A 76-year-old woman was diagnosed with lung tuberculosis. On the second day of anti-tuberculosis treatment, she became unconscious and developed status epilepticus accompanied by hyponatremia. The hyponatremia was caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Detailed examinations revealed that the patient's status epilepticus had occurred due to hyponatremia, which was caused by lung tuberculosis-associated SIADH. Previous case reports noted that patients with tuberculosis-associated SIADH showed mild clinical manifestations. They also reported that extensive lung involvement was associated with SIADH development. We herein report a rare case of SIADH complicated with status epilepticus that was caused by tuberculosis with mild lung involvement.

Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition-mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

Background The postoperative pulmonary complication (PPC) is an important surgical risk as common as the cardiac one, containing atelectasis, pneumonia, and respiratory failure. Objective The purpose of this study is to evaluate the risk factors for PPC in the patients with major respiratory underlying diseases such as bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) in our university hospital. Methods Totally 10699 patients were surgically treated in our university hospital from April to December in 2014. Among them, there were 68 COPD patients and 181 BA ones studied here. Eight of 68 COPD patients (11.8%) had PPC with 6 consolidations and 2 consolidations + respiratory failures, whereas 16 of 181 BA patients (8.8%) had PPC with 14 asthma attacks and 2 consolidations. We retrospectively evaluated physiological background, pulmonary function, duration of surgery, and perioperative specific treatment for pulmonary diseases to analyze the risk for PPC in these patients. Results In the BA patients, smoking index> 20 pack-year was significantly associated with PPC [OR (95%CI) = 11.7(2.6-52.1), P= 0.0013]. In the COPD patients, induction of COPD specific treatment and duration of surgery >300minites were significantly associated with PPC [OR (95%CI) = 0.09(0.01-0.63), P= 0.016; OR (95%CI) = 9.5(1.4-65.3), P= 0.022, respectively] Conclusions To prevent PPC, smoking cessation in BA and induction of specific treatment and shortening of surgery time in COPD were critically important.

Nakayama and Kazuyoshi Kuwano Yamashita, Makoto Odaka, Toshiaki Morikawa, Katsutoshi Kawaishi, Yumi Kaneko, Hisatoshi Asano, Makoto Jun Kojima, Kenichiro Shimizu, Takanori Numata, Makoto Haruhiko Yanagisawa, Mitsuo Hashimoto, Hiroshi Wakui, Saburo Ito, Yu Fujita, Naoki Takasaka, Hirofumi Utsumi, Sato, Masahiro Yoshida, Kazuya Tsubouchi, Yusuke Kurita, Hiromichi Hara, Nayuta Saito, Tsukasa Kadota, Nahoko Kenji Kobayashi, Jun Araya, Shunsuke Minagawa,

Background: Community-acquired pneumonia (CAP) has high morbidity and mortality. Unfortunately, the pathogen detection rate using conventional culture methods is relatively low. We compared comprehensive real-time polymerase chain reaction (real-time PCR) analysis of nasopharyngeal swab specimens (NPS) and sputum samples against conventional methods for ability to detect causative pathogens of CAP.Methods: We prospectively enrolled adult CAP patients, including those with prior antibiotic use, from December 2012 to May 2014. For each patient, causative pathogens were investigated conventionally and by real-time PCR that can identify 6 bacterial and 11 viral pathogens.Results: Patients numbered 92 (mean age, 63 years; 59 male), including 30 (33%) with prior antibiotic use. Considering all patients, identification of causative pathogens by real-time PCR was significantly more frequent than by conventional methods in all patients (72% vs. 57%, p=0.018). In patients with prior antibiotic use, identification rates also differed significantly (PCR, 77%; conventional, 50%; p=0.027). Mixed infections were more frequent according to real-time PCR than conventional methods (26% vs. 4%, p<0.001). By the real-time PCR, Streptococcus pneumoniae was most frequently identified (38%) as a causative pathogen, followed by Haemophilus influenzae (37%) and Mycoplasma pneumoniae (5%). PCR also identified viral pathogens (21%), with sensitivity enhanced by simultaneous examination of both NPS and sputum samples rather than only NPS samples.Conclusions: Real-time PCR of NPS and sputum samples could better identify bacterial and viral pathogens in CAP than conventional methods, both overall and in patients with prior antibiotic treatment.

Background Accumulation of profibrotic myofibroblasts in fibroblastic foci (FF) is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis (IPF) pathogenesis, and transforming growth factor (TGF)-β plays a key regulatory role in myofibroblast differentiation. Reactive oxygen species (ROS) has been proposed to be involved in the mechanism for TGF-β-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMP-activated protein kinase (AMPK), which regulates not only energy homeostasis but also stress responses, including ROS. Therefore, we sought to investigate the inhibitory role of metformin in lung fibrosis development via modulating TGF-β signaling. Methods TGF-β-induced myofibroblast differentiation in lung fibroblasts (LF) was used for in vitro models. The anti-fibrotic role of metfromin was examined in a bleomycin (BLM)-induced lung fibrosis model. Results We found that TGF-β-induced myofibroblast differentiation was clearly inhibited by metformin treatment in LF. Metformin-mediated activation of AMPK was responsible for inhibiting TGF-β-induced NOX4 expression. NOX4 knockdown and N-acetylcysteine (NAC) treatment illustrated that NOX4-derived ROS generation was critical for TGF-β-induced SMAD phosphorylation and myofibroblast differentiation. BLM treatment induced development of lung fibrosis with concomitantly enhanced NOX4 expression and SMAD phosphorylation, which was efficiently inhibited by metformin. Increased NOX4 expression levels were also observed in FF of IPF lungs and LF isolated from IPF patients. Conclusions These findings suggest that metformin can be a promising anti-fibrotic modality of treatment for IPF affected by TGF-β.

Respiratory infection is a major cause of exacerbation in chronic obstructive pulmonary disease (COPD). Infectious contributions to exacerbations remain incompletely described. We therefore analyzed respiratory tract samples by comprehensive real-time polymerase chain reaction (PCR) in combination with conventional methods. We evaluated multiple risk factors for prolonged hospitalization to manage COPD exacerbations, including infectious agents. Over 19 months, we prospectively studied 46 patients with 50 COPD exacerbations, collecting nasopharyngeal swab and sputum samples from each. We carried out real-time PCR designed to detect six bacterial species and eleven viruses, together with conventional procedures, including sputum culture. Infectious etiologies of COPD exacerbations were identified in 44 of 50 exacerbations (88%). Infections were viral in 17 of 50 exacerbations (34%). COPD exacerbations caused by Gram-negative bacilli, including enteric and nonfermenting organisms, were significantly associated with prolonged hospitalization for COPD exacerbations. Our results support the use of a combination of real-time PCR and conventional methods for determining both infectious etiologies and risk of extended hospitalization.

Cigarette smoke (CS)-induced mitochondrial damage with increased reactive oxygen species (ROS) production has been implicated in COPD pathogenesis by accelerating senescence. Mitophagy may play a pivotal role for removal of CS-induced damaged mitochondria, and the PINK1 (PTEN-induced putative kinase 1)-PARK2 pathway has been proposed as a crucial mechanism for mitophagic degradation. Therefore, we sought to investigate to determine if PINK1-PARK2-mediated mitophagy is involved in the regulation of CS extract (CSE)-induced cell senescence and in COPD pathogenesis. Mitochondrial damage, ROS production, and cell senescence were evaluated in primary human bronchial epithelial cells (HBEC). Mitophagy was assessed in BEAS-2B cells stably expressing EGFP-LC3B, using confocal microscopy to measure colocalization between TOMM20-stained mitochondria and EGFP-LC3B dots as a representation of autophagosome formation. To elucidate the involvement of PINK1 and PARK2 in mitophagy, knockdown and overexpression experiments were performed. PINK1 and PARK2 protein levels in lungs from patients were evaluated by means of lung homogenate and immunohistochemistry. We demonstrated that CSE-induced mitochondrial damage was accompanied by increased ROS production and HBEC senescence. CSE-induced mitophagy was inhibited by PINK1 and PARK2 knockdown, resulting in enhanced mitochondrial ROS production and cellular senescence in HBEC. Evaluation of protein levels demonstrated decreased PARK2 in COPD lungs compared with non-COPD lungs. These results suggest that PINK1-PARK2 pathway-mediated mitophagy plays a key regulatory role in CSE-induced mitochondrial ROS production and cellular senescence in HBEC. Reduced PARK2 expression levels in COPD lung suggest that insufficient mitophagy is a part of the pathogenic sequence of COPD.

Introduction: Senescence has been implicated in the pathogenesis of COPD, and cigarette smoke is known to induce cellular senescence. One of the typical manifestations of cellular senescence is accumulation of damaged proteins and organelles, which is mainly regulated through lysosomal degradation. Recent advances demonstrate that TFEB is a central regulator of lysosomal biogenesis and cellular degradative pathways in association with autophagy machinery. Methods: Using human bronchial epithelial cells (HBEC), senescence associated beta-galactosidase staining and western blotting of p21 were performed to evaluate senescence. Fluorescence microscopic detection of mature lysosome was performed by LysoTracker staining. To characterize the autophagy-lysosomal degradation pathway, western blotting of p62, ubiquitin, and LC3 were performed. TFEB expression levels were modulated by cDNA and siRNA transfection. Results: We demonstrated that TFEB expression levels were decreased in lung homogenates from COPD patients. CSE induced HBEC senescence with concomitant decrease in TFEB. CSE-induced HBEC senescence was inhibited by TFEB overexpression, while TFEB knock down further enhanced HBEC senescence. TFEB overexpression induced activation of the autophagy-lysosomal pathway, as demonstrated by increased LC3-II conversion in western blotting and enhanced dot formation in LysoTracker staining. Conclusion: These findings suggest that TFEB-mediated activation of the autophagy-lysosomal pathway plays a key regulatory role in CSE-induced cellular senescence. Thus, sufficient levels of TFEB induction may be a novel medical intervention to prevent cellular senescence in COPD pathogenesis.

A 63-year-old woman was diagnosed with advanced lung adenocarcinoma complicated by Trousseau's syndrome characterized by non-bacterial thrombotic endocarditis, asymptomatic brain infarction, deep venous thrombosis, and low-grade disseminated intravascular coagulation (DIC). The patient's DIC rapidly became widespread, and multiple micropulmonary embolisms led to severe respiratory failure. She received a blood transfusion and anticoagulant treatment with heparin and recombinant human soluble thrombomodulin, which modestly ameliorated her symptoms, and additional chemotherapy led to tumor shrinkage with concomitant resolution of Trousseau's syndrome. Although there are no established medical approaches for managing Trousseau's syndrome, intensive anticoagulant treatment may be effective for improving the patients' general condition in order for them to be able to undergo subsequent combination chemotherapy.

Introduction: Contractile myofibroblast accumulation has been implicated in pathological lung remodeling. We have reported the involvement of insufficient autophagy, a process of lysosomal self-degradation, in myofibroblast differentiation. Insufficient mitophagy, the selective autophagic degradation of mitochondria, results in increased reactive oxygen species (ROS) production. ROS is involved in the process of myofibroblast differentiation through the modulation of cell signaling pathways. Methods: To explore the regulatory role of mitophagy in ROS production and its involvement in myofibroblast differentiation, human lung fibroblasts were used in vitro. Transfection of PINK1 and Parkin siRNA were performed to inhibit mitophagy. DCFH-DA and MitoSOX Red were used to evaluate ROS production, and NAC and MitoTEMPO were employed for inhibition of ROS. Wortmannin and AG1296 were used to inhibit PI3K-Akt pathway and PDGF receptor (PDGFR) tyrosine kinase, respectively. Results: Inhibition of mitophagy via PINK1 and Parkin knockdown increased mitochondrial ROS production and induced myofibroblast differentiation, which was inhibited by treatment with anti-oxidants. Mitophagy inhibition activated PI3K-Akt pathway, and both wortmannin and Akt1/2 kinase inhibitor abrogated myofibroblast differentiation. PDGFR-mediated signaling was partly responsible for myofibrobalst differentiation in the setting of insufficient mitophagy, as elucidated by anti-oxidants and AG1296 treatments. Conclusion: These findings suggest insufficient mitophagy-induced ROS production with subsequent PDGFR-PI3K-Akt activation is a potent underlying mechanism for myofibroblast differentiation in the pathogenic sequence of fibrotic lung disorders.

Cigarette smoke (CS)-induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

Introduction: Cigarette smoke-induced mitochondrial damage accompanying enhanced ROS production has been implicated in COPD pathogenesis in terms of acceleration of cell senescence. Mitophagy may play a pivotal role for removal of CSE-induced damaged mitochondria and phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-Parkin pathway has been proposed as a part of the mechanism for mitophagic degradation. Methods: Using HBEC, senescence associated beta-galactosidase (SA-β-gal) staining and western blotting of p21 were performed to evaluate senescence. Mitophagy was assessed in BEAS-2B cells stably expressing EGFP-LC3, using confocal microscopy to measure colocalization between TOM20 stained mitochondria and EGFP-LC3 dots as a representation of autophagosome formation. Mitophagy was also evaluated using electron microscopy in HBEC. To elucidate the involvement of Parkin and PINK1 in mitophagy, knockdown (KD) by transfection of siRNAs was performed. Results: CSE markedly induced EGFP-LC3 dot formation with concomitant colocalization with TOM20 in the presence of Bafilomycin A, suggesting that CSE treatment induces mitophagy, which was subsequently reduced by Parkin KD. CSE-induced mitophagy was further confirmed by electron microscopic detection of autophagosomes with mitochondria inside. Inhibition of mitophagy via PINK1 and Parkin KD increased mitochondrial ROS production and enhanced cell senescence in HBEC. Conclusion: These findings suggest PINK1-Parkin pathway-mediated mitophagy plays a key regulatory role in CSE-induced oxidative stress and cell senescence through the degradation of damaged mitochondria.

Background: We reported the utility of multiplex real-time polymerase chain reaction (MRT-PCR) to diagnose pathogens causing community-acquired pneumonia (CAP) in Japanese adults at ERS 2013. The number of samples was limited, so we extended the study to Jan 2014. Aims: To confirm usefulness of MRT-PCR in diagnosing causative pathogens in a large number of adult Japanese CAP patients as compared with conventional tests (sputum/blood culture, urine antigen for Streptococcus pneumoniae [S.p]/Legionella pneumophila [L.p], and paired serum of Mycoplasma pneumoniae [M.p] antibody) Methods: We prospectively enrolled adult CAP patients from Sep 2012 to Jan 2014. CAP was defined based on respiratory symptoms and laboratory/chest X-ray findings excluding noninfectious causes.We collected sputum, nasopharyngeal swab, urine, and blood samples of each patient. MRT-PCR can identify 6 bacteria and 11 viruses in sputum and nasopharyngeal swab samples. Causative pathogens were identified by each test. Results: We analyzed 92 patients (mean age, 60 years; 53 men). Sensitivity of MRT-PCR was significantly higher than that of conventional tests in all cases (78% vs. 56%; pl0.01). S.p was the most common causative pathogen of CAP by MRT-PCR (21 cases, 23%). Causative pathogens of 12 cases (13%) were atypical bacteria such as L.p, M.p, and Chlamydophila pneumoniae. Virus infection rate was also high (22%). Conclusions: Compared with conventional tests, MRT-PCR was useful for diagnosing CAP. It can simultaneously identify ≥2 pathogens including atypical bacteria and uncultivable viruses and maintain high sensitivity in a large number of patients.

Introduction: Accumulation of profibrotic myofibroblasts is a crucial step for fibrotic remodeling in idiopathic pulmonary fibrosis (IPF), and transforming growth factor (TGF)-bhas a key regulatory role in myofibroblast differentiation. Reactive oxygen species (ROS) has been proposed to be involved in the mechanism for TGF-b-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMPK, which regulates not only energy homeostasis but also stress responses including ROS. Hence, we hypothesized that metformin may modulate TGF-b-induced myofibroblast differentiation through the regulation of ROS production. Methods: Using human lung fibroblast (LFB), western blotting (WB) of alpha-smooth muscle actin (SMA) was performed to evaluate TGF-b-induced myofibroblast differentiation in the presence and absence of metformin. AMPK activation was detected by showing phosphorylation via WB. AMPK was inhibited by siRNA-mediated knockdown. CM-H2DCFDA was used to evaluate intracellular ROS production. Results: TGF-b induced myofibroblast differentiation, which was clearly inhibited by metformin treatment. AMPK inhibition illustrates that metformin-mediated activation of AMPK was responsible for suppression of TGF-b-induced myofibroblast differentiation. Intriguingly, metformin also suppressed TGF-b-induced NADPH oxidase 4 (NOX4) expression and ROS production via AMPK activation. Conclusion: Metformin suppresses NOX4 expression and ROS production via AMPK activation, resulting in inhibition of TGF-b-induced myofibroblast differentiation. Therefore, metformin may also be used for the treatment of IPF.

Introduction: S-1 is an oral fluoropyrimidine anticancer drug that contains tegafur, gimeracil, and oteracil potassium. The target of S-1 is considered thymidylate synthase, which is known as that of pemetrexed (PEM). Recently, phIIIstudies have demonstrated that S-1 in combination with platinum agent has promising efficacy for patients with advanced non-small cell lung cancer as first-line treatment. However, clinical outcome of S-1 monotherapy after treatment of PEM has not been evaluated yet. Aims: To evaluate the efficacy of single agent S-1 in patients with advanced non-squamous non-small cell lung cancer (NSCLC) after PEM treatment. Methods: To assess the clinical outcome of S-1 monotherapy in patients with non-squamous NSCLC after PEM treatment, we reviewed the clinical records of patients treated with S-1 in Jikei University Hospital, from June 2009 to February 2013. Response rate (RR) and progression free survival (PFS) and toxity were evaluated. Results: The 14 patients with lung adenocarcinoma were reviewed in this retrospective study. There were 8 males and 6 females with the median age of 69 years (range, 54-82 years). The subjects included 2 patients with PS 0, 5 with PS 1, and 7 with PS 2, and 1 patients in the stage of IIIA and 13 in IV.S-1 was used as third -line treatment for 2 patient, fourth-line treatment for 6, fifth-line treatment for 3, and sixth-line treatment for 3. As the results, the RR were 0 %, but 8 patients had SD and 3 patients had non-PR / non-PD. The median PFS were 5.1 months (range, 0.4-14.8 months). Conclusions: Advanced non-squamous NSCLC patients receiving S-1 after treatment of PEM have not response but have better PFS.

Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated β-galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial-specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito-TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development.

A 32-year-old female with epilepsy presented at our hospital with high-grade fever, seizures, and unconsciousness. She was initially treated for aspiration pneumonia with ampicillin/sulbactam. Despite antibiotic therapy, her chest X-ray findings dramatically worsened, showing extension to the bilateral lung field. Her PaO2/FiO2 ratio decreased to 70.6. Rapid progression of hypoxia, unconsciousness, and hyponatremia led to the suspicion of Legionella pneumonia; however, it was difficult to make a definitive diagnosis because she had denied using a whirlpool spa and the initial urinary Legionella antigen test results were negative. Therefore, we repeated the Legionella urinary antigen test, which was positive. On the basis of these results, sputum polymerase chain reaction findings, and the four-fold elevation of paired antibodies, the patient was diagnosed as having Legionella pneumonia accompanied by acute respiratory distress syndrome. We considered administering fluoroquinolone antibiotics, that are recommended for severe Legionella pneumonia, although quinolones have a potential risk for causing convulsions. In this case, we carefully administered ciprofloxacin. The patient recovered consciousness after treatment without any relapse of epileptic seizures. We also administered a corticosteroid for severe pneumonia with the expectation of clinical improvement and to avoid intubation. We emphasize the importance of aggressive workup and empirical therapy for patients with Legionella pneumonia with rapidly worsening symptoms and clinical features such as unconsciousness, epilepsy, and hyponatremia and in whom fluoroquinolone and corticosteroid therapy are effective despite the presence of epilepsy.

Rationale: The airflow limitation of COPD is related to neutrophilic inflammation and subepithelial fibrosis in the small airways. Thrombospondin-1(TSP-1)is reported to be a key molecule downstream of MyD88/TLRs, which is associated with smoking-related airway inflammation. TSP-1 is also known as a mediator of fibrosis in mouse airway epithelial cells. However, the role of TSP-1 in COPD pathogenesis is not yet fully evaluated. We examined the correlation between TSP-1 expression and lung function, and involvement of TSP-1 in COPD pathogenesis in patients with smoking history. Methods: Human bronchial epithelial cells (HBECs) were isolated from surgical lung specimens and cultured. 48h later, supernatants were recovered. TSP-1 concentrations in supernatants were evaluated by ELISA. The correlation between TSP-1 and pulmonary function was analyzed with linear regression analysis. IL-8 production induced by TSP-1 in HBECs was analyzed by ELISA. Results: Surgical specimens were classified as non-smokers, healthy smokers, or COPD patients. In COPD patients, TSP-1 concentrations were found to be higher than those in non-smokers and healthy smokers. In a correlation analysis between TSP-1 and pulmonary function, TSP-1 had an inverse correlation with %FEV1 and FEV1/FVC. IL-8 concentrations rose after stimulation by TSP-1 in a dose-dependent manner. Conclusions: TSP-1 expression in lung specimen from subjects with smoking history appears to be associated with obstructive ventilatory impairment. It was suggested that IL-8 expression by TSP-1 could be involved in pathogenesis of COPD.