich in medium-chain triacylglycerols allowed extubation. Acupuncture-induced thoracic duct injury, although extremely rare, should be considered as a cause of chylothorax.

We describe a patient with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) that clinically resembled acute promyelocytic leukemia (APL). The karyotype of his leukemic cells was 46, XY, del (3) (q?) and did not include a chromosomal translocation involving the retinoic acid receptor-α gene. However, retinoic acid syndrome developed, and partial remission was achieved after treatment with all-trans retinoic acid (ATRA) followed by chemotherapy. Our case might provide new insights into the mechanism of the growth inhibitory effect of ATRA on APL-like cells.

We here report a rare case of a patient with IgD-lambda-positive multiple myeloma presenting with FDG-PET/CT negative bone marrow involvement. A 72-year-old man was admitted to our hospital for evaluation of a paravertebral tumor of the chest. Thoracotomy was performed and a histopathological evaluation of resected intrathoracic tumor demonstrated a plasmacytic neoplasma. Initially we thought that this case was a solitary plasmacytoma because there were no positive findings on postoperative FDG-PET/CT. However, bone marrow aspiration study demonstrated massive infiltration of myeloma cells (72%). It is necessary to recognize that IgD-lambda type myeloma cells may not be sufficiently metabolically active to form high uptake on FDG-PET/CT.

We report an autopsy case of rapid progressive atypical carcinoid of the lung discovered as multiple nodular shadows. The patient was an 82-year-old man with non-productive cough. Both chest radiography and computed tomography revealed multiple nodules in both the lung and pleural effusion. Multiple metastases to bone and liver were also noted. Samples from the wall-side pleural lesion were obtained by video-assisted thoracoscopic surgery under local anesthesia, and histological examination led to a diagnosis of atypical carcinoid. Treatment was ineffective and the patient died on day 39 after admission. The primary site was identified as the lung after autopsy. We believe that early detection is crucial in the treatment of atypical carcinoid due to poor prognosis.

Rationale: Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect., Objectives: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha(1)-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance., Methods: The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin-induced pulmonary fibrosis in mice., Measurements and Main Results: Addition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin-exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects., Conclusions: AGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis.

A-37-year old woman was referred to our hospital because of bilateral pulmonary micronodular shadows on chest X-ray. Prednisolone was reported to be administered for her coughs and dyspnea more than a month, but was discontinued recently. Under the diagnosis as miliary tuberculosis, we started to treat her with the combined use of pyrazinamide, isoniazid, rifampicin, and ethambutol. Then her symptoms subsided gradually. Two months later, however, high fever developed, followed by exacerbation of the radiographic shadows, and marked cervical and mediastinal lymphadenopathy. We considered them so-called paradoxical worsening, and continued the antituberculosis therapy unchanged. Those clinical manifestations began to subside about 4 months after the initiation of the treatment. Paradoxical worsening has been described as a relatively rare manifestation, and seem to be attributable to prompt recovery of the immunity to mycobacterial antigens after the use of antituberculous therapy. We considered that, in this case, disseminated tuberculosis and firstly administered steroid that might suppress immune function, and discontinuation of steroid therapy followed by the bactericidal antituberculous chemotherapy were associated with the development of the paradoxical reactions, by analogy with immune reconstitution syndrome frequently reported in HIV-related tuberculosis patients.

Toluene diisocyanate (TDI) is known as one of causes of occupational asthma and hypersensitivity pneumonitis. To investigate the stimulatory effect on bronchial epithelial cells in response to TDI, the authors examined production of cytokines by the bronchial epithelial cell line BEAS-2B and intercellular signal transduction stimulated by TDI-human serum albumin (HSA) conjugate. The production of interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and regulated on activation normal T cell expressed and secreted (RANTES) from the bronchial epithelial cells were augmented by the TDI-HSA conjugate. Extracellular signal-regulated kinase (Erk) 1/2 and p38 mitogen-activated protein kinase (MAPK) were phosphorylated by the TDI-HSA conjugate. AG1478, SB203580, and dexamethasone prevented augmentation of these cytokine production. TDI-HSA conjugate did not augment release of epidermal growth factor (EGF) ligands from BEAS-2B. These results suggest that TDI directly induces production of proinflammatory cytokines and chemokines through p38 MAPK and EGF receptor (EGFR)-Erk pathway without an autocrine mechanism. Thus, TDI was shown to have a stimulatory effect on bronchial epithelial cells, suggesting the potent role of bronchial epithelial cells in TDI-induced asthma.

Macrophage-derived chemokine (MDC/CCL22) and thymus-and activation-regulated chemokine (TARC/CCL17) are ligands for CC chemokine receptor 4. Recently, TARC has been reported to play a role in the pathogenesis of idiopathic eosinophilic pneumonia (IEP). The purpose of this study was to evaluate the role of MDC in IEP and other interstitial lung diseases (ILDs). MDC and TARC in the bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay in patients with ILDs and healthy volunteers (HV). We also examined the expression of MDC mRNA in alveolar macrophages (AM) by real-time quantitative reverse transcriptase-polymerase chain reaction. Both MDC and TARC were detected only in BALF obtained from IEP patients. The concentration of MDC was higher than that of TARC in all cases. The level of MDC in IEP correlated with that of TARC. AM from IEP patients expressed a significantly higher amount of MDC than that from HV at the levels of protein and mRNA. MDC in BALF from IEP dramatically decreased when patients achieved remission. These findings suggest that MDC, in addition to TARC, might be involved in the pathogenesis of IEP, and AM play a role in the elevation of MDC in IEP.

A 71-year-old man visited the surgical department of our hospital due to back pain in November, 1999. Esophagogram showed bronchoesophageal fistula and a plain chest radiograph showed a nodular shadow in the left upper area with left pleural effusion. As the symptom disappeared on treatment with an antimicrobial agent, he was followed up as an outpatient. In August, 2001, he presented to the Respiratory Department of our hospital with low-grade fever and productive cough. Since tubercle bacilli were detected in a sputum culture, combined treatment with antituberculous chemotherapy was started. But, none of the symptoms were improved. These bacilli were identified as being multi-drug-resistant. After the chemotherapy regimen was changed, the symptoms disappeared and the esophagorespiratory fistula was closed. We report a rare case of esophagorespiratory fistula with multi-drug resistant tuberculosis, which was improved by chemotherapy.

Objective: CC chemokines are mainly chemotactic for monocytes and lymphocytes. The aim of this study was to evaluate the involvement of the CC chemokines, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, in the pathogenesis of bronchiolitis obliterans organizing pneumonia (BOOP)., Methodology: The concentrations of MIP-1alpha and MIP-1beta in BAL fluid (BALF) obtained from patients with BOOP (n = 13) and control patients (CP, n= 18) were measured by enzyme-linked immunosorbent assay., Results: MIP-1alpha in BALF was significantly higher in patients with BOOP (mean +/- SD; 123.8 +/- 98.0 pg/mL) than in CP (62.5 +/- 46.1 pg/mL). Significantly higher MIP-1beta was also detected in patients with BOOP (51.6 +/- 72.5 pg/mL) than in CP (6.4 +/- 3.7 pg/mL). The concentration of MIP-1alpha significantly correlated with the percentage of lymphocytes in BALF, and the concentration of MIP-1beta significantly correlated with the numbers of lymphocytes, neutrophils and eosinophils in BALF. Both MIP-1alpha and MIP-1beta in BALF were decreased after corticosteroid therapy and this was accompanied by decreased lymphocytes in BALF., Conclusion: This study suggests that MIP-1alpha and MIP-1beta may play important roles in the recruitment of immuno-inflammatory cells into the lungs, and may contribute to the pathogenesis of BOOP.

Although cigarette smoking is a recognized cause of acute eosinophilic pneumonia (AEP), and an increase in eosinophils in the lung is a common occurrence in AEP, early-phase neutrophilia in AEP is not well understood. We describe three cases of cigarette smoke (menthol type)-induced AEP with neutrophilia in the lungs or blood. Increased in-vitro production of the neutrophil chemoattractant interleukin (IL)-8 by human bronchial epithelial cells (HBECs) was correlated with neutrophilia. We suggest that IL-8 released from HBECs is involved in neutrophilia in the lung in AEP, and is newly recognized as an important factor in the early phase of AEP development.

Although pulmonary fibrosis is a frequent and serious consequence of radiotherapy for thoracic malignant diseases such as lung cancer, the pathogenesis of this radiation-induced lung disorder remains unclear. To clarify the mechanisms underlying radiation pneumonitis and pulmonary fibrosis, we investigated the expression of platelet-derived growth factor receptor (PDGFR) on fibroblasts obtained from irradiated rat lungs and on control fibroblasts. Whole lungs of male Wistar rats were irradiated with a single dose of 15 Gy, and lung fibroblasts were isolated at 4 weeks after the irradiation. The chemotactic response of irradiated lung fibroblasts to PDGF-BB was significantly higher than that of control lung fibroblasts, whereas there was no significant difference between irradiated lung fibroblasts and control lung fibroblasts in the response to PDGF-AA. Receptor binding assay showed more specific binding sites for PDGF-BB on irradiated lung fibroblasts than on control lung fibroblasts, and the displacement of (125)I-labeled PDGF binding to fibroblasts by unlabeled PDGF showed that (125)I-labeled PDGF-BB was displaced by PDGF-BB but not by PDGF-AA. These results suggest that the increased binding sites for PDGF-BB on irradiated lung fibroblasts correspond mainly to PDGFRB. Scatchard analysis of the saturation data demonstrated an approximately twofold increase both in the number of PDGF-BB binding sites and in the binding affinity in irradiated lung fibroblasts compared to that in control lung fibroblasts. Those results suggest that the increased chemotactic response of irradiated lung fibroblasts to PDGF-BB is related to the overexpression of PDGFRB, which may have an important role in the pathogenesis of radiation-induced pneumonitis and pulmonary fibrosis.

Smoking causes various changes in the lung. This report describes a case of cigarette smoke-induced acute eosinophilic pneumonia (CS-AEP) with neutrophilia in the blood. However, the precise mechanism is unknown, so we examined the effect of exposure to cigarette smoke extracts on the production of interleukin (IL)-4, IL-5, IL-8, IL-18, granulocyte macrophage-colony stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) by human bronchial epithelial cells (HBECs) obtained from the patient. We found that IL-8 released from HBECs was involved in neutrophilia in the blood, and is a new factor in the development of AEP, especially in the early phase.

CD13/aminopeptidase N is a cell surface glycoprotein that is widely distributed in a variety of mammalian cells. It was recently shown to have chemotactic activity for T lymphocytes. This study examined the role of CD13/aminopeptidase N in lymphocytic alveolitis in radiation-induced lung injury caused by a single-dose thoracic irradiation (15 Gy) in rats. Significantly increased aminopeptidase activity was detected in bronchoalveolar lavage fluid obtained from irradiated rats at 4 weeks after irradiation compared to the activity in unirradiated rats. Significantly higher aminopeptidase activity was detected on alveolar macrophages from irradiated rats at 2 and 4 weeks than on those from unirradiated rats. Western blot analysis showed an increased expression of CD13/aminopeptidase N protein in alveolar macrophages from irradiated rats at 4 weeks. Chemotactic activity for normal rat lymphocytes was detected in bronchoalveolar lavage fluid from irradiated rats at 4 weeks, and approximately 60% of the activity was inhibited by pretreatment of bronchoalveolar lavage fluid with bestatin, a specific aminopeptidase inhibitor. This study suggests that CD13/aminopeptidase N may play an important role as a lymphocyte chemoattractant in lymphocyte-mediated alveolitis in experimental radiation-induced lung injury.

A 54-year-old man was admitted to our hospital complaining of a high fever and watery diarrhea. The chest radiograph on admission revealed a homogeneous consolidation of the left upper lobe. Laboratory findings included proteinuria, oligouria, hematuria, myoglobinuria, hyponatremia, and serum CPK elevation. On the basis of these findings, a tentative diagnosis of Legionella pneumonia was made. He was treated with sulbactam/cefoperazon and erythromycin, but his high fever remained and the consolidation shadow deteriorated. He was therefore given both erythromycin and ciprofloxacin intravenously. After several days the fever had returned to normal, the appearance of the chest radiograph had improved, and his symptoms were quickly relieved. This case suggests that intravenous administration of ciprofloxacin and erythromycin can be an effective treatment against Legionella pneumonia.

The migration of leukocytes such as neutrophils, monocytes and lymphocytes into inflamed lesions is one of the critical events of inflammation. Although the traditional function of neutrophil-derived antimicrobial proteases is to ingest and kill bacteria, some neutrophil serine proteases have been shown to induce leukocyte migration and activation. Mast cell-derived chymase also has the chemotactic activity for leukocytes. During the acute phase of inflammatory and allergic diseases, the predominantly migrated cells are neutrophils and mast cells, respectively, and in the subsequent chronic phase, monocytes and lymphocytes are mainly migrated. The chemotactic activity for monocytes and lymphocytes of neutrophil-derived serine proteases and mast cell-derived chymase may have a role in switching acute inflammation to chronic inflammation and delayed-type hypersensitivity. Recently, aminopeptidase N and endothelin were shown to induce chemotactic migration of leukocytes. Thus, protease-induced leukocyte chemotaxis and activation may play an important role in immunologic events of inflammatory and allergic diseases.

To clarify the clinical significance of autoantibodies to interleukin-1 alpha (IL-1 alpha autoantibodies) in rapidly progressive idiopathic pulmonary fibrosis (IPF), we measured the level of IL-1 alpha autoantibodies in serum of 11 patients on the first hospital day, when patients were admitted due to severe symptoms, and on the 21st hospital day. IL-1 alpha autoantibodies in serum were measured using radioimmunoassay, and the limitation of this assay for IL-1 alpha autoantibodies was 5 ng/ml. These antibodies were detected in 5 of 11 patients on the first hospital day. On the 21st hospital day, these antibodies were detected in all patients, and its level was increased compared with that on the first hospital day. IL-1 alpha autoantibodies that appeared in patients corresponded to that of IgG. The half life of exogenous autoantibodies was investigated following administration of autoantibody rich plasma obtained from healthy blood donors to 6 control patients (CP) and 6 progressive IPF patients. These autoantibody levels in their serum were less than 5 ng/ml before administration. Serum was obtained at the indicated time after administration of IL-1 alpha autoantibodies and the level of these autoantibodies in serum was measured, then the half life was calculated. Half life of exogenous IL-1 alpha autoantibodies in progressive IPF patients was significantly shorter than that in CP (71.3 +/- 31.8 hr vs 352.0 +/- 98.3 hr, p < 0.01). These findings suggested that IL-1 alpha autoantibodies were generated in response to the inflammatory process of rapidly progressive IPF and may act as a regulatory factor for IL-1 alpha.

Huang, L., Ogushi, F., Tani, K., Ogawa, H., Kawano, T., Endo, T., Izumi, K., Ueno, J., Nishitani, H. and Sone, S. Thrombin Promotes Fibroblast Proliferation during the Early Stages of Experimental Radiation Pneumonitis. Radiat. Res. 156, 45-52 (2001). To clarify the role of thrombin in the pathogenesis of radiation-induced pneumonitis, we measured the thrombin activity and fibroblast growth-inducing activity in bronchoalveolar lavage fluid obtained from the irradiated lungs of rats at 1, 2, 4, 8 and 18 weeks after irradiation. Thrombin activity was not detected in the bronchoalveolar lavage fluid from unirradiated rats, but the bronchoalveolar lavage fluid from irradiated rats showed significantly increased thrombin activity which reached a maximum at 4 weeks after treatment. Higher fibroblast growth-inducing activity was detected in the bronchoalveolar lavage fluid from irradiated rats at 4 and 18 weeks than in fluid from unirradiated rats. Bronchoalveolar lavage fluid from irradiated rats that were pretreated with the thrombin inhibitors antithrombin III and argatroban showed significantly inhibited fibroblast growth-inducing activity and thrombin activity at 4 weeks. However, these thrombin inhibitors did not inhibit fibroblast growth-inducing activity in bronchoalveolar lavage fluid from irradiated rats at 18 weeks. Purified rat thrombin similarly induced proliferation of fibroblasts derived from irradiated and unirradiated rats. These findings suggest that thrombin may play an important role as a fibroblast growth-inducing factor during the early stages of radiation pneumonitis.

Objective: To clarify the clinical significance of autoantibodies (auto-Ab) to interleukin-1alpha (IL-1alpha) in rheumatoid arthritis (RA) with interstitial lung disease (ILD), we examined the IL-1alpha auto-Ab level in serum of patients with RA with/without ILD., Methodology: We investigated the level of IL-1alpha auto-Ab in serum of 70 patients with RA with/without ILD and 40 control patients (CP). Levels of IL-1alpha auto-Ab were measured by radioimmunoassay, and serum was regarded as IL-1alpha auto-Ab positive at an auto-Ab level of more than 5 ng/mL., Results: Interleukin-1alpha auto-Ab was detected in the serum of 30 out of 70 RA patients (42.9%), and six out of 40 CP (15%) (P < 0.05). Interleukin-1alpha auto-Ab were detected in the serum of 18 out of 32 patients with RA with ILD (56.2%) and 12 out of 38 patients with RA without ILD (31.5%). The positive rate of these autoantibodies in RA with ILD was significantly higher than that in RA without ILD (P < 0.05). Although C-reactive protein, immunoglobulin G, rheumatoid factor and rheumatoid arthritis particle agglutination levels in serum from patients with RA with ILD were not significantly different between the IL-1alpha auto-Ab-positive and -negative groups, the lactate dehydrogenase level (LDH) and AaDO, in the IL-1alpha auto-Ab-positive group were significantly higher than those in the negative group (LDH: P < 0.001, AaDO2: P < 0.05)., Conclusion: These results suggest that IL-1alpha auto-Ab are generated in response to the immunoinflammatory process of ILD in RA, and these autoantibodies may neutralize and regulate the IL-1alpha activity.

We report a 70-year-old man with hepatopulmonary syndrome (HPS) in C liver cirrhosis. Hypoxemia worsened markedly, especially on exertion, while the hepatic function was clinically stable. Contrast echocardiography, 99mTc macroaggregated albumin (99mTcMAA) lung scan, and pulmonary angiography were performed. The findings suggested the presence of both intrapulmonary vascular dilatation and substantial right-to-left shunt. The contribution of intrapulmonary vascular abnormalities in patients with severe liver cirrhosis without abnormal chest radiography and spirometry tests when marked hypoxemia is present should be investigated.

CD13/aminopeptidase N (E.C.3.4.11.2) is an ectoenzyme located in the outer membrane of a variety of cells. Because aminopeptidase expression was shown to be upregulated by a Th1-related cytokine, IFN-gamma, we examined here the significance of CD13/aminopeptidase N in pulmonary sarcoidosis. The activity of aminopeptidase in bronchoalveolar lavage fluid (BALF) was significantly higher in patients with sarcoidosis than in normal volunteers (NV) and control patients (CP). The activity significantly correlated with lymphocyte percentages and the ratio of CD4+ to CD8+ T lymphocytes in the BALF, and was higher in patients with sarcoidosis with parenchymal involvement than in those without the involvement. CD13/aminopeptidase N protein, which has a molecular mass of approximately 150 kD, was detectable in alveolar macrophages (AM) from patients with sarcoidosis at higher levels than in those from NV. CD13/aminopeptidase N induced in vitro chemotactic migration of human lymphocytes in a concentration range of 10(-)(5) to 10(-)(1) U/ml. The chemotactic activity was greater for CD4+ T lymphocytes than for CD8+ T lymphocytes. The enzymatic activity of CD13/aminopeptidase N was responsible for the chemotactic activity because bestatin, an inhibitor of CD13/aminopeptidase N, abolished the chemotactic activity. Higher chemotactic activity for lymphocytes was detected in the BALF from patients with sarcoidosis than in that from NV, and the activity was significantly decreased by treatment with bestatin. This study indicates that CD13/ aminopeptidase N expressed in AM may have a role in T-lymphocyte involvement in the sarcoid lung and the pathogenesis of alveolitis in this disorder.

Chymase is a major chymotrypsin-like serine protease expressed in the secretory granules of mast cells in many mammalian species. In this study, we revealed the chemotactic activity of chymase for human mononuclear cells and neutrophils with a 48-well microchemotaxis chamber technique. Human chymase showed the potent chemotactic activity for monocytes and neutrophils dose-dependently in a concentration range from 0.1 to 10 microg/mL, corresponding to about 4-400 microM. The activity was as potent as that of N-formyl-methionyl-leucyl-phenylalanine. Chymase also stimulated cell migration of lymphocytes and purified T cells, but checkerboard analysis revealed that the effect was chemokinetic rather than chemotactic. Inhibition of chymase activities with chymase inhibitors, such as antileukoprotease and Bowman-Birk soybean trypsin inhibitor, significantly inhibited the chemotactic activity of chymase, suggesting that the proteolytic activity of chymase participates in the chemotactic activity. Our results suggest that mast cell chymase acts as a chemoattractant, and may play a role in the accumulation of inflammatory cells in development of the chronic inflammatory responses of allergic and nonallergic diseases.

Objective: Immunoglobulin binding factor (IgBF) is known to bind immunoglobulin, to interact with anti-Fc gamma-III antibodies and to be present in the lower respiratory tract of normal healthy subjects. In this study, in order to clarify the role of IgBF in respiratory diseases, we investigated whether IgBF exists in the airway of patients with chronic airway diseases., Methodology: IgBF was measured in the sputum of 28 normal subjects and 59 patients with chronic airway diseases including 37 cases of chronic bronchitis, 18 bronchiectasis, and four diffuse panbronchiolitis by enzyme-linked immunosorbent assay., Results: Immunoglobulin binding factor concentration in the sputum of patients with chronic airway diseases (purulent sputum, 50.2 +/- 8.2 microg/mL; mucoid sputum, 88.6 +/- 12.8 microg/mL) was higher than that in induced sputum of normal subjects (6.3 +/- 5.5 microg/mL; P < 0.001). Immunoglobulin binding factor level in mucoid sputum was significantly higher than that in purulent sputum (P < 0.05). A significant inverse correlation was shown between the IgBF level and the elastase activity in sputum, and the concentration of IgBF purified from seminal plasma was decreased by treatment with neutrophil elastase, indicating that IgBF might be degraded by elastase. In the gel filtration chromatography of both types of sputum, IgBF was eluted in a region corresponding to a molecular weight of 27 kDa as a single peak. Western blot analysis with a monoclonal antibody to IgBF indicated that IgBF in both types of sputum had a molecular weight of 27 kDa under non-reducing conditions and of 16 kDa under reducing conditions., Conclusion: These results demonstrate that a high level of IgBF is present in the respiratory tract of patients with chronic airway diseases and may be related to the pathogenesis of these diseases.

In order to clarify the mechanism of pulmonary fibrosis, we examined the functional changes of lung fibroblasts in bleomycin (BLM)-induced pulmonary fibrosis. Lung fibroblastic cells were obtained from rat lungs after an intratracheal treatment of BLM or saline. The spontaneous proliferation of BLM-treated rat fibroblasts (BRF), which was estimated by 3H-TdR incorporation and direct cell counting, was significantly more rapid than that of normal saline-treated rat fibroblasts (NRF). Next, we investigated prostaglandin (PG) E2 synthesis by BRF and NRF, with or without stimulation by interleukin (IL)-1 alpha, and found that PGE2 production by BRF was significantly less than that by NRF. There was no significant difference in cyclooxygenase (COX) activity and COX-2 mRNA level between BRF and NRF, indicating that the change in PGE2 production was independent of COX, a rate-limiting enzyme for the production of PGE2. These results suggest that the proliferation of fibroblasts is down-regulated by PGE2 released from themselves in normal lungs in an autocrine fashion, thus the decreased PGE2 production observed in lung fibroblasts from rats with BLM-induced pulmonary fibrosis may result in the excessive fibroblast proliferation in this disorder. Overall, these findings throw some light on the mechanism of development of BLM-induced pulmonary fibrosis.