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Background Allergic bronchopulmonary aspergillosis (ABPA) and chronic eosinophilic pneumonia (CEP) both display peripheral eosinophilia as well as pulmonary infiltration, together described as pulmonary eosinophilia, and differentiation is sometimes problematic. This study therefore examined the distinctions between ABPA with and without CEP-like shadows. Methods This retrospective cohort study from a single center included 25 outpatients (median age, 65 years) with ABPA diagnosed between April 2015 and March 2019, using criteria proposed by the International Society of Human and Animal Mycology (ISHAM), which focuses on positive specific IgE for Aspergillus fumigatus. Patients were assigned to either the eosinophilic pneumonia (EP) group or Non-EP group, defined according to findings on high-resolution computed tomography (HRCT). The EP group included patients with HRCT findings compatible with CEP; i.e., the presence of peripheral consolidation (p-consolidation) or ground-glass opacities (GGO), with no evidence of high-attenuation mucus. The Non-EP group comprised the remaining patients, who showed classical findings of ABPA such as mucoid impaction. Differences between the groups were analyzed. Results Baseline characteristics, frequency of a history of CEP (EP, 50% vs. Non-EP, 26%) and tentative diagnosis of CEP before diagnosis of ABPA (67% vs. 16%) did not differ significantly between groups. Although elevated absolute eosinophil count and Aspergillus-specific immunoglobulin E titers did not differ significantly between groups, the Non-EP group showed a strong positive correlation between these values (R = 0.7878, p = 0.0003). The Non-EP group displayed significantly higher levels of the fungal marker beta-D glucan (median, 11.7 pg/ml; interquartile range, 6.7–18.4 pg/ml) than the EP group (median, 6.6 pg/ml; interquartile range, 5.2–9.3 pg/ml). Both groups exhibited frequent recurrence of shadows on X-rays but no cases in the EP group had progressed to the Non-EP group at the time of relapse. Conclusions The ABPA subgroup with imaging findings resembling CEP experienced frequent recurrences, as in typical ABPA. In pulmonary eosinophilia, even if there are no shadows indicating apparent mucous change, the Aspergillus-specific immunoglobulin E level is important in obtaining an accurate diagnosis and in the selection of appropriate therapies for this type of ABPA.

The association between Mycobacterium avium complex pulmonary disease (MAC-PD) and pleuroparenchymal fibroelastosis (PPFE) has been reported previously, and interstitial pneumonia as a comorbidity is associated with a worse prognosis. However, no study has thoroughly reported on PPFE associated with MAC-PD. The present study investigated the prevalence, clinical characteristics, and prognostic impact of PPFE in patients with MAC-PD.A total of 224 patients, newly diagnosed with MAC-PD, were retrospectively reviewed. At the time of diagnosis, chest high-resolution computed tomography (HRCT), sputum examination, and clinical characteristics were collected. The extent of PPFE and MAC-PD was evaluated semi-quantitatively using HRCT scores. Risk factor analysis for clinical or radiological deterioration necessitating multidrug antimicrobial treatment within 3 years, and all-cause mortality within 5 years, from the initial diagnosis was performed based on the PPFE score.PPFE was observed in 59 out of 224 patients (26.3%). A higher PPFE score was a risk factor for dyspnoea, fatigue, and lower body mass index (BMI) (pPPFE is a relatively common complication and an independent poor prognostic factor of MAC-PD. This study highlights the need for further studies investigating whether the presence of PPFE can be a clinical indicator for initiating treatment of MAC-PD.

Although the utility of oscillometry for predicting disease severity in idiopathic pulmonary fibrosis (IPF) had been researched, little has been reported on the mechanism of why respiratory impedance reflects disease severity. In addition, traction bronchiectasis has been considered to reduce respiratory resistance and correlate negatively with airflow obstruction, but this hypothesis has not been validated. The present study aimed to investigate the correlations between oscillometric parameters and fibrosis-related lung abnormalities in IPF and to assess the utility of oscillometry as a surrogate marker for traction bronchiectasis and airflow obstruction. Eighty Japanese patients with IPF underwent high-resolution computed tomography (HRCT), spirometry, and oscillometry and were retrospectively investigated. Fibrosis-related HRCT findings were scored regarding airspace consolidation, honeycombing, architectural distortion, traction bronchiectasis, and fibrosis. Correlations between the HRCT scores, spirometric parameters, and oscillometric parameters were analysed. Respiratory reactance correlated positively with all fibrosis-related HRCT scores. Vital capacity and forced vital capacity (FVC) correlated negatively with oscillometric parameters and HRCT scores, reflecting the severity of restrictive ventilatory deficiency. Respiratory resistance was not related to any of the HRCT scores or forced expiratory volume in 1 s/FVC. However, forced expiratory volume in 1 s/FVC correlated positively with HRCT scores, which showed that airflow obstruction became milder as the disease progressed. In conclusion, respiratory reactance reflects fibrosis and restrictive ventilatory deficiency in IPF. Moreover, respiratory resistance is independent of traction bronchiectasis and airflow obstruction in patients with IPF, which implies that respiratory resistance might reflect different properties of the airways., Respiratory reactance measured by oscillometry correlates with fibrosis-related computed tomography findings in idiopathic pulmonary fibrosis (IPF). Respiratory resistance is independent of traction bronchiectasis and airflow obstruction in IPF. https://bit.ly/36zoGtf

Background Oscillometry is a tool to measure respiratory impedance that requires minimal patients' effort. In patients with chronic obstructive pulmonary disease (COPD), the correlation of respiratory impedance at rest with exertional ventilatory parameters, including exercise tolerance, has scarcely been reported. In addition, the utility of oscillometric parameters might differ between the inspiratory and expiratory phases due to airflow obstruction during expiration, but the hypothesis had not been validated. The aim of the present study was to investigate whether oscillometric parameters are associated with exertional ventilatory parameters in patients with COPD. Methods Fifty-five subjects with COPD who attended clinics at the National Hospital Organization Osaka Toneyama Medical Center performed spirometry, oscillometry, and cardiopulmonary exercise testing (CPET) within 2 weeks. The correlations between parameters of spirometry, oscillometry, and CPET were analyzed using Spearman's rank correlation coefficient, univariate, and multivariate analyses. Results Respiratory reactance had better correlations with the CPET parameters than respiratory resistance. Moreover, inspiratory reactance at rest correlated with the CPET parameters stronger than expiratory reactance. In particular, inspiratory resonant frequency (Fres-ins) correlated with peak oxygen uptake (rS=-0.549, p

Background Lung resection in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) has been reported to be associated with favorable outcomes. However, little is known regarding the risk and prognostic factors for refractory and recurrent cases. We aimed to evaluate the overall impact and benefit of adjuvant lung surgery by comparing NTM-PD patients who underwent adjuvant lung resection with those treated exclusively with antibiotics. We also investigated the efficacy of serum IgA antibody against glycopeptidolipid (GPL) core antigen (GPL core antibody) to monitor disease activity and predict the recurrence of disease after adjuvant lung resection. Methods We retrospectively evaluated the clinical characteristics and surgical outcomes of 35 patients surgically treated for NTM-PD. Furthermore, we compared surgically treated patients and control patients treated exclusively with antibiotics who were matched statistically 1:1 using a propensity score calculated from age, sex, body mass index, and radiologic features of disease. Results In the surgically treated patients, the median age was 58 (interquartile range, 47–65) years and 65.7% were female. Twenty-eight patients had Mycobacterium avium complex. Operations comprised four pneumonectomies, two bilobectomies, one bilobectomy plus segmentectomy, 17 lobectomies, two segmentectomies, and nine lobectomies plus segmentectomies. Postoperative complications occurred in seven patients (20%), there were no operative deaths, and 33 (94.3%) patients achieved negative sputum culture conversion. Refractory and recurrent cases were associated with remnant bronchiectasis, contralateral shadows, and positive acid-fast bacilli staining or culture. Of 28 statistically matched pairs, long-term sustained negative culture conversion was observed in 23 (82.2%) surgical group patients and in 14 (50.0%) non-surgical group patients (0.0438). The mortality rate was lower in the surgical group, but did not reach statistical significance (one in the surgical group and four in the non-surgical group, p = 0.3516). GPL core antibody was correlated with disease activity and recurrence. Conclusions NTM-PD patients who underwent adjuvant lung resection experienced overall favorable outcomes and achieved sputum culture conversion more frequently. Long-term mortality may have been reduced by this procedure, and the level of GPL core antibody was shown to be a good clinical indicator of disease activity after surgery.

Influenza vaccination can trigger various adverse reactions, and thrombocytopenia is also rarely reported. Although patients with mild thrombocytopenia are sometimes asymptomatic, severe thrombocytopenia can cause severe bleeding. We herein report a rare case of severe thrombocytopenia that occurred within one day of influenza vaccination and diffuse alveolar hemorrhage (DAH) leading to acute respiratory failure. The patient was treated with glucocorticoid pulse therapy, intravenous immunoglobulin, and temporary mechanical ventilation, and eventually he made a full recovery. Vaccine-related thrombocytopenia and DAH should be considered adverse reactions, even if they develop very soon after vaccination.

Mycolicibacterium mageritense (M. mageritense) is a rare species among rapidly growing mycobacteria, and M. mageritense pleurisy is very rare. Here, we report for the first time, an immunocompetent patient with pleurisy caused by M. mageritense. The patient had no history of immunodeficiency and no recurrence of lung cancer after surgery. However, 8 months after surgery, he developed a new lung shadow and pleurisy. Although whole-genome analysis of the colony cultured from the patient's pleural fluid revealed M. mageritense, we could not identify it in time, resulting in a poor outcome. M. mageritense pleurisy in this case might have occurred via a bulla rupture of the lung lesion because computed tomography of the patient's chest showed pneumothorax and a lung lesion in contact with thoracic cavity. This case emphasized that nontuberculous mycobacterial pleurisy should be considered in the differential diagnoses of pleural effusion even in immunocompetent patients. Advancement of comprehensive and rapid analyses of genomic data from clinical specimens will lead to better treatment strategies.

Aims: In contrast to cardiovascular disease, low rather than high ventilatory inefficiency, evaluated by the minute ventilation-carbon dioxide output (V’E-V’CO2)-slope, has been recognized as being related to greater disease severity in chronic obstructive pulmonary disease (COPD). To better care for patients with cardiopulmonary disease, understanding the physiological correlation between ventilatory inefficiency and exercise limitation is necessary, but remains inadequate. Given that oxygen uptake (V’O2) evaluated by cardiopulmonary exercise testing (CPET) depends on both the ventilatory capability and oxygen extraction, i.e., the difference between inspiratory and expiratory oxygen concentration (delta FO2), the aim of this study was to investigate the correlations between V’E-V’CO2-slope and the delta FO2 during exercise and their physiological implications in patients with COPD. Methods: A total of 156 COPD patients (mean age, 70.9 ± 7.2 years) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I–IV and 16 controls underwent CPET with blood gas analysis. Results: With the progression of COPD, mechanical ventilatory constraints together with a slower respiratory frequency led to exertional respiratory acidosis. In GOLD IV cases, 1) decrease in the dependence of reduced peak V’O2 on V’E led to an increase in its dependence on peak delta FO2 during exercise; and 2) the delta FO2-V’CO2-slope became steeper, correlating with the severity of exertional respiratory acidosis (r=0.6359, p

The association between airflow obstruction and bronchial dilation has been researched in bronchiectasis. However, the impact of bronchial wall thickening on airflow obstruction has not been thoroughly investigated. This study assessed the underlying mechanism of airflow obstruction in bronchiectasis due to abnormal bronchial wall thickening using oscillometry. A total of 98 patients with bronchiectasis were retrospectively reviewed. At the time of diagnosis, spirometric and oscillometric parameters, high-resolution computed tomography scores, and clinical characteristics were collected. The bronchial diameter, bronchial wall thickness, and extent of emphysema were evaluated semi-quantitatively. Correlations between patient data and characteristics were analyzed. Thirty-three patients with airflow obstruction showed higher respiratory resistance, more negative respiratory reactance (Xrs) at 5 Hz (X5), and higher bronchial wall thickness score than those without airflow obstruction. The bronchial wall thickness score negatively affected forced expiration volume in 1 s /forced vital capacity and X5. Abnormal bronchial wall thickening might make Xrs more negative and progress airflow obstruction in bronchiectasis.

Diffuse pulmonary ossification (DPO) is an uncommon diffuse lung disease characterized by metaplastic bone formation in the lung parenchyma and is rarely diagnosed in life. While DPO usually occurs as a secondary disease, idiopathic cases are extremely rare. We describe three cases of idiopathic DPO, two of which were definitively diagnosed by surgical lung biopsy. One case was observed in a 43-year-old man with a history of recurrent pneumothorax who developed pneumothorax after the surgical biopsy. Few reports have described cases of DPO with recurrent pneumothorax; however, pneumothorax should be considered as a potential complication when such patients are encountered.

While both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are multifactorial disorders characterized by distinct clinical and pathological features, their commonalities and differences have not been fully elucidated. We sought to investigate the preventive roles of tetraspanins Cd151 and Cd9 -that are involved in diverse cellular processes in lung pathophysiology- in pulmonary fibrosis and emphysema, respectively, and to obtain a deeper understanding of their underlying molecular mechanisms toward facilitating improved therapeutic outcomes. Using an integrative approach, we examined the transcriptomic changes in the lungs of Cd151- and Cd9-deficient mice using functional-enrichment-analysis, pathway-perturbation-analysis and protein-protein-interaction (PPI) network analysis. Circadian-rhythm, extracellular-matrix (ECM), cell-adhesion and inflammatory responses and associated factors were prominently influenced by Cd151-deletion. Conversely, cellular-junctions, focal-adhesion, vascular-remodeling, and TNF-signaling were deeply impacted by Cd9-deletion. We also highlighted a “common core” of factors and signaling cascades that underlie the functions of both Cd151 and Cd9 in lung pathology. Circadian dysregulation following Cd151-deletion seemingly facilitated progressive fibrotic lung phenotype. Conversely, TGF-β signaling attenuation and TNF-signaling activation emerged as potentially novel functionaries of Cd9-deletion-induced emphysema. Our findings offer promising avenues for developing novel therapeutic treatments for pulmonary fibrosis and emphysema.

No effective therapy exists for fatal fibrosis. New therapeutic targets are needed for hepatic fibrosis because the incidence keeps increasing. The activation and differentiation of fibroblasts into myofibroblasts that causes excessive matrix deposition is central to fibrosis. Here, we investigated whether (and which) integrin receptors for matrix proteins activate hepatic stellate cells (HSCs). First, integrin α‐subunits were investigated systematically for their expression over the course of HSC activation and their distribution on fibroblasts and other systemic primary cells. The most upregulated in plate culture‐activated HSCs and specifically expressed across fibroblast linages was the α8 subunit. An anti‐α8 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl4 treatment), non‐alcoholic steatohepatitis‐associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and α‐smooth muscle actin) were improved following the mAb injection. We also CCl4‐treated mice with inducible Itga8−/−; these mice were protected from increased hydroxyproline levels. Furthermore, ITGA8 was upregulated in specimens from 90 patients with liver fibrosis, indicating the relevance of our findings to liver fibrosis in people. Mechanistically, inhibition or ligand engagement of HSC α8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast α8 activated latent TGFβ. Finally, integrin α8β1 potentially fulfils the growing need for anti‐fibrotic drugs and is an integrin not to be ignored. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Bronchial thermoplasty (BT) had been reported to improve the symptoms of severe asthma. However, the exertional responses of BT based on the mechanisms have not been elucidated. A 57-year-old man and a 60-year-old woman underwent BT due to intractable severe asthma. We evaluated the therapeutic effects of BT using cardiopulmonary exercise testing (CPET). After BT, the exercise time during CPET substantially prolonged reducing exertional dyspnea in the former (good), but not in the latter (poor). In the good responder, the high air remaining in the lung after expiration (i.e., inspiratory tidal volume minus expiratory tidal volume) during CPET decreased after BT. In contrast, in the poor responder, the high air remaining after expiration during exercise was not obtained before BT. Further investigations are necessary to confirm that the presence or absence of the exertional wasted ventilation on CPET may be informative to evaluate the therapeutic effects of BT. J. Med. Invest. 67 : 386-390, August, 2020.

Although the diagnostic value of impulse oscillometry (IOS) in bronchiectasis for the differential diagnosis of healthy subjects has been researched, the usefulness of each IOS parameter for predicting disease severity in bronchiectasis has not been thoroughly investigated. In addition, the usefulness of IOS in patients with nontuberculous mycobacteria (NTM) infection has not been reported. This study aimed to determine the predictive significance of respiratory impedance and detect the other most significant IOS parameters for predicting disease severity in bronchiectasis patients and to validate the usefulness of IOS in patients with NTM infection. A total of 206 patients with bronchiectasis who attended clinics at the National Hospital Organization Osaka Toneyama Medical Center were included. Chest high-resolution computed tomography, spirometry and IOS were performed. Hospital admissions, mortality and disease severity indices for bronchiectasis (Bronchiectasis Severity Index (BSI), FACED, and E-FACED scores) were calculated to assess disease severity. The patients were divided into subgroups with and without NTM infection, and subgroup analyses were performed. Respiratory reactance, especially resonant frequency (fres), correlated with both BSI and FACED score better than respiratory resistance. Inspiratory but not expiratory impedance was strongly correlated with BSI, FACED and E-FACED scores. Inspiratory fres was the most useful predictor, increasing as the disease became more severe. The usefulness of IOS was almost equivalent in patients both with and without NTM infection. Inspiratory reactance measured by IOS is useful for estimating disease severity in bronchiectasis. Inspiratory fres best predicts disease severity in bronchiectasis patients both with and without NTM infection., Inspiratory reactance measured by impulse oscillometry may be useful for estimating disease severity of bronchiectasis. Inspiratory fres can be used to evaluate severity in the disease both with and without NTM infection. https://bit.ly/3fvG0Rn

The combination of rifamycin (RFP), ethambutol (EB), and macrolides is currently the standard regimen for treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). However, poor adherence to the standardized regimens recommended by current guidelines have been reported. We undertook a single-centred retrospective cohort study to evaluate the long-term outcomes in 295 patients with MAC-PD following first line treatment with standard (RFP, EB, clarithromycin [CAM]) or alternative (EB and CAM with or without fluoroquinolones (FQs) or RFP, CAM, and FQs) regimens. In this cohort, 80.7% were treated with standard regimens and 19.3% were treated with alternative regimens. After heterogeneity was statistically corrected using propensity scores, outcomes were superior in patients treated with standard regimens. Furthermore, alternative regimens were significantly and independently associated with sputum non-conversion, treatment failure and emergence of CAM resistance. Multivariate cox regression analysis revealed that older age, male, old tuberculosis, diabetes mellitus, higher C-reactive protein, and cavity were positively associated with mortality, while higher body mass index and M. avium infection were negatively associated with mortality. These data suggest that, although different combination regimens are not associated with mortality, first line administration of a standard RFP + EB + macrolide regimen offers the best chance of preventing disease progression in MAC-PD patients.

Rationale: Although gastric aspirate culture is used for diagnosing pulmonary tuberculosis, its usefulness in diagnosing pulmonary infections of nontuberculous mycobacteria (NTM) is unknown.Objecti...

Background Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient. Case presentation A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly. Conclusion We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/β1 and αV/β5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.

Background Exertional prolonged expiration should be identified as a therapeutic target in COPD. The efficacy of expiratory or inspiratory pressure load training (EPT/IPT) based on the degree of prolonged expiration was investigated. Methods A total of 21 patients with COPD were divided into two groups according to the exertional change in the inspiratory duty cycle (TI/Ttot). For 12 weeks, patients whose exertional TI/Ttot decreased received EPT (EPT group, n=11, mean percentage forced expiratory volume in 1 s (%FEV1), 32.8%) and those whose exertional TI/Ttot increased received IPT (IPT group, n=10, mean %FEV1, 45.1%). Results The therapeutic responses were as follows. In both groups, endurance time (EPT, +5.7 min, p, Expiratory or inspiratory pressure load training (EPT/IPT) based on the degree of prolonged expiration improves exercise performance in COPD patients. If managing COPD with EPT/IPT is chosen appropriately, it could become widespread as home-based training. https://bit.ly/2ZWutWq

Background: Multidrug therapy is essential for preventing respiratory failure in patients with highly progressive Mycobacterium avium complex pulmonary disease (MAC-PD). However, the prognosis and long-term outcome following combination therapy is poorly understood. Methods: We retrospectively evaluated the clinical characteristics and long-term outcomes in patients with chemo-na&iuml, ve progressive MAC-PD, hospitalized for first-line multidrug therapy. Results: Among 125 patients, 86 (68.8%) received standardized treatment (rifampicin, ethambutol, clarithromycin), 25 (20.0%) received a fluoroquinolone (FQ)-containing regimen, and 53 (42.4%) received aminoglycoside injection. The sputum conversion rate was 80.0%, and was independently associated with standardized treatment. The incidence of refractory disease (45.6%) was independently and negatively associated with standardized regimen and aminoglycoside use. Choice of an FQ-containing regimen was not associated with positive outcome. Clarithromycin resistance occurred in 16.8% and was independently associated with refractory disease. MAC-PD-associated death occurred in 3.3% of patients with non-cavitary nodular bronchiectasis (NB) and 21.3% with cavitary MAC-PD over a median follow-up period of 56.4 months. The rates of MAC-PD-associated death were comparable between cavitary-NB and fibrocavitary disease. Concurrent chronic pulmonary aspergillosis (CPA) occurred in 13 (17.3%) patients with cavitary MAC-PD, and age, diabetes mellitus, and CPA were independent risk factors for mortality. Conclusions: Standardized intensive multidrug treatment reduces disease progression and persistence in progressive MAC-PD. Cavitary NB may differ from, rather than being just an advanced stage of, non-cavitary NB. The high incidence and significant mortality of CPA in cavitary MAC-PD highlight the need for early diagnosis and treatment.

In autoantibody-mediated autoimmune diseases, pathogenic autoantibodies generated by a failure of central or peripheral tolerance, have different effects mediated by a variety of mechanisms. Interestingly, even non-autoimmune chronic diseases have a set of disease-specific natural autoantibodies that are maintained for a long time. Because most of these natural autoantibodies target intracellular proteins or long non-coding RNAs, they are speculated to be non-pathological and have some important as yet unrecognized physiological functions such as debris clearance. Recently, we revealed a set of disease-specific natural autoantibodies of chronic pulmonary diseases with unknown etiology by protein arrays that enable detection of specific autoantibodies against >8000 targets. Surprisingly, some of the targeted antigens of disease-specific autoantibodies were subsequently reported by other laboratories as strongly associated with the disease, suggesting that these antigens reflect the pathology of each disease. Furthermore, some of these autoantibodies that target extracellular antigens might modify the original course of each disease. Here, we review the disease-specific natural autoantibodies of chronic pulmonary diseases, including chronic fibrosing idiopathic interstitial pneumonias, sarcoidosis, and autoimmune pulmonary alveolar proteinosis, and discuss their utility and effects.

Arc-welders’ pneumoconiosis (AWP) is an occupational lung disease and has nonspecific symptoms typically with the patterns of centrilobular and/or branching opacities on chest high-resolution computed tomography (HRCT) which are similar to those of hypersensitivity pneumonitis (HP) and/or respiratory tract infections. Therefore, the differential diagnosis is often difficult if they are not suspected.We report a case of AWP which was initially suspected to be pulmonary tuberculosis because of the chest HRCT findings: centrilobular opacities distributed predominantly on the right lobe. On detailed review of the work history, however, the patient was found to be involved in welding. Prussian blue staining of the lung tissues and the bronchoalveolar lavage fluid (BALF) ferritin analysis were useful for the final diagnosis and the appropriate treatment for AWP. The atypical lymphocytosis in BALF in this case suggested the involvement of HP in the pathogenesis due to the occupational sensitization to causal antigens.To the best of our knowledge, this is the first case report of AWP showing features of HP. AWP should be noted even in patients with the typical patterns of centrilobular opacities on chest HRCT. Medical history, iron staining of lung tissues, and the BALF ferritin analysis would be useful for the diagnosis of these patients. The BALF findings are sometimes indeterminate for the diagnosis because the occupational sensitization to causal antigens might be involved in some cases of AWP. Keywords: Hemosiderin-laden macrophage, Hypersensitivity pneumonitis, Iron oxide, Occupational lung disease, Welding

Background Although cavities are an important finding in Mycobacterium avium complex pulmonary disease (MAC-PD), there is little information regarding the types of cavities that indicate disease progression. This study was performed to identify cavity characteristics that were associated with disease progression in patients with MAC-PD. Methods This retrospective cohort study included 97 patients presenting with MAC-PD with cavities between December 2006 and June 2016. We compared initial and final computed tomography (CT) findings, classified 52 and 45 patients in the progressive and non-progressive cavity groups, respectively, and examined the progression-related imaging features in initial CT images. A progressive cavity was defined by more than two-fold increase in internal diameter or emergence of a new cavity around the initial cavity. Results Patients in the progressive group were older (p p = 0.043), and showed higher diabetes complication rates (p = 0.005). The initial CT in the progressive group showed a longer maximum internal diameter of the cavity (p p p = 0.023), consolidation around the cavity (p p = 0.011), and pleural thickening (p p=0.012) and consolidation around the cavity (OR: 16.15, 95% CI: 4.05–64.46; p p p Conclusions Large cavity size and consolidation on CT showed strong relationships with disease progression, which led to respiratory failure and high mortality rate.

The aim of this study was to investigate the effect of activated ghrelin with dietary octanoic acids or medium-chain triglyceride (MCT) administration to underweight patient with chronic obstructive pulmonary disease (COPD). Eleven severe and very severe COPD patients received a 5-day treatment with edible MCT. Sequentially, 10 patients received a 3-week combination treatment with MCT and intravenous acyl ghrelin. Five-day MCT treatment increased endogenous acyl ghrelin (p = 0.0049), but the total ghrelin level was unchanged. MCT–ghrelin combination treatment improved the peak oxygen uptake (p = 0.0120) during whole treatment course. This effect was attributed to the resultant improvements in cardiac function by O2 pulse, and to the difference between inspired and expired oxygen concentration rather than minute ventilation. Addition of dietary MCT to ghrelin treatment improved the aerobic capacity of underweight COPD patients, likely by mechanisms of increased O2 delivery through improvements in primary cardiocirculatory and muscular crosstalk.

The presence of anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is closely associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis. Despite intensive immunosuppressive therapies, some of these patients still have a poor prognosis with few treatment options. Although removal of pathogenic autoantibodies and cytokines by plasma exchange (PE) could be a treatment option, its safety and efficacy have never been determined. We report a patient with anti-MDA5 Ab-positive RP-ILD who was refractory to intensive therapies including steroids, cyclosporine, and intravenous cyclophosphamide, and then treated by PE to prevent the progression of RP-ILD. Shortly after the initiation of PE therapy, however, his respiratory condition suddenly deteriorated due to acute pulmonary edema and the patient died on the following day. Transfusion-related acute lung injury (TRALI) would be the most likely cause of the acute pulmonary edema because there was no sign of circulatory overload. To the best of our knowledge, this is the first report showing a critical adverse event associated with PE therapy for these patients. This case supports the idea that the presence of ILD could increase a risk for TRALI and therefore we should carefully evaluate the eligibility for PE therapy of anti-MDA5 Ab-positive RP-ILD patients given the risk of acute lung injury. Further studies collecting more clinical data are necessary to assess the efficacy, safety, and risk factors of PE therapy for these patients. Keywords: Acute lung injury, Plasma exchange, Anti-MDA5 antibody, Interstitial pneumonia, Clinically amyopathic dermatomyositis

Inspiratory muscle training (IMT) has been attracting attention as one of the useful treatments in patients with chronic obstructive pulmonary disease (COPD). IMT is reportedly effective in most patients with COPD. However, little is known about the benefits of IMT, especially in patients with advanced COPD. We reported two cases of COPD that received 12-week IMT to explore intolerance to and the limitations of IMT in advanced COPD. The effectiveness of IMT was evaluated using cardiopulmonary exercise testing (CPET), spirometry, and respiratory muscle strength testing before and after the training. A 75-year-old man with normal body mass index (BMI) and forced expiratory volume in 1 s (FEV1) of 1.63 L responded well to IMT, but a 78-year-old man with low BMI and FEV1 of 0.83 L did not. In the responder, IMT resulted in increased minute ventilation (V’E) and oxygen uptake at peak exercise in incremental load testing. Moreover, IMT increased endurance time in constant load testing and maximal inspiratory pressure. In both patients, breathing frequency (fR) increased, but tidal volume and the inspiratory-expiratory ratio were not improved during exercise. Despite the high fR obtained after IMT, V’E at peak exercise did not increase and endurance time shortened in the non-responder. In underweight patients with advanced COPD, IMT might lead to tachypnea and ventilatory inefficiency, which in turn might decrease exercise performance. Therefore, underweight patients with advanced COPD might be unable to tolerate IMT and should avoid receiving the training.

Background: Patients with chronic obstructive pulmonary disease (COPD) show varying mechanisms of exertional dyspnea with different exercise capacities.Methods: To investigate the pathophysiologic conditions related to exertional dyspnea, 294 COPD patients were evaluated using cardiopulmonary exercise testing (CPET) with arterial blood analyses, with the patients classified into two groups according to their exercise limitation: the leg fatigue group (n = 58) and the dyspnea group (n = 215). The dyspnea group was further subdivided into four groups based on peak oxygen uptake (V°O2 in mL/min/kg): group A (< 11), group B (11 to < 15), group C (15 to < 21), and group D (≥21).Results: In the dyspnea group, group A (n = 28) showed the following findings: (i) the forced expiratory volume in 1 s was not correlated with the peak V°O2 (p = 0.288), (ii) the arterial oxygen tension (PaO2) slope (peak minus resting PaO2/ΔV°O2) was the steepest (p < 0.0001) among all subgroups, (iii) reduced tidal volume (VT) was negatively correlated with respiratory frequency at peak exercise (p < 0.0001), and (iv) a break point in exertional VT curve was determined in 17 (61%) patients in group A. In these patients, there was a significant negative correlation between bicarbonate ion (HCO3-) levels at peak exercise and VT level when the VT-break point occurred (p = 0.032). In group D (n = 46), HCO3- levels were negatively correlated with plasma lactate levels (p < 0.0001). In all subgroups, the HCO3- level was negatively correlated with minute ventilation. The dyspnea subgroups showed no significant differences in the overall mean pH [7.363 (SD 0.039)] and Borg scale scores [7.4 (SD, 2.3)] at peak exercise.Conclusions: During exercise, ventilation is stimulated to avoid arterial blood acidosis and hypoxemia, but ventilatory stimulation is restricted in the setting of reduced respiratory system ability. These conditions provoke the exertional dyspnea in COPD. Although symptom levels were similar, the exertional pathophysiologic conditions differed according to residual exercise performance; moreover, COPD patients showed great inter-individual variability. An adequate understanding of individual pathophysiologic conditions using CPET is essential for proper management of COPD patients.

Background Bronchial thermoplasty (BT) is a bronchoscopic treatment that can ameliorate the symptoms of severe asthma. However, little is known about the mechanism by which BT improves exertional dyspnea without significantly changing the resting pulmonary function in asthmatics. To understand the mechanism, cardiopulmonary variables were investigated using cardiopulmonary exercise testing (CPET) in a patient with severe asthma before and after BT. Case presentation A 57-year-old Japanese man visited our hospital for consultation of the intractable asthma, which we managed with three treatment sessions of BT. Comparison of the findings pre-BT and at 1 year after BT demonstrated that (1) the resting tests for respiration showed no improvement in forced expiratory volume in 1 s, but the forced oscillation technique showed decreases in both inhalation and exhalation respiratory resistance values, and (2) the CPET results showed (i) improvement in exertional dyspnea, exercise endurance, and arterial oxygen saturation at the end of exercise; (ii) that the expiratory tidal volume exceeded the inspiratory tidal volume during exercise, which implied that a sufficient exhalation enabled longer inspiratory time and adequate oxygen absorption; and (iii) that an increase in respiratory frequency could be prevented throughout exercise. Conclusions This case report described a novel mechanism of BT in improving exertional dyspnea and exercise duration, which was brought about by ventilatory improvements related to the breathing pattern of inspiration to expiration.

Rationale: Little is known about the applicability of respiratory muscle training based on exertional conditions in chronic obstructive pulmonary disease (COPD) patients. The aim of this study was to investigate the relationship between breathing timing and exertional responses, and whether exertional changes in the inspiratory duty cycle (Ti/Ttot) affect pathophysiological conditions, including respiratory muscles. Methods: Forty–five stable COPD patients were evaluated. To compare exertional cardiopulmonary responses and the balance of inspiratory–to–expiratory muscle strength, the patients were divided into two groups according to whether the Ti/Ttot increased (Ti/Ttot–increased group: resting Ti/Ttot ≤ peak Ti/Ttot, n = 21) or decreased during exercise (Ti/Ttot–decreased group: resting Ti/Ttot > peak Ti/Ttot, n = 24). Results: At peak exercise, the Ti/Ttot was positively correlated with minute ventilation (VE), and oxygen uptake (VO2) in all patients. No significant differences were seen in breathing frequency, tidal volume, or VE at peak exercise between the two groups. Compared with the Ti/Ttot–increased group, the Ti/Ttot–decreased group had significantly lower mean values of VO2 and ΔFO2 (the inspired − expired oxygen concentration) at peak exercise, and significantly higher mean values of the ratio of maximal inspiratory pressure/maximal expiratory pressure. Conclusions: The exertional change of breathing timing affected exercise tolerance and the balance of inspiratory-to-expiratory muscle strength; this finding might be helpful in making the choice of managing COPD patients with inspiratory or expiratory muscle training.

Rationale Little is known about the applicability of respiratory muscle training based on exertional pathophysiological conditions in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the relationship between breathing timing and exertional responses, as well as whether exertional changes in the inspiratory duty cycle (Ti/Ttot) affect pathophysiological conditions, including respiratory muscles. Methods Forty-five stable COPD patients (mean age: 71.2 years, severe and very severe COPD: 80%) were evaluated based on exertional cardiopulmonary function and respiratory muscle strength. To compare exertional responses and the balance of inspiratory-to-expiratory muscle strength, the patients were divided into two groups according to whether the Ti/Ttot increased (Ti/Ttot-increased group: resting Ti/Ttot ≤ peak Ti/Ttot, n = 21) or decreased during exercise (Ti/Ttot-decreased group: resting Ti/Ttot > peak Ti/Ttot, n = 24). Results At peak exercise, the Ti/Ttot was positively correlated with minute ventilation ([Formula: see text] E), and oxygen uptake ([Formula: see text]) in all patients. No significant differences were seen in breathing frequency, tidal volume, or [Formula: see text] E at peak exercise between the two groups. Compared with the Ti/Ttot-increased group, the Ti/Ttot-decreased group had significantly lower mean values of [Formula: see text] and ΔFO2 (the inspired minus expired oxygen concentration) at peak exercise, and significantly higher mean values of the absolute ratio of maximal inspiratory pressure/maximal expiratory pressure. Conclusions The exertional change of breathing timing affected exercise tolerance and the balance of inspiratory-to-expiratory muscle strength; this finding might be helpful in making the contradictory choice of managing COPD patients with inspiratory or expiratory muscle training.

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor β (PDGFRβ) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFRβ promoter–driven Cre system to delete αv integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFRβ-Cre line to isolate and study renal fibroblasts ex vivo. We found that renal fibroblasts express three αv integrins, namely αvβ1, αvβ3, and αvβ5. Blockade of αvβ1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-β1 and prevented activation of the latent TGF-β complex. Continuous administration of a recently described potent small molecule inhibitor of αvβ1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of αvβ1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

Mice that globally overexpress the transcription factor Fos-related antigen-2 (Fra-2) develop extensive pulmonary fibrosis and pulmonary vascular remodeling. To determine if these phenotypes are a consequence of ectopic Fra-2 expression in vascular smooth muscle cells and myofibroblasts, we generated mice that overexpress Fra-2 specifically in these cell types (α-SMA-rtTA;tetO-Fra-2). Surprisingly, these mice did not develop vascular remodeling or pulmonary fibrosis but did develop a spontaneous emphysema-like phenotype characterized by alveolar enlargement. Secondary septa formation is an important step in the normal development of lung alveoli, and α-smooth muscle actin (SMA)-expressing fibroblasts (myofibroblasts) play a crucial role in this process. The mutant mice showed reduced numbers of secondary septa at postnatal day 7 and enlarged alveolae starting at postnatal day 12, suggesting impairment of secondary septa formation. Lineage tracing using α-SMA-rtTA mice crossed to a floxed TdTomato reporter revealed that embryonic expression of α-SMA Cre marked a population of cells that gave rise to nearly all alveolar myofibroblasts. Comprehensive transcriptome analyses (RNA sequencing) demonstrated that the overwhelming majority of genes whose expression was significantly altered by overexpression of Fra-2 in myofibroblasts encoded secreted proteins, components of the extracellular matrix (ECM), and cell adhesion-associated genes, including coordinate upregulation of pairs of integrins and their principal ECM ligands. In addition, primary myofibroblasts isolated from the mutant mice showed reduced migration capacity. These findings suggest that Fra-2 overexpression might impair myofibroblast functions crucial for secondary septation, such as myofibroblast migration across alveoli, by perturbing interactions between integrins and locally produced components of the ECM.

The efficacy and feasibility of targeting transforming growth factor-β (TGFβ) in pulmonary fibrosis and lung vascular remodeling in systemic sclerosis (SSc) have not been well elucidated. In this study we analyzed how blocking TGFβ signaling affects pulmonary abnormalities in Fos-related antigen 2 (Fra-2) transgenic (Tg) mice, a murine model that manifests three important lung pathological features of SSc: fibrosis, inflammation, and vascular remodeling. To interrupt TGFβ signaling in the Fra-2 Tg mice, we used a pan-TGFβ-blocking antibody, 1D11, and Tg mice in which TGFβ receptor type 2 ( Tgfbr2) is deleted from smooth muscle cells and myofibroblasts (α-SMA-CreER; Tgfbr2 flox/flox). Global inhibition of TGFβ by 1D11 did not ameliorate lung fibrosis histologically or biochemically, whereas it resulted in a significant increase in the number of immune cells infiltrating the lungs. In contrast, 1D11 treatment ameliorated the severity of pulmonary vascular remodeling in Fra-2 Tg mice. Similarly, genetic deletion of Tgfbr2 from smooth muscle cells resulted in improvement of pulmonary vascular remodeling in the Fra-2 Tg mice, as well as a decrease in the number of Ki67-positive vascular smooth muscle cells, suggesting that TGFβ signaling contributes to development of pulmonary vascular remodeling by promoting the proliferation of vascular smooth muscle cells. Deletion of Tgfbr2 from α-smooth muscle actin-expressing cells had no effect on fibrosis or inflammation in this model. These results suggest that efforts to target TGFβ in SSc will likely require more precision than simply global inhibition of TGFβ function.

Scleroderma, also called systemic sclerosis (SSc), is an autoimmune connective tissue disease characterized by abnormality of the immune system, cardiovascular disorder, and fibrosis of the skin, lung, kidney, and other internal organs. Skin symptom and stiffness of the skin with accumulation of collagen cause severe disability, and cardiovascular and lung complications lead to high mortality. Despite recent progress, therapies for these complications in SSc are limited and the underlying mechanisms are poorly understood. Animal models are one strategy to identify molecular mechanisms and pathways underlying these complications of SSc and could provide a mechanistic basis for a design of clinical trials. However, although several animal models have been reported to reproduce some aspects of SSc, none of them recapitulates all of the pathological features of SSc. In this review, we describe previously reported animal models of scleroderma and discuss their utility and limitations in efforts to understand the mechanisms underlying scleroderma and develop new treatments for this disease.

IntroductionThere are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been adequately studied.MethodsWe performed a systematic search in PubMed for randomized phase II and III trials of NSCLC from January 2000 to December 2009, examining ethnic difference in hematological toxicity due to cytotoxic chemotherapy. Ethnicity was classified into Asian and non-Asian. We chose three treatment regimens used for NSCLC globally: cisplatin plus gemcitabine (CG), cisplatin plus vinorelbine (CV), and carboplatin plus paclitaxel (CP). We applied sensitivity analysis to examine unreported ethnic differences in hematological toxicities by changing the percentage of Asian patients from 0 to 18% in trials reported from the United States and Europe.ResultsWe identified 12 phase II trials and 38 phase III trials of NSCLC with a total of 11,271 patients. Among these, 14 trials had reported ethnic origins. Grade 3/4 toxicities were more frequently observed in the Asian studies. On the basis of sensitivity analysis, odds ratio of grade 3/4 neutropenia was significantly higher in Asian patients than non-Asian, when treated with CG (OR = 1.55–3.45, p < 0.001), CV (OR = 2.99–4.43, p < 0.001), and CP (OR = 4.79–6.22, p < 0.001). Grade 3/4 anemia was also significantly higher in Asians with CG (OR = 3.10–3.27, p < 0.001), CV (OR = 1.99–2.43, p < 0.001), and CP (OR = 1.34–1.52, p < 0.001–0.004). However, no significant difference was observed in thrombocytopenia with CG (OR = 0.66–2.04, p < 0.001–1.000), CV (OR = 0.42–0.57, p = 0.097–0.323), or CP (OR = 1.21–1.39, p = 0.114–0.152).ConclusionsSevere hematological toxicity was frequently observed in Asian patients compared with non-Asian (mostly whites) in the treatment of chemotherapy for NSCLC.

Integrins are transmembrane heterodimeric receptors that contribute to diverse biological functions and play critical roles in many human diseases. Studies using integrin subunit knockout mice and inhibitory antibodies have identified important roles for nearly every integrin heterodimer and led to the development of a number of potentially useful therapeutics. One notable exception is the αvβ1 integrin. αv and β1 subunits are individually present in numerous dimer pairs, making it challenging to infer specific roles for αvβ1 by genetic inactivation of individual subunits, and αvβ1 complex-specific blocking antibodies do not yet exist. We therefore developed a potent and highly specific small-molecule inhibitor of αvβ1 to probe the function of this understudied integrin. We found that αvβ1, which is highly expressed on activated fibroblasts, directly binds to the latency-associated peptide of transforming growth factor-β1 (TGFβ1) and mediates TGFβ1 activation. Therapeutic delivery of this αvβ1 inhibitor attenuated bleomycin-induced pulmonary fibrosis and carbon tetrachloride-induced liver fibrosis, suggesting that drugs based on this lead compound could be broadly useful for treatment of diseases characterized by excessive tissue fibrosis.

Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38–resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.

Animal disease models are pivotal in investigating the pathogenesis of emphysema and developing novel drugs, but the modalities to evaluate murine emphysema models have been of limited validity and sensitivity. In this study, we evaluated hyperpolarized (129)Xe magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) compared with traditional methods, such as plethysmography and histology. Elastase-treated mice and adiponectin knockout mice were used as murine emphysema models to evaluate these modalities. Three weeks after elastase administration, significant and heterogeneous emphysema was evaluated according to the mean linear intercept and plethysmography parameters. Notably, the distribution of low-density areas, as examined by micro-CT, correlated with the mean linear intercept and plethysmography parameters in whole lungs. These correlations were also observed in regional areas. Furthermore, we introduced hyperpolarized (129)Xe MRI, which can evaluate gas exchange between the alveoli and blood during spontaneous breathing. Parameters of gas exchange (fD) and alveolar size (Vs/Va) were significantly decreased in elastase-treated mice, and moderately correlated with the plethysmography parameters. Of importance, we could detect a decrease of the fD value in low-density areas with micro-CT, suggesting that gas exchange decreased in emphysematous lesions. Likewise, these parameters (fD and Vs/Va) were also decreased in adiponectin knockout mice, which exhibit emphysema with a homogeneous distribution. We demonstrated the feasibility of (129)Xe MRI and micro-CT in combination with traditional modalities. These noninvasive modalities provide complementary data that can be used for repeated estimations of regional gas exchange and lung morphology.

Non-small cell lung cancer (NSCLC) in never smokers has emerged as a global public health issue. The cause is still unclear, and few studies have focused on the prevalence of human papillomavirus (HPV) in the never smokers. We performed a systematic search of PubMed for articles of HPV infection in human subjects with NSCLC up to September 2012. Although smoking status was not fully reported in all studies, we contacted the authors by e-mail to supplement this information. Differences in the distribution of patients with and without HPV infection were tested with the Chi squared test. We identified 46 eligible articles, including 23 from Asian countries (N=2337 NSCLC cases), 19 from European countries (N=1553) and 4 from North and South America (N=160). The HPV prevalence was 28.1% (95% confidence interval (CI) 26.6-30.3%), 8.4% (95% CI 7.1-9.9%) and 21.3% (95% CI 15.2-28.4%), respectively. Eleven studies from East Asia (N=1110) and 4 from Europe (N=569) provided information on smoking status. The number of never smoker was 392 patients (33.9%) in East Asia and 54 patients (14.8%) in Europe. The HPV prevalence in East Asian countries was similar between never and ever smokers (33.9% vs 39.2%, P=0.080). Based on the literature confirming the presence of HPV in lung cancer in never smokers, the virus plays a role in carcinogenesis in the disease. There were different patterns of HPV prevalence between Asian and European countries in the never smokers as well as in ever smokers.

Tetraspanins organize protein complexes in tetraspanin-enriched membrane microdomains that are distinct from lipid rafts. Our previous studies suggested that reduction in the levels of tetraspanins CD9 and CD81 may be involved in the progression of inflammatory lung diseases, especially COPD. To search for agents that increase the levels of these tetraspanins, we screened 1,165 drugs in clinical use and found that statins upregulate CD9 and CD81 in RAW264.7 macrophages. The lipophilic statins, fluvastatin and simvastatin, reversed LPS-induced downregulation of CD9 and CD81, simultaneously preventing TNF-α and matrix metalloproteinase-9 production and spreading of RAW264.7 cells. These statins exerted anti-inflammatory effects in vitro in wild-type macrophages but not in CD9 knockout macrophages, and decreased lung inflammation in vivo in wild-type mice but not in CD9 knockout mice, suggesting that their effects are dependent on CD9. Mechanistically, the statins promoted reverse transfer of the LPS-signaling mediator CD14 from lipid rafts into CD9-enriched microdomains, thereby preventing LPS receptor formation. Finally, upregulation of CD9/CD81 by statins was related to blockade of GTPase geranylgeranylation in the mevalonate pathway. Our data underscore the importance of the negative regulator CD9 in lung inflammation, and suggest that statins exert anti-inflammatory effects by upregulating tetraspanin CD9 in macrophages.