Keitaro Nakamoto

Changes in the airway lumen and surrounding parenchyma in chronic obstructive pulmonary disease

Background The purpose of this study was to examine changes in the airway lumen and parenchyma in relation to lung function in patients with chronic obstructive pulmonary disease (COPD) compared with controls. Methods We studied 70 patients with COPD and 15 normal subjects. Using reconstructed computed tomography (CT) images, we traced the bronchial trees and reconstructed 3 cm circle images around the airways exactly perpendicular to the airway axis at the peripheral, middle, and central zones of the bronchi. We measured the number of airways and vessels, the airway inner diameter, and the area of emphysema in the circles, and analyzed the relationship of these image parameters to lung function. Results Reduced airway numbers and increased upper lobe emphysema were observed even in early spirometric stages in patients with COPD compared with controls. Other findings included decreased airway inner diameter in advanced spirometric stages. The numbers of peripheral zone bronchi, the extent of the middle zone emphysematous area, and the mean airway inner diameter of the airways were the best predictors of spirometric parameters. A portion of the airways in patients with COPD showed a loss of airway patency at middle or central zone bronchi predominantly in the late spirometric stages. Lumen-obliterated bronchial trees could be traced into emphysematous areas showing air trapping. Conclusion Compared with controls, our CT observations in patients with COPD showed that airway lumen and lung parenchyma changes along airways differed by spirometric stage, and these changes were associated with decreased lung function. A portion of CT-identified emphysema in patients with COPD appeared to be due to lumen-obliterated airways in the bronchial tree.

IL-17A synergistically stimulates TNF-α-induced IL-8 production in human airway epithelial cells: A potential role in amplifying airway inflammation

ABSTRACT Background: Recent reports have suggested an involvement of neutrophilic inflammation driven by interleukin (IL)-17 from Th17 cells, especially in severe, refractory asthma. It remains unknown about the possible interactions of this cytokine and other proinflammatory cytokines to direct neutrophilic airway inflammation. Materials and Methods: We evaluated the effects of IL-17A, IL-17E, and IL-17F in combination with other stimuli such as tumor necrosis factor (TNF) –α on the production and expression of IL-8 in human bronchial epithelial cells. We also studied their effects on other cytokine production. The possible role of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways was evaluated by specific inhibitors. We examined the effects of anti-asthma drugs, such as steroids or salmeterol. Results: IL-17A alone induced only a minimal effect on IL-8 expression. IL-17A, but not IL-17E or IL-17F, in combination with TNF-α showed a synergistic effect on IL-8 expression. Similar findings were found when combination with IL-1β and IL-17A were used, but such was not the case with lipopolysaccharide (LPS). In addition, we further found such synergy on GM-CSF production. The synergy with TNF-α and IL-17A was significantly inhibited by MAPKs inhibitors. Corticosteroids such as fluticasone propionate and dexamethasone, but not salmeterol, partially suppressed the IL-17A and TNF-α-induced IL-8 production. Conclusions: IL-17A in the combination with TNF-α or IL-1β showed a synergistic augmenting effect on IL-8 and GM-CSF production in human airway epithelial cells.

Clarithromycin ameliorates pulmonary inflammation induced by short term cigarette smoke exposure in mice

BACKGROUND Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. METHODS C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. RESULTS The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. CONCLUSION We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice.

Lobe-based computed tomography assessment of airway diameter, airway or vessel number, and emphysema extent in relation to the clinical outcomes of COPD.

Objective The aim of this study was to evaluate the relationship between computed tomography assessed lobe-based lung parameters and the clinical outcomes of patients with chronic obstructive pulmonary disease (COPD), including the frequency of exacerbation and annual change in forced expiratory volume in 1 second (FEV1). Patients and methods We studied 65 patients with COPD. We reconstructed computed tomography images to trace the bronchial tree from right B1 to B10 and created 3 cm circle images around the airways exactly perpendicular to the airway axis in the central, middle, and peripheral zones of the bronchi. The number of airways and vessels, airway inner diameter and area of emphysema in the circles were calculated for each segment. Then, we analyzed the relationships between the lobe-based image parameters and the frequency of exacerbation and annual decline in the FEV1. In addition, we assessed the effects of proximal airway lumen-obliterated emphysema (ALOE) on these clinical features. Results The airway diameter was not associated with the frequency of exacerbation or annual decline in FEV1. Among the structural parameters, lower lobe emphysema was most associated with the frequency of exacerbation. The reductions in the number of airways and vessels in total lobe were associated with the annual decline in FEV1. The subgroup of patients with ALOE demonstrated lower FEV1 and more frequent exacerbation than those without ALOE. Conclusion Lower lobe emphysema predicts frequent COPD exacerbation, whereas the annual decline in FEV1 is associated with the number of airways and vessels in total lobe.

Serum Reactive Oxygen Metabolite Levels Predict Severe Exacerbations of Asthma

Background and Purpose Bronchial asthma (BA) is a chronic airway disease characterized by airway hyperresponsiveness and remodeling, which are intimately linked to chronic airway inflammation. Reactive oxygen species (ROS) such as hydrogen peroxide are generated by inflammatory cells that are involved in the pathogenesis of BA. However, the role of ROS in the management of BA patients is not yet clear. We attempted to determine the role of ROS as a biomarker in the clinical setting of BA. Subjects and Methods We enrolled patients with BA from 2013 through 2015 and studied the degrees of asthma control, anti-asthma treatment, pulmonary function test results, fractional exhaled nitric oxide (FeNO), serum reactive oxygen metabolite (ROM) levels, and serum levels of interleukin (IL)-6 and IL-8. Results We recruited 110 patients with BA. Serum ROM levels correlated with white blood cell (WBC) count (rs = 0.273, p = 0.004), neutrophil count (rs = 0.235, p = 0.014), CRP (rs = 0.403, p < 0.001), and IL-6 (rs = 0.339, p < 0.001). Serum ROM levels and IL-8 and CRP levels negatively correlated with %FEV1 (rs = -0.240, p = 0.012, rs = -0.362, p < 0.001, rs = -0.197, p = 0.039, respectively). Serum ROM levels were significantly higher in patients who experienced severe exacerbation within 3 months than in patients who did not (339 [302–381] vs. 376 [352–414] CARR U, p < 0.025). Receiver-operating characteristics analysis showed that ROM levels correlated significantly with the occurrence of severe exacerbation (area under the curve: 0.699, 95% CI: 0.597–0.801, p = 0.025). Conclusions Serum levels of ROM were significantly associated with the degrees of airway obstruction, WBC counts, neutrophil counts, IL-6, and severe exacerbations. This biomarker may be useful in predicting severe exacerbations of BA.

Phantom tumour of the lung.

A 74-year-old previously healthy man was referred to our hospital due to dyspnoea on effort lasting for 2 months and paroxysmal nocturnal dyspnoea over the previous month. He had no remarkable medical history and was an ex-smoker (45 pack-years). Vital signs were normal with a heart rate of 80 bpm, respiratory rate 18 breaths/min, body temperature 36.3°C and oxygen saturation 97% measured at ambient air, but only mild elevation of blood pressure (148/80 mm Hg) was noted. Physical examination showed decreased first heart sound, but jugular venous dilation or oedema was …

Multi-drug-resistant tuberculosis with galaxy and cluster signs on high-resolution computed tomography: MDR-TB with galaxy and cluster signs

The galaxy sign and cluster sign were first reported in pulmonary sarcoidosis. From those reports, these two signs became known as one of the characteristic computed tomography (CT) findings of sarcoidosis. We report a patient with pulmonary tuberculosis who had these two signs. A 44‐year‐old man was referred to our hospital for general fatigue, cough, and low‐grade fever lasting about two months. Thoracic CT showed a large parenchymal nodule arising from coalescent small nodules (galaxy sign) and clusters composed of numerous small nodules (cluster sign) in the bilateral lungs. Three specimens of sputum acid‐fast smear were negative. However, we performed a bronchoscopy, and Mycobacterium tuberculosis was proven to be positive by the acid‐fast culture test of the obtained bronchoalveolar lavage fluid. Moreover, drug sensitivity testing revealed this to be a case of multi‐drug‐resistant tuberculosis. Patients with these signs must be examined carefully to differentiate tuberculosis from pulmonary sarcoidosis.

Comparison of findings on thoracic computed tomography with the severity and duration of bronchial asthma in patients with eosinophilic granulomatosis with polyangiitis

BACKGROUND Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis with eosinophilia. EGPA can occur in patients with comorbid bronchial asthma (BA) and other pulmonary diseases. However, because of its rarity, there are few reports on thoracic computed tomography (CT) findings in patients with EGPA, especially in relation to comorbid BA. The aim of this study was to compare between the clinical characteristics of EGPA, the severity and duration of BA, and the findings on thoracic CT. METHODS We retrospectively reviewed the records of patients with EGPA who were admitted to our hospital from 2001 to 2015. All patients satisfied the criteria for EGPA according to American College of Rheumatology or Lanhams criteria. Patients without asthma (n = 2) and those in whom CT was not performed (n = 3) were excluded. RESULTS We identified 31 patients who had EGPA comorbid with BA. The median duration of BA was 6 years. CT revealed parenchymal opacification (ground-glass opacity and/or consolidation; n = 17), airway abnormalities (bronchial wall thickening and/or bronchiectasis; n = 15), pleural effusion (n = 4), interlobular septal thickening (n = 5), and mediastinal lymphadenopathy (n = 4). Importantly, the group with severe BA had a significantly higher incidence of airway abnormalities than the group with mild to moderate BA (81.8% vs 30.0%, P = 0.009). The frequency of airway abnormalities was significantly higher in patients with EGPA who had a history of asthma of 5 years or more than in their counterparts with a shorter asthma history (66.7% vs 10.0%, P = 0.006), particularly bronchial wall thickening (52.4% vs 10.0%, P = 0.046). CONCLUSIONS The most common finding on thoracic CT in patients who had EGPA comorbid with BA was parenchymal opacification followed by airway abnormalities. The severity and duration of BA in these patients may affect the findings on thoracic CT.

Bucillamine-induced interstitial pneumonitis

We diagnosed as bucillamine‐induced interstitial pneumonitis and were able to observe changes in pulmonary lesions and therapeutic effects by using HRCT.

Asthma phenotypes: An important step for tailor-made therapy

Recently, many bronchial asthma patients have achieved good control with inhaled corticosteroid and longacting beta2agonists. However, some patients suffer from persistent asthmatic symptoms and have asthma attacks despite treatment with high doses of inhaled corticosteroid. This condition is called severe asthma, refractory asthma, or difficulttotreat asthma. Severe asthma is a serious sociomedical problem that affects 5%10% of patients, and the associated medical costs are high.1 Bronchial asthma was once considered to be a homogeneous disease, but nowadays, based on the accumulated knowledge, it can be recognized as a heterogeneous disease. Recently, in fact, one strategy for the management of severe asthma was established with the discovery of asthma phenotypes. Phenotype describes “observable characteristics” with no direct relationship to a disease process including physiology, triggers, and inflammatory parameters.2 A review article with special reference to asthma phenotypes by Horiguchi3 summarized two previous articles4,5 referring to asthma phenotypes. For example, one report by Haldar et al.4 analyzed 184 asthma patients and identified five phenotypes using cluster analysis. Each cluster was as follows: (i) earlyonset atopic asthma, (ii) obese, noneosinophilic asthma, (iii) earlyonset symptompredominant asthma, (iv) benign asthma, and (v) inflammationpredominant asthma. Similarly, in another report, Moore et al.5 also analyzed 726 asthma patients and identified five phenotypes. Thus, cluster analysis has emerged as another tool for characterizing asthmatic patients. Schatz et al.6 examined 4130 patients (children: n=518, adolescents and adults: n=3612) who were enrolled in The Epidemiology and Natural History of Asthma Outcomes and Treatment Regimens (TENOR) study and also divided asthma into five phenotypes. They performed cluster analysis using seven variables: (i) sex, (ii) atopy, (iii) race, (iv) age at asthma onset, (v) smoking status (children: passive smoking, adolescents and adults: smoker or not), (vi) obesity, and (vii) aspirin sensitivity. This article reported that sex, atopic status, and nonwhite race were distinguishing variables in both strata. In particular, in asthmatic pediatric patients, the rate of passive smoke exposure was different among the five phenotypes, and aspirin sensitivity also differed among the five phenotypes in adult patients. Because this study recruited a large number of Caucasian patients (up to 75% of the enrolled subjects), the results might not be applicable to Japanese patients. Indeed, Kaneko et al.7 examined phenotypes in Japanese patients with adult asthma. They also used cluster analysis and identified six phenotypes (A: older age at onset, no airflow obstruction; B: childhood onset, normaltomild airflow obstruction; C: childhood onset, the longest disease duration, and moderatetosevere airflow obstruction; D: older age at onset, severe airflow obstruction; E: middleage at onset, no airflow obstruction; F: older age at onset, mildtomoderate airflow obstruction). Those six phenotypes were not consistent with those of Schatz et al. possibly due to racial diversity in the latter group. Interestingly, Lockey simply divided asthma phenotypes into two main categories: major asthma phenotypes and other asthma phenotypes, as shown in Table 1. He described the usefulness of identifying phenotypes, which enable physicians to treat the patients appropriately.8 To date, six articles have been published,3–8 and all of them recommend phenotype classification in the management of severe asthma. The article by Horiguchi demonstrated tailormade treatment based on each of the phenotype. In Japan, an antiIgE monoclonal antibody (omalizumab) has been used for severe asthma; however, Horiguchi stated that omalizumab should be applied cautiously because it actually shows a poor response in lowbiomarker (low fractional exhaled nitric oxide (FeNO), peripheral blood eosinophil count,