坂東 政司

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone.

Background: There have been no prospective large-scale multicenter epidemiological studies on the clinical course and treatment from the time of diagnosis of idiopathic interstitial pneumonias (IIPs) in Japan. The purpose of this study was to clarify the current clinical situation of IIP in Japan. Methods: This study was supported by a grant from the Ministry of Health, Labour and Welfare to the Diffuse Lung Diseases Research Group. Data including clinical findings, course, and treatment of IIP from a web database created by a collaborative effort of medical institutions across Japan that specialize in the care of interstitial pneumonias were collected and analyzed. Results: A total of 436 IIP patients from 19 institutions were newly registered during a 5-year period. Idiopathic pulmonary fibrosis (IPF) was the most frequently encountered IIP, and 28% of the IPF cases were initially diagnosed by abnormal chest X-ray or CT in asymptomatic patients. Until the 2008 fiscal year, no treatment was given for most cases of IPF. After the end of 2008, when pirfenidone was approved for manufacture, the number of patients for whom no treatment was recommended declined, and pirfenidone therapy was initiated in 32.9% of cases in 2009. The median survival times for IPF from the onset symptoms and from the initial visit were 105 months and 69 months, respectively. Conclusions: This study should provide valuable information for understanding the current state of IIP in Japan.

Background: National surveys conducted in Japan between 1960 and 2004 suggest a gradually increasing incidence of sarcoidosis in women >50 years old with increased involvement of the eye, skin, and heart. However, whether this involvement is due to the increased age at diagnosis is still unclear. We aimed here to identify the age-related differences in organ involvement in sarcoidosis in Japan, as well as the historical changes in clinical characteristics and the age-specific distribution of cases at diagnosis. Methods: We reviewed 588 consecutive Japanese patients newly diagnosed with sarcoidosis between 1974 and 2012 at Jichi Medical University Hospital. We compared organ involvement between subgroups differentiated by sex and age (<45 years; n = 275; >= 45 years; n = 313) at diagnosis and identified historical changes in the age-specific distribution in 10-year intervals. Results: Younger patients had more common involvement of extrathoracic lymph nodes, parotid/salivary gland, and liver, while older patients had more common involvement of nonlymphatic extrathoracic organs such as the eye, heart, muscle, and kidney. The age at diagnosis has consistently increased over the past four decades. The monophasic distribution in men has tended to become biphasic, and the biphasic distribution in women monophasic. Increasing trends were apparent for hypercalcemia and involvement of the gastrointestinal tract, skin, nervous system, muscle, and kidney. Conclusions: Elderly patients at diagnosis had various extrathoracic involvement including eye, skin, and cardiac lesions. Moreover, the age at diagnosis of sarcoidosis has continued to increase in both sexes, influencing the recent trends in clinical characteristics. (C) 2015 Elsevier Ltd. All rights reserved.

Rationale: Idiopathic pulmonary fibrosis (IPF) has an unknown etiology and poor prognosis. Several large-scale epidemiologic studies have been conducted predominantly in Western countries. There are few studies reported from Asian countries. It remains unclear whether ethnic difference exists in IPF. It is important to determine the current IPF status in Asian populations and compare it with that of Western populations. Objectives: To provide the epidemiologic status of IPF in Japan and to investigate ethnic differences. Methods: We selected Hokkaido prefecture (population, 5.6 million) as the epidemiologic cohort of IPF among Japanese. On the basis of the clinical records of 553 patients with IPF who were accepted based on the application of the Certificate of Medical Benefit between 2003 and 2007, we conducted a retrospective epidemiologic and prognostic analysis. Measurements and Main Results: The prevalence and cumulative incidence of IPF was 10.0 and 2.23 per 100,000 population, respectively, with 72.7% predominance of males and an increase in frequency with age. The median survival time was 35 months, and the most common (40%) cause of death was acute exacerbation. The most important factor influencing IPF prognosis was the percent vital capacity. Conclusions: The status of IPF in the Japanese population was clarified for the first time through our study. Our results showed that in men, the incidence of death caused by acute exacerbation was higher and that caused by cardiovascular disease was lower in Japan than in Western countries. These results may suggest ethnic differences in IPF.

A 59-year-old woman, who was given a diagnosis of sarcoidosis by supraclavicular lymph node biopsy 5 years previously, was admitted for further examination following abnormal radiologic findings. Nodular pulmonary and abdominal lesions were observed by computed tomography, and liver biopsy was performed and showed epithelioid cell granulomas. She was asymptomatic and was followed up with no therapy. At 1 year follow-up, the pulmonary and abdominal lesions had nearly complete resolution. Nodular pulmonary and abdominal lesions in patients with sarcoidosis can mimic metastatic disease, lymphoma, and infection, and can reappear during disease activity. Therefore, differential diagnosis and continual follow-up are important. © 2013 The Japanese Respiratory Society.

Objective We retrospectively investigated the clinical features of pulmonary aspergillosis associated with interstitial pneumonia. Methods We reviewed the medical records of all patients treated for interstitial pneumonia with or without pulmonary aspergillosis at our institution between April 2006 and August 2012 and evaluated the clinical features as well as risk and prognostic factors for pulmonary aspergillosis associated with interstitial pneumonia. Results Among 539 patients with interstitial pneumonia, 15 who suffered from pulmonary aspergillosis were identified. The median age was 69.2 +/- 7.0 years, and fourteen patients were men. The subtypes of pulmonary aspergillosis were chronic pulmonary aspergillosis (n=14) and invasive pulmonary aspergillosis (n=1). The forms of interstitial pneumonia included idiopathic pulmonary fibrosis (n=9), rheumatoid arthritisrelated interstitial pneumonia (n=4) and pleuroparenchymal fibroelastosis (n=2). The underlying conditions were emphysema (n=9) and a history of oral corticosteroid and/or immunosuppressive use (n=4). Home oxygen therapy (HOT) was administered in 11 patients. Following the diagnosis of pulmonary aspergillosis, all patients were treated with antifungal drugs. Ten patients (66.6%) died. A comparison of the interstitial pneumonia patients with and without pulmonary aspergillosis showed that the presence of emphysema, use of HOT and death were significantly associated with pulmonary aspergillosis. Conclusion Pulmonary aspergillosis is one of the major complications of interstitial pneumonia and its prognosis is poor. Therefore, providing careful monitoring and proper treatment is extremely important.

<p>〔目的〕入院前に結核が疑われず，入院後に結核と診断された症例の臨床的特徴を比較すること。〔対象方法〕2007年4月から2011年3月までに当院入院後に結核と診断された39症例を対象とし，入院前の抗酸菌検査非施行群と施行群とに分けて2群の臨床的特徴を比較検討した。〔結果〕非施行群22例，施行群17例であった。非施行群では施行群と比べて，悪性腫瘍合併症例（9例 vs. 2例，p＝0.04），肺結核を伴わない肺外結核症例（9例 vs. 2例，p＝0.04），塗抹陰性結核症例（16例 vs. 7例，p＝0.04）が有意に多く，肺結核症例の胸部CT所見において，コンソリデーション（2例 vs. 11例，p＜ 0.01）と空洞病変（0例 vs. 6例，p＜0.01）が有意に少なく，結節病変（8例 vs. 2例，p＜0.01）が有意に多かった。また39例を悪性腫瘍合併の有無で2群に分けて比較検討したところ，入院から結核診断までの日数は悪性腫瘍合併群で有意に長かった（23.5日 vs. 10.5日，p＜0.01）。〔考察・結論〕入院前に抗酸菌検査が施行されず入院後に結核と診断された症例は，基礎疾患に悪性腫瘍を有することが多く，また悪性腫瘍合併は結核診断の遅れの一因になるため，注意が必要であると考えられた。</p>

Background: Interleukin 33 (IL-33) works as a functional mediator in allergic disease by enhancing the activity of eosinophils and inducing expression of T helper 2 (Th2)-associated cytokines. However, the role of IL-33 in pulmonary eosinophilia has not been elucidated. We investigated the levels of IL-33 in eosinophilic pneumonia (EP) together with associated cytokines, and discussed the clinical significance of IL-33 in EP. Methods: Sera and bronchoalveolar lavage fluid (BALF) were obtained from 16 patients with EP, including acute eosinophilic pneumonia (AEP) and chronic eosinophilic pneumonia (CEP). Twelve patients with acute respiratory distress syndrome (ARDS) were also included for comparison. The concentration of IL-33 and Th2 cytokines (IL-4, IL-5, IL-13) were measured by enzyme-linked immunosorbent assay (ELISA). Results: The concentration of serum IL-33 was significantly higher in patients with AEP than in CEP. In CEP, only patients with atopic factors showed mild increase of serum IL-33. The concentration of BALF IL-33 was also significantly elevated in AEP, however, it remained quite low in CEP. Among Th2 cytokines, IL-5 was significantly increased in both serum and BALE in AEP, and the level of IL-5 was positively correlated with that of IL-33. ARDS showed no increase of serum and BALF IL-33. Conclusions: The remarkable increase of BALE IL-33 in AEP indicated the local production of IL-33 in lungs. IL-33 is considered to be a local key molecule for triggering pulmonary eosinophilia, together with IL-5. BALF IL-33 appears to be a useful marker for discriminating AEP from CEP and ARDS.

Diabetes mellitus reduces immunological activity and increases susceptibility to various infections. Hochuekkito (TJ-41) has been reported to improve the weakened physical condition of various chronic diseases. BALB/c mice were divided into three groups; groups A and B were fed a standard diet, and group C, a TJ-41 diet. Two weeks after starting these diets, hyperglycemia was induced in groups B and C by injection with streptozotocin. Two weeks later, bronchoalveolar lavage was performed. Toll-like receptor (TLR) ligands (TLR2: peptidoglycan, PGN; TLR4: lipopolysaccharide, LPS; TLR5: flagellin, FLG) were used to stimulate alveolar macrophages (AMs), and TNF-alpha production was measured. Under hyperglycemic conditions and PGN or FLG stimulation, TNF-alpha production from AMs was significantly reduced in group B compared with group A. However, treatment with TJ-41 (group C) significantly improved the impaired production of TNF-alpha. These results suggest that, under hyperglycemic conditions, TJ-41 can improve the inflammatory responses of AMs with stimulation of TLR ligands.

To investigate the effect of hyperglycemic state on the activation of alveolar macrophages (AMs) mediated via Toll-like receptors (TLRs) typically associated with bacterial infection. AMs obtained from normoglycemic control mice and streptozotocin-induced diabetic mice were stimulated ex vivo with the following: a TLR2 ligand, peptidoglycan (PGN); a TLR4 ligand, lipopolysaccharide (LPS); or a TLR5 ligand, flagellin (FLG). Cytokine production and mRNA expression were measured by ELISA and real-time PCR, respectively. TLR expression was assessed by real-time PCR and flow cytometry. AMs from diabetic mice produced significantly less TNF-alpha after PGN or FLG stimulation, and less IL-6 after FLG stimulation, compared with AMs from control mice. The decrease in the production of these cytokines was associated with reduced mRNA expression of the corresponding cytokines. In contrast, production of TNF-alpha and IL-6 after LPS stimulation did not differ between groups. Furthermore, there was no substantial difference in the expression of TLR2, TLR4, and TLR5 in AMs between the groups. The increased JNK phosphorylation induced by PGN or FLG stimulation was downregulated in AMs from diabetic mice. Hyperglycemic state impairs the reactivity of AMs to multiple TLR ligands. This effect might result from hyperglycemia-induced alteration of intracellular signaling and is unlikely due to the modulation of TLR expression.

Background and objective: Chronic obstructive pulmonary disease (COPD) is considered to be a systemic inflammatory disease, and systemic inflammation has been noted as a factor contributing to cardiovascular disease, which is one of the comorbidities associated with COPD. On the other hand, pleiotropic effects, such as the anti-inflammatory effects of statins, have attracted attention in recent years, and there have been a variety of reports regarding the usefulness of statins for patients with COPD. Methods: We investigated whether the use or non-use of statins influenced the prevalence of airflow limitation. All outpatients who were over the age of 40 years and who regularly visited a primary health care facility were invited to participate. Each participant underwent spirometry and completed a questionnaire regarding their clinical status, which was used to screen for COPD. A variety of factors that are potentially related to airflow limitation were assessed. Results: Of the 853 patients included in the study, 81 (9.5%) had airflow limitation. The prevalence of airflow limitation was 2.3% among the 89 patients with a history of statin use, which was five times lower than the prevalence of airflow limitation among patients who had not used statins (10.5%). Among the 347 patients with a history of past or current smoking, airflow limitation was not observed in the 30 patients who had used statins. However, by multivariate analysis, statin use was not significantly associated with a lower prevalence of airflow limitation. Conclusions: This is the first cross-sectional study from Japan that has demonstrated that statin use has a potential impact on airflow limitation in patients with COPD.

Objective The prognosis of idiopathic pulmonary fibrosis (IPF) patients with acute exacerbation (AE) is reported to be extremely poor. Several clinical studies suggest that direct hemoperfusion with polymyxin Bimmobilized fiber (PMX) may have beneficial effects on AE in patients with interstitial pneumonia (IP). The aim of this multicenter retrospective analysis was to investigate whether PMX treatment could provide improvement of oxygenation and survival benefits in IPF patients with AE. Methods We conducted a retrospective study of 160 IP patients (including 73 IPF) with AE treated by PMX at 18 institutions in Japan. PMX treatment was carried out twice. The total hemoperfusion time of PMX treatment was, on average, 12 hours. Data concerning oxygenation on PMX treatment and survival after AE were collected and analyzed. Results In IPF patients with AE, arterial oxygen tension (PaO2)/inspiratory oxygen fraction (FiO(2)), (P/F) ratio was significantly improved at the end of the 2nd treatment with PMX (173.9 +/- 105.4 to 195.2 +/- 106.8 Torr, p=0.003). White blood cell count was significantly reduced at the end of the 2nd treatment (13,330 +/- 7,002 to 9,426 +/- 5,188/mm(3), p&lt;0.001). These clinical changes were also observed on analysis of all 160 IP patients with AE. The one-and three-month survival rates of IPF patients after AE were 70.1% and 34.4%, respectively. Conclusion PMX treatment may improve oxygenation and survival in IPF patients with AE. Prospective, controlled trials of PMX treatment for IPF with AE are warranted to verify this potential benefit.

Background Pulmonary arteriovenous malformations (PAVMs) are rarely encountered in clinical practice. The prevalence of PAVMs associated with hereditary hemorrhagic telangiectasia (HHT) has been estimated based on the rate in the family members of HHT patients, but the prevalence of PAVMs in the general population remains unknown. Methods We retrospectively examined the prevalence and clinical characteristics of PAVMs as detected by a low-dose thoracic CT screening program for lung cancer at the Hitachi Medical Center and the Hitachi General Health Care Center in the northern part of Ibaraki Prefecture, Japan. Results From 2001 to 2007, we identified eight patients (seven females and one male) with PAVMs among 21,235 initial screening participants (the mean age of the patients with PAVMs and that of the screening participants was 60.6 years). The prevalence of PAVMs was estimated at 38 per 100,000 individuals [95% confidence interval (CI)=18-76]. The diameter of the PAVMs was a mean of 6.6 mm, and none of the lesions could be detected by chest X-ray. Females older than 60 years tended to have larger PAVMs than younger women did (p=0.06). Two patients (25%) were diagnosed with HHT. One patient had previously undergone surgery for a brain abscess. Conclusion PAVMs are more prevalent than previously reported, especially among females.

A 26-year-old man presented at our hospital in 2008 to undergo detailed investigations as part of a routine health examination. Chest computed tomography (CT) showed linear and reticular opacities with, in part, diffuse calcification in the lung fields bilaterally. A surgical lung biopsy was performed and the histological findings were compatible with a diagnosis of diffuse pulmonary ossification (DPO) of the dendriform type. DPO usually occurs as a secondary disease. As the histological changes in interstitial fibrosis were minimal rather than diffuse and not significant enough to be regarded as interstitial pneumonia, we considered this to be an idiopathic case. However, the findings appear to suggest that inflammation and fibrosis were associated with ossification.

Objective Renal angiomyolipomas (R-AMLs) are major complications of lymphangioleiomyomatosis (LAM). The objective of this study was to better understand the influence of R-AMLs in patients with LAM on the prognosis and other clinical factors related to respiration, and to investigate the management of R-AMLs in patients with LAM. Patients and Methods We retrospectively investigated the clinical features of 7 patients with LAM [ 4 were TSC (Tuberous sclerosis complex)-LAM and 3 were S (sporadic)-LAM] complicated by R-AMLs admitted to our hospital from 1997 to 2008. Results All patients were females and the mean age at diagnosis of LAM was 40.7 years (31.7 years for TSC-LAM and 52.7 years for S-LAM). Although 5 patients had symptoms related to R-AMLs, only 1 patient experienced symptoms related to R-AMLs at the time of diagnosis. Five patients had bilateral and 2 patients had unilateral R-AMLs. R-AMLs ruptured in 4 cases (3 patients were TSC-LAM) including 2 patients in whom they ruptured bilaterally, and who underwent bilateral nephrectomy. In 1 case, unilateral R-AMLs grew larger and appeared on the other side during the follow-up period. Conclusion Although only rare cases of LAM show symptoms related to R-AMLs initially, R-AMLs are a notable complication. To avoid nephrectomy, R-AMLs should be diagnosed when they are small and should be followed up carefully by periodic echograms or CT scans.

Transparent conductive films (TCFs) are critical components of a myriad of technologies including flat panel displays, light-emitting diodes, and solar cells. Graphene-based TCFs have attracted a lot of attention because of their high electrical conductivity, transparency, and low cost. Carrier doping of graphene would potentially improve the properties of graphene-based TCFs for practical industrial applications. However, controlling the carrier type and concentration of dopants in graphene films is challenging, especially for the synthesis of p-type films. In this article, a new method for doping graphene using the conjugated organic molecule, tetracyanoquinodimethane (TCNQ), is described. Notably, TCNQ is well known as a powerful electron accepter and is expected to favor electron transfer from graphene into TCNQ molecules, thereby leading to p-type doping of graphene films. Small amounts of TCNQ drastically improved the resistivity without degradation of optical transparency. Our carrier doping method based on charge transfer has a huge potential for graphene-based TCFs. © 2011 Ishikawa et al.

A 70-year-old woman was admitted to our hospital with pleuritis and pericarditis. Cytological examination of pleural and pericardial effusion, and pleural biopsy specimens under thoracoscopy revealed no specific pathological findings. The pleural effusion was drained continuously; however, she died of circulatory insufficiency at day 45 from admission. At autopsy, a fragile hemorrhagic mass arising from the right auricle had invaded bilateral pleura and the pericardium directly without distant metastasis. Immunohistochemical staining showed that the tumor cells expressed endothelial markers such as CD31 and CD34 antibodies, and factor VIII-related protein. These findings supported the diagnosis of a poorly differentiated angiosarcoma.

Background Inhalation of N-acetylcysteine (NAC) has been carried out in our department since 1994 for treating interstitial pneumonia such as idiopathic pulmonary fibrosis (IPF). In this study, the clinical efficacy and safety of long-term NAC inhalation monotherapy for IPF was investigated. Methods NAC inhalation was carried out in 23 of 34 cases diagnosed as IPF by surgical lung biopsy in our department between 1994 and 2008. The treatment was continued for one year or longer in 14 cases. In these 14 cases and in 11 cases without treatment, the clinical courses, prognosis, lung function (%FVC, %DLco, and %TLC), and changes in serum markers for interstitial pneumonia (KL-6 and SP-D) were examined. Results There were no significant differences in survival curves between the two groups. Acute exacerbation was observed in 4 of 14 cases (28.6%) receiving NAC inhalation. Compared with the results just before the beginning of NAC inhalation, Delta%FVC and Delta%DLco in the treated cases were -4.7% and -2.9% one year later and -4.0% and -5.8% two years later, respectively. In cases without treatment, Delta%FVC and Delta%DLco were -3.5% and +5.3% one year later and +0.2% and +1.0% two years later, respectively. Conclusion Since this study is an open case-control study in a single institute and the number of cases is not large, its use in evaluating the efficacy of NAC inhalation monotherapy is limited. In addition, the role of NAC inhalation in combination with a steroid, an immunosuppressive agent, and a new anti-fibrosis drug should also be investigated.

Bleomycin (BLM)-induced lung injury consists of excessive inflammatory cell infiltration and fibrosis. IS-741 has been reported to be an anti-inflammatory drug through an inhibitory action on cell adhesion. In this study we investigated whether IS-741 could inhibit the progression of pulmonary fibrosis through inflammatory cell infiltration. Lung injury was induced in female C57BL/6 mice by intratracheal instillation of BLM. IS-741 was administered daily intraperitoneally. The hydroxyproline content and fluid content in the lung on Day 28 were significantly lower in the IS-741-treated mice. The histological degree of lung injury or fibrosis was reduced in IS-741-treated mice. Administration of IS-741 caused significant reduction in the absolute number of total cells, monocyte chemoattractant protein (MCP)-1, and cysteinyl leukotriene (cysLTs) levels in bronchoalveolar lavage fluid on Day 7. Furthermore, the hydroxyproline content was significantly lower in IS-741-treated mice even though IS-741 was started on Day 14 after BLM instillation. Treatment with IS-741 had an inhibitory effect on BLM-induced lung injury and fibrosis via the repression of MCP-1 or cysLTs in this murine experimental model.

Biopsy by video-assisted thoracoscopic surgery (VATS) for interstitial pneumonia allows collection of samples sufficient for accurate histologic diagnosis. Although VATS is relatively safe, several reports have suggested that surgical lung biopsy may be a risk factor for acute exacerbation of idiopathic pulmonary fibrosis (IPF). We retrospectively reviewed data on the 113 cases that underwent biopsy by VATS to diagnose diffuse parenchymal lung disease in our department between 1994 and 2006, and analyzed its complications, in particular, risk of acute exacerbation of IPF. As the final diagnosis, idiopathic interstitial pneumonia was most frequent, involving 52 cases, of which IPF was most frequently found followed by nonspecific interstitial pneumonia and cryptogenic organizing pneumonia, in that order. Among our cases, there were 2 deaths after VATS (mortality rate, 1.8%), and both were IPF cases with acute exacerbation. When examining clinical markers in the 2 fatal IPF cases with acute exacerbation, we found that the percentage of predicted forced vital capacity was 55 or lower, percentage of predicted carbon monoxide diffusing capacity was 40 or lower, serum interstitial pneumonia markers KL-6 and SP-D were elevated, intraoperative inhalation of 100% O2 was 80 minutes or longer, and postoperative thoracic drainage was required for 10 days or longer. Although acute exacerbations of IPF seem to occur at any time during the course of disease, it is important to be aware of the possibility of acute exacerbation of IPF after VATS. Copyright © 2009 by Lippincott Williams &amp Wilkins.

Background and objective: Reactive oxygen species (ROS) play an important role in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. It was hypothesized that edaravone, a free radical scavenger, would be able to attenuate LPS-induced lung injury in mice by decreasing oxidative stress. Methods: For the in vivo experiments, lung injury was induced in female BALB/c mice by the intranasal instillation of LPS. Edaravone was given by intraperitoneal administration 1 h before the LPS challenge. For the in vitro experiments, MH-S cells (murine alveolar macrophage cell line) were exposed to edaravone, followed by stimulation with LPS. Results: In the LPS-induced ALI mouse model, the administration of edaravone attenuated cellular infiltration into and the concentrations of albumin, IL-6, tumour necrosis factor-alpha, keratinocyte-derived chemokine and macrophage inflammatory protein-2 in BAL fluid. In addition, the in vitro studies showed that the elevated IL-6 secretion from MH-S cells in response to LPS was significantly attenuated by co-incubation with edaravone. Conclusions: In an experimental murine model, a free radical scavenger may prevent ALI via repression of pro-inflammatory cytokine production by lung macrophages.

Background and objective: IPF is an independent risk factor for lung cancer, but the mechanism of this association has not fully been elucidated. The role of Torque teno virus (TTV) in respiratory disease is poorly understood, although it has been shown that infection with TTV is associated with the activity and prognosis of IPF. This study aimed to investigate the prevalence and titre of TTV DNA among patients with IPF and lung cancer. Methods: The presence of TTV DNA was determined by PCR in the sera of patients with both lung cancer and IPF (n = 22), patients with IPF only (n = 35), and patients with lung cancer only (n = 142). Results: TTV DNA was detectable in all patients with both IPF and lung cancer, in 94.3% of the patients with IPF only and 97.2% of the patients with lung cancer only. The TTV DNA titre in the patients with IPF and lung cancer was significantly higher than that in the patients with IPF only or lung cancer only. The percentage of TTV-positive patients with a high TTV titre in the IPF and lung cancer group was significantly higher than that in the IPF only group. Conclusions: These findings are the first report on the association between TTV and the complication of lung cancer in IPF and suggest that TTV infection might be associated with the development of lung cancer in IPF.

A 74-year-old man with idiopathic pulmonary fibrosis (IPF) developed severe dyspnea on exertion after the readministration of imatinib mesylate for chronic myeloid leukemia. Chest X-ray and CT showed ground-glass opacities in both lungs in addition to preexisting honeycombing. Discontinuation of imatinib and methylprednisolone pulse therapy followed by administration of oral prednisolone resulted in improvement in both symptoms and radiographic findings. Imatinib-induced pneumonitis was diagnosed based on the clinical course and findings. Only five previous reports of imatinib-induced pneumonitis have been published in the literature, and this is the first case reported in a patient with IPF. Copyright (c) 2006 S. Karger AG, Basel.

Objective: Pulmonary fibrosis is thought to be closely associated with the T-helper type-2 (Th2) immune response. Recent studies have shown that hochu-ekki-to (TJ-41), a Japanese herbal medicine, may correct the Th1/Th2 imbalance skewed to Th2. The present study was designed to investigate the preventive effect of TJ-41 on the development of bleomycin (BLM)-induced lung injury in mice. Methods: Female C57BL/6 mice were divided into a group given ordinary feed and another group given the same feed plus TJ-41 mixed in at a dose of 1 g/kg/day. Both groups were maintained on this diet for 8 weeks before and 5 weeks after administration of 2 mg/kg BLM intratracheally. Results: Mortality after BLM-induced lung injury was significantly lower in the TJ-41-treated mice. The hydroxyproline content and fluid content in the lung on day 35 was significantly lower in the TJ-41-treated mice. Histologically, TJ-41 reduced the number of infiltrating cells, thus ameliorating the destruction of the lung architecture, and attenuated the lung fibrosis score. Furthermore, TJ-41 inhibited the expression of the interleukin-5/interferon-gamma mRNA ratio in the lung on day 7. Conclusion: Treatment with TJ-41 partially prevented experimental lung fibrosis through the correction of the Th1/Th2 imbalance skewed to Th2.

Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

The authors have investigated gene expression of ST2 in the lung tissue of a bleomycin (BLM)-induced lung fibrosis model in vivo and in a human lung fibroblast cell line, WI38, and a human type II alveolar epithelial cell line, A549, reacting to proinflammatory and type 2 helper T cell (Th2)-type cytokine stimuli in vitro. The lung mRNA expression of interleukin (IL)-4, IL-5, IL-1 beta, and tumor necrosis factor (TNT)-alpha increased significantly at day 7 after instillation of BLM, whereas interferon (IFN)-gamma mRNA expression did not increase. ST2 and transforming growth factor (TGF)-beta 1 mRNA expression of the lung increased significantly between days 7 and 21, and increased to maximal levels at day 14 post-BLM challenge. ST2 mRNA expression statistically correlated with TGF-beta 1 mPLNA expression. In addition, the combination of IL-1 beta, TAT-alpha, and IL-4 had an additive effect on ST2 mRNA expression from A549 cells and WI38 cells. These findings suggest that soluble ST2 gene may increase, possibly reflecting the development of the inflammatory process and the Th2-type immune response in the fibrotic lung tissue, and may modulate a process of pulmonary fibrosis.