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Background: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT., Methods: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated., Results: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity., Conclusion: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan., Competing Interests: Declaration of Competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus. It involves multiple organ systems, including the lungs. However, the significance of the lung involvement in SFTS remains unclear. In the present study, we aimed to investigate the relationship between the clinical findings and abnormalities noted in the chest computed tomography (CT) of patients with SFTS. The medical records of 22 confirmed SFTS patients hospitalized in five hospitals in Nagasaki, Japan, between April 2013 and September 2019, were reviewed retrospectively. Interstitial septal thickening and ground-glass opacity (GGO) were the most common findings in 15 (68.1%) and 12 (54.5%) patients, respectively, and lung GGOs were associated with fatalities. The SFTS patients with a GGO pattern were elderly, had a disturbance of the conscious and tachycardia, and had higher c-reactive protein levels at admission ( p = 0.009, 0.006, 0.002, and 0.038, respectively). These results suggested that the GGO pattern in patients with SFTS displayed disseminated inflammation in multiple organs and that cardiac stress was linked to higher mortality. Chest CT evaluations may be useful for hospitalized patients with SFTS to predict their severity and as early triage for the need of intensive care.

Background: Mycobacterial culture is the gold standard for the diagnosis of nontuberculous Mycobacterium (NTM) infections. However, this method is not suitable for detection of coinfection with different NTMs., Research Question: The goal of this study was to determine if clone library analysis of BAL fluid (BALF) was useful for detection of NTM phylotypes, including multiple NTM phylotypes, in pulmonary NTM infections., Study Design and Methods: BALF samples obtained from 120 patients with suspected pulmonary NTM infections were retrospectively evaluated by using the mycobacterial culture and clone library methods between July 2010 and August 2016., Results: In total, 55 (45.8%) patients were diagnosed as NTM positive according to results of mycobacterial culture, and 52 patients were NTM positive as determined by using the clone library method. Furthermore, 45 (86.5%) and seven (13.5%) patients exhibited a single phylotype (mono-phylotype group) and multiple phylotypes of NTM (multi-phylotype group), respectively. Compared with the mono-phylotype group, the multi-phylotype group had a significantly higher incidence of adverse chest CT findings (P = .048). In addition, 11 patients who were NTM negative according to results of BALF mycobacterial culture were determined to be NTM positive according to the clone library method. Six of these 11 patients were eventually diagnosed as NTM positive by using mycobacterial culture results within 6.2 ± 2.1 months following the initial sample collection., Interpretation: Coinfection multiple phylotypes could be associated with adverse clinical findings. In addition, patients who test positive for NTM genes but negative for mycobacterial culture may be diagnosed with NTM lung infection within 1 year of the initial sample collection. Further follow-up of these patients may facilitate early detection of NTM species., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Aspergillus fumigatus is an opportunistic mold that infects patients who are immunocompromised or have chronic lung disease, causing significant morbidity and mortality in these populations. While the factors governing the host response to A. fumigatus remain poorly defined, neutrophil recruitment to the site of infection is critical to clear the fungus. Galectin-3 is a mammalian β-galactose-binding lectin with both antimicrobial and immunomodulatory activities, however the role of galectin-3 in the defense against molds has not been studied. Here we show that galectin-3 expression is markedly up-regulated in mice and humans with pulmonary aspergillosis. Galectin-3 deficient mice displayed increased fungal burden and higher mortality during pulmonary infection. In contrast to previous reports with pathogenic yeast, galectin-3 exhibited no antifungal activity against A. fumigatus in vitro. Galectin-3 deficient mice exhibited fewer neutrophils in their airways during infection, despite normal numbers of total lung neutrophils. Intravital imaging studies confirmed that galectin-3 was required for normal neutrophil migration to the airspaces during fungal infection. Adoptive transfer experiments demonstrated that stromal rather than neutrophil-intrinsic galectin-3 was necessary for normal neutrophil entry into the airspaces. Live cell imaging studies revealed that extracellular galectin-3 directly increases neutrophil motility. Taken together, these data demonstrate that extracellular galectin-3 facilitates recruitment of neutrophils to the site of A. fumigatus infection, and reveals a novel role for galectin-3 in host defense against fungal infections., Competing Interests: The authors have declared that no competing interests exist.

Microbial involvement in the pathogenesis have been suggested in both antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and sarcoidosis, both of which have lung involvement. However, exhaustive research to assess the bacteria in the lung in AAV and in sarcoidosis have not been performed. We sought to elucidate the distinct dysbiotic lung microbiota between AAV and sarcoidosis. We used 16S rRNA gene high-throughput sequencing to obtain the bacterial community composition of bronchoalveolar lavage fluid (BALF) in patients with AAV (n = 16) compared to patients with sarcoidosis (n = 21). The patients had not undergone therapy with immunosuppressive medication when their BALF was acquired. No difference was observed in α-diversity between patients with AAV and patients with sarcoidosis when using all the detected taxa. We defined the taxa of the oral cavity by using the data of oral microbiota of healthy individuals from the Human Microbiome Project (HMP). The analysis using only oral taxa made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. Besides, the analysis using detected taxa except for oral taxa also made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. A linear negative relationship between the α-diversity and Birmingham vasculitis activity score (BVAS) was detected in the AAV group. The observed p-value for the effect of the disease groups on the ß-diversity was small while the effect of other factors including sex and smoking status did not have small p-values. By excluding oral taxa from all the detected taxa, we found a cluster mainly consisted of sarcoidosis patients which was characterized with microbial community monopolized by Erythrobacteraceae family. Our results suggested the importance of considering the influence of oral microbiota in evaluating lung microbiota.

The alteration of the microbial community in the upper respiratory tract (URT) can contribute to the colonization and invasion of respiratory pathogens. However, there are no studies regarding whether the characteristics of the URT microbiota can be affected by infections in lower respiratory tract (LRT). To elucidate the microbial profiles of the URT during pneumonia, the oral, nasal, and lung microbiota was evaluated at the early phase in a murine pneumonia model by direct intratracheal inoculation of Klebsiella pneumoniae. The meta 16S rRNA sequencing of bronchoalveolar lavage fluid after K. pneumoniae inoculation presented alterations in the beta diversity of the microbes, but not in the alpha diversity. At this point, a significant increase in microbial alpha diversity was observed in the oral cavity, but not in the nasal cavity. The significant increase was observed in the family Carnobacteriaceae and family Enterococcaceae. These results suggest that characterizing the microbial community of the respiratory tract may not just involve a simple downstream relationship from the URT to the LRT. The health status of the LRT may influence the oral microbiota. Thus, evaluation of the oral microbiota may contribute towards monitoring lung health; the oral microbiota may act as a diagnostic marker of pneumonia., Competing Interests: The authors have declared that no competing interests exist.

Background: Acute exacerbation of interstitial pneumonia (AE-IP) is a serious complication of pulmonary surgery in patients with IP. However, little is known about AE-IP after non-pulmonary surgery. The aim of this study was to determine the frequency of AE-IP after non-pulmonary surgery and identify its risk factors., Methods: One hundred and fifty-one patients with IP who underwent pulmonary surgery and 291 who underwent non-pulmonary surgery were retrospectively investigated., Results: AE-IP developed in 5 (3.3%) of the 151 patients in the pulmonary surgery group and 4 (1.4%) of the 291 in the non-pulmonary surgery group; the difference was not statistically significant. A logistic regression model showed that serum C-reactive protein (CRP) was a predictor of AE-IP in the non-pulmonary surgery group (odds ratio 1.187, 95% confidence interval 1.073-1.344, P = 0.002)., Conclusions: This is the first study to compare the frequency of AE-IP after pulmonary surgery with that after non-pulmonary surgery performed under the same conditions. The results suggest that the frequency of AE-IP after non-pulmonary surgery is similar to that after pulmonary surgery. A high preoperative C-reactive protein level is a potential risk factor for AE-IP after non-pulmonary surgery.

Background: There have been no reports on the relationship between lung radiological patterns and rheumatoid arthritis (RA) disease activity or RA treatment response in patients with RA-associated lung disease (RA-LD)., Methods: Patients with RA-LD who underwent treatment for RA from April 2005 to March 2015 were retrospectively evaluated. RA-LD patients were divided into three groups based on high-resolution computed tomography (HRCT) patterns [usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and bronchiolitis]. The disease activity score of 28 joints-erythrocyte sedimentation rate (DAS28-ESR) and the response of RA to treatment, as measured by the European League Against Rheumatism (EULAR) response criteria, were investigated., Results: A total of 77 patients (21 with UIP, 23 with NSIP, and 33 with bronchiolitis) were enrolled. Median scores (interquartile range) on the DAS28-ESR at baseline were 5.27 (4.76-5.74), 5.48 (4.24-6.34), and 5.04 (3.90-5.66) for UIP, NSIP, and bronchiolitis, respectively; there were no statistical differences between the three groups (p = 0.412). One year after baseline, 19 (90%), 14 (61%), and 19 (58%) of patients in the UIP, NSIP, and bronchiolitis groups, respectively, were considered good or moderate responders, as evaluated using the EULAR response criteria; there was a significant difference between these three groups (p = 0.014). Multiple logistic regression analysis revealed that the UIP pattern was significantly associated with good or moderate response to RA treatment 1 year after baseline (p = 0.012)., Conclusions: These results suggest that NSIP and bronchiolitis HRCT patterns may be risk factors for resistance to RA therapy., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

With the advent of new technologies evaluating the microbiome in the sample such as next-generation sequencer (NGS), current increase of an interest in understanding of the lung microbiome and its roles in lung diseases are marked. Gathering the data of bacterial flora in the lung and their changes during disease courses is unraveling the pathogenesis and the mechanism of disease progression particularly in patients with bronchial asthma, chronic obstructive pulmonary disease and infectious lung diseases. To clarify the relationship between the lung microbiome and pulmonary diseases, new information may help us to create new treatment and prevention strategies of some pulmonary diseases by controlling the lung microbiome. Using bacterial 16S ribosomal RNA gene sequence, NGS can rapidly estimate large amount of bacterial sequences in the phylum and genus levels, and some of them in species levels in a very short period of time. In addition to new information of the microbiome using NGS in the respiratory tract, other techniques using basically Sanger method in combination with the clone library construction can also be useful to identify pathogenic bacterial species with their ratio in the respiratory samples such as bacterial pneumonia, lung abscess and nontuberculous mycobacteriosis. These modalities to identify and semi-quantify bacterial burden in the respiratory tract have revealed new bacterial information in each infectious lung disease. This review describes current understanding of the lung microbiome in several representative lung diseases., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objective: Although high-resolution computed tomography (HRCT) is useful for the characterization of minute morphological changes in the lungs, no study has investigated risk factors for lung involvement detected by HRCT in patients with Sjögren's syndrome with or without respiratory symptoms. The aim of the current study was to investigate risk factors for lung involvement in patients with primary Sjögren's syndrome detected by HRCT, with a particular focus on airway and interstitial lung diseases., Methods: We performed a retrospective cohort study of patients with primary Sjögren's syndrome and investigated risk factors for lung involvement detected by HRCT. A total of 101 patients with primary Sjögren's syndrome with initial HRCT examinations were enrolled., Results: Higher age, dry mouth, and higher labial gland biopsy focus scores (≥4) were risk factors for airway diseases (odds ratio [OR] 1.064 confidence interval [CI] 1.026-1.102, OR 8.795 CI 2.317-33.378 and OR 3.261 CI 1.100-9.675, respectively) in the multivariable analysis. Higher age, male sex, and higher labial gland biopsy focus scores (≥4) were risk factors for interstitial lung diseases (OR 1.078 CI 1.032-1.127, OR 12.178 CI 1.121-132.307 and OR 3.954 CI 1.423-10.987, respectively) in the multivariable analysis. The presence of anti-T-lymphotropic virus type 1 antibodies was significantly more common in patients with airway diseases., Conclusions: This study showed significant associations of labial gland biopsy focus scores and dry mouth with pulmonary manifestations in patients with primary Sjögren's syndrome. Focus scores as well as dry mouth may reflect lymphoproliferative activity in the lungs in patients with primary Sjögren's syndrome., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Pulmonary emphysema is an important radiological finding in chronic obstructive pulmonary disease patients, but bacteriological differences in pneumonia patients according to the severity of emphysematous changes have not been reported. Therefore, we evaluated the bacteriological incidence in the bronchoalveolar lavage fluid (BALF) of pneumonia patients using cultivation and a culture-independent molecular method. Japanese patients with community-acquired pneumonia (83) and healthcare-associated pneumonia (94) between April 2010 and February 2014 were evaluated. The BALF obtained from pneumonia lesions was evaluated by both cultivation and a molecular method. In the molecular method, ~600 base pairs of bacterial 16S ribosomal RNA genes in the BALF were amplified by polymerase chain reaction, and clone libraries were constructed. The nucleotide sequences of 96 randomly selected colonies were determined, and a homology search was performed to identify the bacterial species. A qualitative radiological evaluation of pulmonary emphysema based on chest computed tomography (CT) images was performed using the Goddard classification. The severity of pulmonary emphysema based on the Goddard classification was none in 47.4% (84/177), mild in 36.2% (64/177), moderate in 10.2% (18/177), and severe in 6.2% (11/177). Using the culture-independent molecular method, Moraxella catarrhalis was significantly more frequently detected in moderate or severe emphysema patients than in patients with no or mild emphysematous changes. The detection rates of Haemophilus influenzae and Pseudomonas aeruginosa were unrelated to the severity of pulmonary emphysematous changes, and Streptococcus species - except for the S. anginosus group and S. pneumoniae - were detected more frequently using the molecular method we used for the BALF of patients with pneumonia than using culture methods. Our findings suggest that M. catarrhalis is more frequently detected in pneumonia patients with moderate or severe emphysema than in those with no or mild emphysematous changes on chest CT. M. catarrhalis may play a major role in patients with pneumonia complicating severe pulmonary emphysema., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Multifocal micronodular pneumocyte hyperplasia (MMPH) is pathologically characterized by multifocal nodular hyperplasia of type Ⅱ pneumocyte-like cells. MMPH is usually complicated with tuberous sclerosis complex (TSC). MMPH patients tend to be asymptomatic or only slightly symptomatic. MMPH tends to progress slowly and needs no treatment. We herein describe two cases of MMPH with its characteristic radiological features and clinical manifestations of TSC. Case 1: a 20-year-old female with definitive TSC in infancy. Chest CT at the age of 18 revealed multiple nodular opacities and ground-glass attenuations in a scattered and random distribution in the bilateral lungs. Case 2: a 44-year-old female with probable TSC at 36 years of age. Chest CT at the age of 43 showed random areas of small ground-glass attenuations, predominantly in the upper lung fields. Case 1 and Case 2 have had no respiratory symptoms or radiographic changes in the recent two years and four years, respectively. Although pathological examinations of the lung were not performed because consent for surgical lung biospies was unobtainable, we considered that these pulmonary manifestations were most likely MMPH with TSC because of these characteristic radiographical findings of multiple nodular opacities and ground-glass attenuations of 10 mm or less in size and their scattered distribution, and because there have been no abnormal laboratory data or changes in their chest radiological findings for years. Neither patient is under treatment for pulmonary lesions. Although MMPH is a rare disease, multiple nodules and ground-glass attenuations on lung imaging findings should be considered as pulmonary manifestations in patients with TSC.

Objective: Prior reports suggested that infection with Helicobacter pylori was associated with respiratory diseases; pathogenetic mechanisms however, were not defined. We tested the hypothesis that VacA, an exotoxin of H. pylori, a gastric pathogen, was aspirated into the lung and could stimulate secretion of inflammatory cytokines by lung epithelial cells., Methods: The presence of VacA was determined by immunohistochemistry in surgical lung biopsy tissue samples from 72 patients with interstitial pneumonia. The effects of VacA on A549 human alveolar epithelial adenocarcinoma cells and normal human bronchial epithelial cells were determined. After incubation with VacA, the secretions of cytokines were measured by Multiplex Luminex(®) Assays., Results: VacA was detected with anti-VacA antibodies in bronchial epithelial cells and alveolar epithelial cells from 10 of 72 patients with interstitial pneumonia. VacA was more prevalent in lungs of patients with collagen vascular disease-associated interstitial pneumonia than in those of patients with idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia and cryptogenic organizing pneumonia. Incubation of A549 cells and normal human bronchial epithelial cells with VacA for 24 h was cytotoxic, and resulted in vacuolation. VacA induced interleukin-8 production by A549 cells and normal human bronchial epithelial cells and interleukin-6 production by A549 cells. Based on multiplex screening, interleukin-8 and interleukin-6 were the primary secretory products induced by VacA., Conclusions: H. pylori VacA is present in human lung and can induce interleukin-8 and interleukin-6 production by human lung cells. VacA could have a role in the pathogenesis of respiratory diseases by its cytotoxic effects and by inducing the secretion of interleukin-8 and interleukin-6 by targeted airway epithelial cells., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A 62-year-old Japanese man was admitted to our hospital for evaluation of bilateral chest abnormal shadow.His lacrimal, submandibular and parotid glands had been swollen for several years. His serum immunoglobulin G4 (IgG4) level was >1,500 mg/dl, and chest computed tomography showed bilateral reticular opacities with enlarged mediastinal lymph nodes. Transbronchial lung biopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) results suggested IgG4-related disease. This is the first report, to our knowledge, in the English literature showing EBUS-TBNA to be useful for diagnosing IgG4-related disease.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. However, few studies have so far reviewed analyses of autopsy findings in patients with AE-IPF., Methods: We retrospectively reviewed 52 consecutive patients with AE-IPF who underwent autopsies at five university hospitals and one municipal hospital between 1999 and 2013. The following variables were abstracted from the medical records: demographic and clinical data, autopsy findings and complications during the clinical course until death., Results: The median age at autopsy was 71 years (range 47-86 years), and the subjects included 38 (73.1%) males. High-dose corticosteroid therapy was initiated in 45 (86.5%) patients after AE-IPF. The underling fibrotic lesion was classified as having the usual interstitial pneumonia (UIP) pattern in all cases. Furthermore, 41 (78.8%) patients had diffuse alveolar damage (DAD), 15 (28.8%) exhibited pulmonary hemorrhage, nine (17.3%) developed pulmonary thromboembolism and six (11.5%) were diagnosed with lung carcinoma. In addition, six (11.5%) patients developed pneumothorax prior to death and 26 (53.1%) developed diabetes that required insulin treatment after the administration of high-dose corticosteroid therapy. In addition, 15 (28.8%) patients presented with bronchopneumonia during their clinical course and/or until death, including fungal (seven, 13.5%), cytomegalovirus (six, 11.5%) and bacterial (five, 9.6%) infections., Conclusions: The pathological findings in patients with AE-IPF represent not only DAD, but also a variety of pathological conditions. Therefore, making a diagnosis of AE-IPF is often difficult, and the use of cautious diagnostic approaches is required for appropriate treatment.

Background: IgG4-related disease (IgG4RD) is a recently recognized disease entity. Differentiating IgG4RD from plasma cell type Castleman's disease (PCD) is important but also difficult using only pathological findings. In addition, little is known about the association between these two diseases with diffuse parenchymal lung involvement., Methods: We analyzed the serum IgG4 levels and the ratio of IgG4/IgG-positive plasmacytes in the lung and lymph node specimens of eight patients previously pathologically diagnosed of PCD with diffuse parenchymal lung involvement (DL-PCD). We also compared the clinical and laboratory findings observed in these patients., Results: Six of the eight patients exhibited abundant IgG4-positive plasmacytes in the lung and lymph node tissues and elevated serum IgG4 levels, thereby fulfilling the diagnostic criteria of IgG4RD with DL (DL-IgG4RD) in addition to having obstructive phlebitis and massive lymphoplasmacytic infiltration with fibrosis. However, three of these six patients exhibited higher levels of serum interleukin-6 and were still diagnosed with DL-PCD. Accordingly, three of these eight patients were considered as IgG4RD with DL (DL-IgG4RD), and the other five patients were ultimately given a diagnosis of DL-PCD. These two diseases have different characteristics in terms of age, symptoms, serum levels of C-reactive protein, and IgA, complicating allergic disorders, response to corticosteroids, and prognosis., Conclusions: This is the first report to show a high prevalence of DL-IgG4RD in DL-PCD patients, although additional large investigations are necessary. Clinical and laboratory findings are important for distinguishing between these two diseases in other organs, as previously described.

We report a case of adult T-cell leukemia/lymphoma (ATL) with rapidly progressive pulmonary areas of ground-glass attenuation (GGA) and nodules resulting from acute transformation of chronic ATL. A 48-year-old Japanese man was admitted for progressive dyspnea. Chest computed tomography showed rapidly progressive bilateral pulmonary areas of GGA and nodules. Flow cytometry of bronchoalveolar lavage fluid and immunohistochemical examination of lung biopsy specimens revealed invasion of ATL cells. Systemic chemotherapy improved the pulmonary findings. Rapidly expanding areas of GGA and nodules are a rare manifestation of pulmonary invasion of ATL that clinicians should nevertheless keep in mind., (Copyright © 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

We herein present a case of Good syndrome complicated by diffuse pulmonary lesions similar to diffuse panbronchiolitis (DPB). A 45-year-old Japanese man was referred to our department due to recurrent lower respiratory tract infections that had started and ameliorated nine months after thymectomy for pure red cell aplasia and myasthenia gravis. Diffuse centrilobular opacities on chest computed tomography and positivity for HLA-B54 were consistent with DPB. Additionally, hypogammaglobulinemia and a marked decrease of B-lymphocytes were observed, and therefore Good syndrome was considered. Combination therapy with azithromycin and clarithromycin alleviated the patient's respiratory symptoms and reduced the exacerbation of chronic bronchitis.

Exposure to urban air pollution is an independent risk factor for increased cardiovascular diseases. Heat shock protein 70 (HSP70) has been implicated in the pathogenesis of vascular dysfunction and cardiovascular diseases. This study has been designed to determine whether inhalation of urban air induces HSP70 expression in the lung and blood as well as the association of HSP70 and air pollution-induced vascular dysfunction. Apolipoprotein E (Apo-E) deficient mice were exposed to diesel exhaust (DE) either acutely (3 days, 200 or 400 µg/m(3) for 6 h/day) or chronically (7 weeks, 200 or 400 µg/m(3) for 6 h/day). HSP70 was measured in the lung using immunohistochemistry, and in the plasma by ELISA. Abdominal aorta rings were used to determine vascular functional responses. Chronic DE-exposure increased the fraction of HSP70 positive alveolar macrophages (AM) that was related to the fraction of particle-laden AM in the lung (r(2) =  0.48, p <0.01). Chronic DE-exposure increased plasma HSP70 levels and reduced blood vessel responses to phenylephrine (PE). The fraction of particle-laden HSP70 positive AM was associated with abnormal vasoconstriction responses to PE induced by DE-exposure (r(2) = 0.12, p = 0.02). Our results show that chronic inhalation of DE increases HSP70 expression in the lung and systemic circulation, and we postulate that HSP70 possibly contributes to air pollution induced vascular dysfunction and cardiovascular diseases.

Background: The frequencies of etiologic bacterial agents of intrapleural infections reported until now have been widely varied, largely depending on the implemented detective methods. The aims of this study were to evaluate bacterial etiologies of bacterial pleurisy using a cultivation-independent method., Methods: Pleural fluids were collected from 42 febrile patients with hemipleural effusion. The bacterial flora was analyzed by a clone library method using amplified fragments of the 16S ribosomal RNA gene (rDNA) with universal primers in addition to conventional cultivation methods., Results: Forty-two specimens were obtained from 26 patients with bacterial pleurisy, seven with mycobacterial pleurisy, and nine with other pleural effusions. In the 26 bacterial cases, 16 (61.5%) showed positive results for 16S rDNA sequencing analysis, of which 11 (42.3%) were also positive for cultivation method. In seven (43.8%) of the 16 polymerase chain reaction-positive cases, anaerobic phylotypes were predominantly detected. Anaerobic phylotypes (six of these seven cases) were not detected by cultivation method. In nine (34.6%) of the 26 bacterial pleural cases, the results from the clone library methods were not accordant with those of the cultivation method. In seven of these nine cases, the discrepancies between the two detection methods were due to the existence of anaerobes., Conclusion: The clone library analysis using the 16S rDNA of pleural fluid showed a higher incidence of anaerobic bacteria in infectious pleurisy than that previously expected and provided additional bacterial information for cultivation methods.

The biological mechanisms responsible for an association between elevated concentrations of ambient particulate matter (PM) and increased cardiovascular morbidity and mortality remain unclear. Our laboratory showed that exposure to PM induces systemic inflammation that contributes to vascular dysfunction. This study was designed to determine whether the lung is a major source of systemic inflammatory mediators, using IL-6 as a surrogate marker. We also sought to determine the impact on vascular dysfunction after exposure to PM of less than 10 μm in diameter (PM(10)). C57BL/6 mice were intratracheally exposed to a single instillation of PM(10) (10 or 200 μg) or saline. Four hours or 24 hours after exposure, venous and arterial blood samples were simultaneously collected from the right atrium and descending aorta. Concentrations of IL-6 were measured in bronchoalveolar lavage fluid (BALF) and serum samples. Vascular functional responses to acetylcholine (ACh) and phenylephrine were measured in the abdominal aorta. Concentrations of IL-6 in BALF samples were increased at 4 and 24 hours after exposure to PM(10). At baseline, concentrations of IL-6 in venous blood were higher than those in arterial blood. Exposure to PM(10) reversed this arteriovenous gradient, 4 hours after exposure. The relaxation responses of the abdominal aorta to ACh decreased 4 hours after exposure to 200 μg PM(10). In IL-6 knockout mice, the instillation of recombinant IL-6 increased IL-6 concentrations in the blood, and exposure to PM(10) did not cause vascular dysfunction. These results support our hypothesis that exposure to PM(10) increases pulmonary inflammatory mediators that translocate to the circulation, contributing to systemic inflammation, with downstream effects such as vascular dysfunction.

alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of lung diseases, including idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and diffuse panbronchiolitis (DPB). In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in IPF and around the airways in CF and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to IPF, CF, and DPB. alpha-Defensins are known to induce interleukin (IL)-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide (HNP)-1 (a subtype of alpha-defensin) on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of IPF, CF, and DPB according to the location in the lung where the alpha-defensins are mainly produced.

Background: The histopathologic pattern is currently the most important prognostic marker for idiopathic interstitial pneumonia (IIP). However, more highly sensitive markers are now required. Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagens, and it has been demonstrated that HSP47 expression is significantly higher in the lung specimens of idiopathic UIP than in UIP associated with collagen vascular diseases (CVD). However, its expression in nonspecific interstitial pneumonia (NSIP), the other common pathological pattern of IIP, has not been well investigated. Therefore, the association between lung fibroblast HSP47 expression and prognosis in fibrotic NSIP was evaluated., Methods: Surgical lung biopsy specimens of 63 patients [idiopathic fibrotic NSIP=19, fibrotic NSIP associated with CVD=9, idiopathic UIP=26, and UIP associated with CVD=9] were reviewed, and a score for lung fibroblast HSP47 expression was assigned. These patients' clinical features and survival were also analyzed., Results: There was no significant difference in HSP47 expression between idiopathic fibrotic NSIP and fibrotic NSIP associated with CVD. The idiopathic fibrotic NSIP patients with higher HSP47 expression levels in their lung specimens had a poorer prognosis than patients with lower HSP47 expression levels., Conclusions: The present results suggest that lung fibroblast HSP47 expression may be a useful new prognostic marker for idiopathic fibrotic nonspecific interstitial pneumonia., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and patients with idiopathic pulmonary fibrosis (IPF). Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen and plays an important role in the pathogenesis of IPF. The present study evaluated the in vitro effects of pirfenidone on expression of HSP47 and collagen type I in cultured normal human lung fibroblasts (NHLF). Expression levels of HSP47 and collagen type I in NHLF stimulated by transforming growth factor (TGF)-beta1 were evaluated genetically, immunologically and immunocytochemically. Treatment with TGF-beta1 stimulated both mRNA and protein expressions of both HSP47 and collagen type I in NHLF, and pirfenidone significantly inhibited this TGF-beta1-enhanced expression in a dose-dependent manner. We concluded that the anti-fibrotic effect of pirfenidone may be mediated not only through direct inhibition of collagen type I expression but also at least partly through inhibition of HSP47 expression in lung fibroblasts, with a resultant reduction of collagen synthesis in lung fibrosis.

We report here 3 cases of chronic bird fancier's lung diagnosed immunologically using antibodies to pigeon dropping extract. None of the patients were bird fanciers but had indirect exposure to birds in their living environment, and had been using feather-filled duvets or pillows for a long time. Two of 3 cases were positive for environmental provocation tests and 2 cases had pathological findings of hypersensitivity pneumonitis such as multinucleated giant cells and non-necrotizing epithelioid cell granulomas. One case was resistant to steroid therapy alone and was successfully treated by coadministration of prednisolone and cyclosporin A. Another case was treated by steroid alone but died of acute exacerbation of unknown cause. These cases suggest that not only feathers but two or more kinds of bird-related antigens were involved in the sensitization immunology and development of bird fancier's disease, and that clinicians should perform thorough history taking with environmental surveillance relevant to birds.

Background: Human beta-defensin-4 (hBD-4), a new member of the beta-defensin family, was discovered by an analysis of the genomic sequence. The objective of this study was to clarify hBD-4 expression in human lung tissue, along with the inducible expression in response to infectious stimuli, localization, and antimicrobial activities of hBD-4 peptides. We also investigated the participation of hBD-4 in chronic lower respiratory tract infections (LRTI) by measuring the concentrations of hBD-4 peptides in human bronchial epithelial lining fluid (ELF)., Methods: The antimicrobial activity of synthetic hBD-4 peptides against E. coli and P. aeruginosa was measured by radial diffusion and colony count assays. We identified hBD-4 in homogenated human lung tissue by reverse-phase high-performance liquid chromatography coupled with a radioimmunoassay (RIA). Localization of hBD-4 was studied through immunohistochemical analysis (IHC). We investigated the effects of lipopolysaccharide (LPS) on hBD-4 expression and its release from small airway epithelial cells (SAEC). We collected ELF from patients with chronic LRTI using bronchoscopic microsampling to measure hBD-4 concentrations by RIA., Results: hBD-4 exhibited salt-sensitive antimicrobial activity against P. aeruginosa. We detected the presence of hBD-4 peptides in human lung tissue. IHC demonstrated the localization of hBD-4-producing cells in bronchial and bronchiolar epithelium. The levels of hBD-4 peptides released from LPS-treated SAECs were higher than those of untreated control cells. ELF hBD-4 was detectable in 4 of 6 patients with chronic LRTI, while the amounts in controls were all below the detectable level., Conclusion: This study suggested that hBD-4 plays a significant role in the innate immunity of the lower respiratory tract.

Background: Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagens, and its expression is increased in various fibrotic diseases. The aim of this study was to determine whether quantitative immunohistochemical evaluation of the expression levels of HSP47, type I procollagen and alpha-smooth muscle actin (SMA) allows the differentiation of idiopathic usual interstitial pneumonia (UIP) from UIP associated with collagen vascular disease (CVD) and idiopathic nonspecific interstitial pneumonia (NSIP)., Methods: We reviewed surgical lung biopsy specimens of 19 patients with idiopathic UIP, 7 with CVD-associated UIP and 16 with idiopathic NSIP and assigned a score for the expression of HSP47, type I procollagen and alpha-SMA in type II pneumocytes and/or lung fibroblasts (score 0 = no; 1 = weak; 2 = moderate; 3 = strong staining)., Results: The expression level of HSP47 in type II pneumocytes of idiopathic UIP was significantly higher than in CVD-associated UIP and idiopathic NSIP. The expression of HSP47 in fibroblasts was significantly higher in idiopathic UIP and idiopathic NSIP than in CVD-associated UIP. The expression of type I procollagen in type II pneumocytes was significantly higher in idiopathic UIP than in idiopathic NSIP. The expression of type I procollagen in fibroblasts was not different in the three groups, while the expression of alpha-SMA in fibroblasts was significantly higher in idiopathic UIP than in idiopathic NSIP., Conclusion: Our results suggest the existence of different fibrotic pathways among these groups involved in the expression of HSP47 and type I procollagen.

Background and Objectives: Sarcoidosis is a systematic granulomatous disorder of unknown origin characterized by accumulation of T lymphocytes and macrophages in multiple organs. We postulated that apoptosis through the Fas/Fas ligand (L) system may be associated with regulation of immune reactions characterized by the formation of noncaseous necrotizing granulomas. Soluble (s) FasL is not equivalent to membrane-associated FasL since conversion of membrane-bound FasL to the soluble form is associated with downregulation of cytotoxicity. To examine the involvement of sFasL in lung inflammation, we compared the levels of sFasL in bronchoalveolar lavage (BAL) fluid and serum of patients with pulmonary sarcoidosis to those of healthy subjects., Methods: sFasL was measured in BAL fluid and in serum of 15 patients with active pulmonary sarcoidosis by sandwich ELISA., Results: High concentrations of sFasL were detected in BAL fluid and serum of patients with sarcoidosis but not in normal subjects. There was a significant correlation between the percentage of lymphocytes and sFasL concentrations in BAL fluid (r = 0.585, p < 0.05)., Conclusions: Our results suggest that sFasL may be upregulated locally in the lung during the inflammatory process of active pulmonary sarcoidosis., (Copyright 2002 S. Karger AG, Basel)

A 69-year-old man was admitted with general fatigue, dyspnea, cough, fever and right pulmonary infiltrations on a chest X-ray films. He had suffered from myocardial infarction 8 years before. Since September 1987, he had been given Aprindine in addition to previous drugs. In early November 1987, he developed dyspnea. Antibiotics were not effective. He was hospitalized on Nov. 13, '87 when crepitations were audible on his right chest. Methylprednisolone pulse therapy was effective, however right pneumothorax developed. He underwent right thoracotomy and lung biopsy. Lung biopsy specimens showed pathological features of bronchiolitis obliterans organizing pneumonia (BOOP). Corticosteroid therapy yielded a remarkable clinical, physiological and roentgenographic recovery. However, approximately two years later during prednisolone maintenance therapy, BOOP recurred. He responded again to corticosteroid treatment, however he died of hepatic failure on Dec. 17, '89. "Idiopathic" rather than "drug induced" was suggested for the cause of BOOP in this case.