階段昇降試験中に認められる酸素飽和度低下 : 肺切除を予定している患者の術後合併症の予測指標

Objective: It is widely accepted that exercise tolerance tests are applicable in perioperative risk assessment for patients who undergo pulmonary resection; however, the relevance of desaturation during the test is unclear. The purpose of this study was to investigate whether the occurrence of desaturation during a stair-climbing test can be a predictor of postoperative complications among patients who will undergo pulmonary resection and are considered "normal risk" according to published guidelines. Methods: Desaturation was defined as a depression of more than 4% points on a pulse oximeter during stair climbing. Among 186 consecutive patients who underwent pulmonary resection, 162 patients who could climb to the 6th floor were selected for the study (excluding 21 patients who could not stair-climb and 3 patients who could not climb from the first floor to the sixth floor). The relationship of desaturation with postoperative complication was investigated using parameters of cardio-pulmonary status associated with additional foci of oxygen supply duration, intensive care unit stay duration, and hospital stay duration. Results: The occurrence ratio of postoperative complications > grade 3 (Clavien-Dindo classification) was 0.75% (1/133) among patients without desaturation and 17.2% (5/29) in patients with desaturation (difference: p = 0.0002). In addition, DS was an indicator of prolonged oxygen supply duration, intensive care unit stay duration, and hospital stay duration. Conclusion: The occurrence of desaturation during a stair-climbing test for patients who will undergo pulmonary resection can be a predictor of postoperative complications among patients who are classified as having normal risk.博士（医学）・乙第1457号・令和2年6月30日© The Japanese Association for Thoracic Surgery 2019© 2019 Springer Nature Switzerland AG. Part of Springer Nature.This is a post-peer-review, pre-copyedit version of an article published in General thoracic and cardiovascular surgery. The final authenticated version is available online at: http://doi.org/10.1007/s11748-019-01153-z.本文の登録不可。本文は以下のURLを参照 "https://doi.org/10.1007/s11748-019-01153-z"（※全文閲覧は学内限定

Associations of CT evaluations of antigravity muscles, emphysema and airway disease with longitudinal outcomes in patients with COPD

Multiple CT indices are associated with disease progression and mortality in patients with COPD, but which indices have the strongest association remain unestablished. This longitudinal 10-year observational study (n=247) showed that the emphysema severity on CT is more closely associated with the progression of airflow limitation and that a reduction in the cross-sectional area of erector spinae muscles (ESMCSA) on CT is more closely associated with mortality than the other CT indices, independent of patient demographics and pulmonary function. ESMCSA is a useful CT index that is more closely associated with long-term mortality than emphysema and airway disease in patients with COPD

IL-9 Induces CCL11 Expression via STAT3 Signalling in Human Airway Smooth Muscle Cells

Background: Previous findings support the concept that IL-9 may play a significant role in mediating both pro-inflammatory and changes in airway responsiveness that characterizes the atopic asthmatic state. We previously demonstrated that human airway smooth muscle (ASM) cells express a functional IL-9R that mediate CCL11 expression. However, the signaling pathway governing this effect is not well understood. Methodology/Principal Findings: In this study, we showed that IL-9 mediated CCL11 expression in ASM cells does not rely on STAT6 or STAT5 but on STAT3 pathway. IL-9 induced rapid STAT3 activation in primary ASM cells that was not observed in case of STAT6 or STAT5. STAT3 binding to CCL11 promoter was also observed in vivo upon IL-9 stimulation of ASM cells. Disruption of STAT3 activity with SH2 domain binding inhibitory peptide results in significant reduction of IL-9 mediated CCL11 promoter activity. DN STAT3b over-expression in ASM cells, but not Ser 727 STAT3 or STAT6 DN, abolishes IL-9 mediated CCL11 promoter activity. Finally, STAT3 but not STAT6 silenced ASM cells showed significant reduction in IL-9 mediated CCL11 promoter activity and mRNA expression. Conclusion/Significance: Taken together, our results indicate that IL-9 mediated CCL11 via STAT3 signalling pathway ma

Physiological Impairments on Respiratory Oscillometry and Future Exacerbations in Chronic Obstructive Pulmonary Disease Patients without a History of Frequent Exacerbations

Respiratory oscillometry allows measuring respiratory resistance and reactance during tidal breathing and may predict exacerbations in patients with chronic obstructive pulmonary disease (COPD). While the Global Initiative for Chronic Obstructive Lung Disease (GOLD) advocates the ABCD classification tool to determine therapeutic approach based on symptom and exacerbation history, we hypothesized that in addition to spirometry, respiratory oscillometry complemented the ABCD tool to identify patients with a high risk of exacerbations. This study enrolled male outpatients with stable COPD who were prospectively followed-up over 5 years after completing mMRC scale and COPD assessment test (CAT) questionnaires, post-bronchodilator spirometry and respiratory oscillometry to measure resistance, reactance, and resonant frequency (Fres), and emphysema quantitation on computed tomography. Total 134 patients were classified into the GOLD A, B, C, and D groups (n = 48, 71, 5, and 9) based on symptoms on mMRC and CAT and a history of exacerbations in the previous year. In univariable analysis, higher Fres was associated with an increased risk of exacerbation more strongly than other respiratory oscillometry indices. Fres was closely associated with forced expiratory volume in 1 sec (FEV1). In multivariable Cox-proportional hazard models of the GOLD A and B groups, either lower FEV1 group or higher Fres group was associated with a shorter time to the first exacerbation independent of the GOLD group (A vs B) and emphysema severity. Adding respiratory oscillometry to the ABCD tool may be useful for risk estimation of future exacerbations in COPD patients without frequent exacerbation history

Low serum free light chain is associated with risk of COPD exacerbation

Background: Most exacerbations of chronic obstructive pulmonary disease (COPD) are triggered by respiratory tract infections. Adaptive immunity via antibody production is important in preventing infections. Impaired antibody production is reported to be associated with an increased risk of exacerbations of COPD. In the present study, we elucidated whether reduced free light chains (FLCs), which are excessive amounts of light chains produced during antibody synthesis and can be used to estimate systemic antibody production, may be a promising biomarker to predict the risk of exacerbations of COPD. Methods: We enrolled stable male patients with COPD and prospectively observed them for 2 years. At baseline, serum combined FLC (cFLC; sum of kappa and lambda values) and pulmonary function were evaluated. Exacerbation was defined as a worsening of symptoms requiring treatments with antibiotics, corticosteroids or both. Results: 63 patients with stable COPD were enrolled (72.8±8.1 years, GOLD A/B/C/D=24/28/6/5), and 51 patients completed the 2-year follow-up. Serum cFLC was 31.1 mg·L−1 on average and ranged widely (1.4 to 89.9 mg·L−1). The patients with low cFLC (below the mean−sd, n=6) experienced a significantly shorter time to the first exacerbation of COPD (p<0.0001 by the log-rank test). A multivariate Cox proportional hazard model, including the COPD assessment test score, % predicted forced expiratory volume in 1 s (FEV1 % pred), and number of previous exacerbations demonstrated that low cFLC and low FEV1 % pred were independently and significantly correlated with the risk for exacerbations of COPD. Conclusion: Low cFLC may be a B-cell-associated novel biomarker associated with risk of COPD exacerbation

p38 mitogen-activated protein kinase determines the susceptibility to cigarette smoke-induced emphysema in mice

BACKGROUND: There is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. p38 mitogen-activated protein kinase (p38 MAPK) has been associated with this disorder, and several inhibitors of this cascade are in clinical trials for its treatment, but their efficacy and utility are unknown. This study evaluated the relationship between p38 MAPK activation and susceptibility to cigarette smoke (CS)-induced emphysema, and whether its inhibition ameliorated the lung inflammation and injury in murine models of cigarette smoke exposure. METHODS: In acute and chronic CS exposure, the activation and expression of p38 MAPK in the lungs, as well as lung inflammation and injury (proteinase production, apoptosis, and oxidative DNA damage), were compared between two mouse strains: C57BL/6 (emphysema-susceptible) and NZW (emphysema-resistant). The selective p38 MAPK inhibitor SB203580 (45 mg/kg) was administrated intra-peritoneally to C57BL/6 mice, to examine whether it ameliorated cigarette smoke-induced lung inflammation and injury. RESULTS: Acute CS-induced lung inflammation (neutrophil infiltration, mRNA expressions of TNF-α and MIP-2), proteinase expression (MMP-12 mRNA), apoptosis, and oxidative DNA damage were significantly lower in NZW than C57BL/6 mice. p38 MAPK was significantly activated and up-regulated by both acute and chronic CS exposure in C57BL/6 but not NZW mice. mRNA expression of p38 MAPK was also upregulated in C57BL/6 by chronic CS exposure and tended to be constitutively suppressed in NZW mice. SB203580 significantly attenuated lung inflammation (neutrophil infiltration, mRNA expressions of TNF-α and MIP-2, protein levels of KC, MIP-1α, IL-1β, and IL-6), proteinase expression (MMP-12 mRNA), oxidative DNA damage, and apoptosis caused by acute CS exposure. CONCLUSIONS: Cigarette smoke activated p38 MAPK only in mice that were susceptible to cigarette smoke-induced emphysema. Its selective inhibition ameliorated lung inflammation and injury in a murine model of cigarette smoke exposure. p38 MAPK pathways are a possible molecular target for the treatment of chronic obstructive pulmonary disease

Disproportionally Impaired Diffusion Capacity Relative to Airflow Limitation in COPD

Forced expiratory volume in 1 s (FEV₁) is a standard physiological index of chronic obstructive pulmonary disease (COPD), but reflects emphysema and vascular abnormalities less sensitively than diffusion capacity for carbon monoxide (D_LCO). This study tested whether a disproportionally impaired D_LCO relative to FEV₁ (FEV₁ z-score>-3 and D_LCO z-score≤-3) is a common functional COPD phenotype associated with distinct clinical and structural features and the prognosis of two cohorts. The cross-sectional analyses of the Korea COPD Subgroup Study (KOCOSS) cohort (multicenter study in Korea) included 743 males with COPD whose D_LCO was available. The cross-sectional and longitudinal analyses of the Kyoto University Cohort (single-center study in Japan) included 195 males with COPD who were prospectively followed for 10 years. A disproportionally impaired D_LCO relative to FEV₁ was observed in 29% and 31% of patients in the KOCOSS and Kyoto University cohorts, respectively. In the multivariable analysis, the disproportionally impaired D_LCO was associated with worse symptoms, shorter 6-minute walking distance, paraseptal and centrilobular emphysema on computed tomography, and reduced arterial oxygen and carbon dioxide pressures compared to the reference (FEV₁ z-score>-3 and D_LCO z-score>-3). In the multivariable Cox proportional hazard model, a higher long-term mortality was observed in the disproportionally impaired D_LCO group than in the reference group (hazard ratio [95% confidence interval] = 3.09 [1.52–6.29]) and similar to the D_LCO z-score≤-3 and FEV₁ z-score≤-3 group. The disproportionally impaired D_LCO relative to FEV₁ is common and associated with increased symptoms, emphysema, arterial blood gas abnormalities, and increased long-term mortality in patients with COPD

Quantitative measurement of airway dimensions using ultra-high resolution computed tomography

Background: Quantitative measurement of airway dimensions using computed tomography (CT) is performed in relatively larger airways due to the limited resolution of CT scans. Nevertheless, the small airway is an important pathological lesion in lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Ultra-high resolution scanning may resolve the smaller airway, but its accuracy and limitations are unclear. Methods: Phantom tubes were imaged using conventional (512 × 512) and ultra-high resolution (1024 × 1024 and 2048 × 2048) scans. Reconstructions were performed using the forward-projected model-based iterative reconstruction solution (FIRST) algorithm in 512 × 512 and 1024 × 1024 matrix scans and the adaptive iterative dose reduction 3D (AIDR-3D) algorithm for all scans. In seven subjects with COPD, the airway dimensions were measured using the 1024 × 1024 and 512 × 512 matrix scans. Results: Compared to the conventional 512 × 512 scan, variations in the CT values for air were increased in the ultra-high resolution scans, except in the 1024×1024 scan reconstructed through FIRST. The measurement error of the lumen area of the tube with 2-mm diameter and 0.5-mm wall thickness (WT) was minimal in the ultra-high resolution scans, but not in the conventional 512 × 512 scan. In contrast to the conventional scans, the ultra-high resolution scans resolved the phantom tube with ≥ 0.6-mm WT at an error rate of < 11%. In seven subjects with COPD, the WT showed a lower value with the 1024 × 1024 scans versus the 512 × 512 scans. Conclusions: The ultra-high resolution scan may allow more accurate measurement of the bronchioles with smaller dimensions compared with the conventional scan

Increased aortic wave reflection and smaller pulse pressure amplification in smokers and passive smokers confirmed by urinary cotinine levels: The Nagahama Study.

[Background]Central blood pressure (cSBP) is suggested to be a better predictor of cardiovascular risk than brachial BP. Although brachial BP levels among smokers have been reported to be the same or somewhat lower than those in nonsmokers, it is suggested that smoking might have a substantial impact on cSBP. [Methods]We conducted a cross-sectional study to clarify the association of smoking habit with arterial tone and cSBP in a general population of 8557 participants using urinary cotinine levels as an objective marker of smoking intensity. Absolute pressure of the late systolic peak (SBP2) was obtained by calibrating the radial waveform with brachial systolic BP (bSBP) and considered to be the cSBP. [Results]Confounding factor-adjusted mean pulse pressure amplification (PPa = bSBP − cSBP) was significantly smaller in habitual smokers (current, 9.3 ± 0.15; past, 10.2 ± 0.13; never, 10.6 ± 0.10 mm Hg; p < 0.001). Further, among smokers, PPa was linearly decreased with increasing urinary cotinine quartile (Q1, 10.9 ± 0.38; Q2, 10.9 ± 0.39; Q3, 10.4 ± 0.39; Q4, 9.7 ± 0.41 mm Hg; p = 0.020). Multiple linear regression analysis identified both smoking habit (p = 0.003) and urinary cotinine levels (p = 0.008) as independent determinants of PPa. Urinary cotinine was also detected in a small fraction of never smokers (1.8%). These passive smokers showed a smaller PPa (passive smoker, 9.4 ± 0.4; never smoker, 10.4 ± 0.12 mm Hg, p = 0.020) but not bSBP (122.7 ± 0.6, 123.1 ± 0.2 mm Hg, p = 0.474). [Conclusions]Not only habitual smoking but also passive smoking had harmful effects on AIx and central BP. Our results strongly emphasize the importance of avoiding passive smoking to the prevention of cardiovascular risks of which the subject is likely unaware