Longitudinal assessment of interstitial lung abnormalities on CT in patients with COPD using artificial intelligence-based segmentation: a prospective observational study.

BACKGROUND: Interstitial lung abnormalities (ILAs) on CT may affect the clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), but their quantification remains unestablished. This study examined whether artificial intelligence (AI)-based segmentation could be applied to identify ILAs using two COPD cohorts. METHODS: ILAs were diagnosed visually based on the Fleischner Society definition. Using an AI-based method, ground-glass opacities, reticulations, and honeycombing were segmented, and their volumes were summed to obtain the percentage ratio of interstitial lung disease-associated volume to total lung volume (ILDvol%). The optimal ILDvol% threshold for ILA detection was determined in cross-sectional data of the discovery and validation cohorts. The 5-year longitudinal changes in ILDvol% were calculated in discovery cohort patients who underwent baseline and follow-up CT scans. RESULTS: ILAs were found in 32 (14%) and 15 (10%) patients with COPD in the discovery (n = 234) and validation (n = 153) cohorts, respectively. ILDvol% was higher in patients with ILAs than in those without ILA in both cohorts. The optimal ILDvol% threshold in the discovery cohort was 1.203%, and good sensitivity and specificity (93.3% and 76.3%) were confirmed in the validation cohort. 124 patients took follow-up CT scan during 5 ± 1 years. 8 out of 124 patients (7%) developed ILAs. In a multivariable model, an increase in ILDvol% was associated with ILA development after adjusting for age, sex, BMI, and smoking exposure. CONCLUSION: AI-based CT quantification of ILDvol% may be a reproducible method for identifying and monitoring ILAs in patients with COPD.

Quantification of airway structures by persistent homology.

We propose two types of novel morphological metrics for quantifying the geometry of tubular structures on computed tomography (CT) images. We apply our metrics to identify irregularities in the airway of patients with chronic obstructive pulmonary disease (COPD) and demonstrate that they provide complementary information to the conventional metrics used to assess COPD, such as the tissue density distribution in lung parenchyma and the wall area ratio of the segmented airway. The three-dimensional shape of the airway and its abstraction as a rooted tree with the root at the trachea carina are automatically extracted from a lung CT volume, and the two metrics are computed based on a mathematical tool called persistent homology; treeH0 quantifies the distribution of branch lengths to assess the complexity of the tree-like structure and radialH0 quantifies the irregularities in the luminal radius along the airway. We show our metrics are associated with clinical outcomes.

A reference equation for lung volume on computed tomography in Japanese middle-aged and elderly adults.

BACKGROUND: Effective use of lung volume data measured on computed tomography (CT) requires reference values for specific populations. This study examined whether an equation previously generated for multiple ethnic groups in the United States, including Asians predominantly composed of Chinese people, in the Multi-Ethnic Study of Atherosclerosis (MESA) could be used for Japanese people and, if necessary, to optimize this equation. Moreover, the equation was used to characterize patients with chronic obstructive pulmonary disease (COPD) and lung hyperexpansion. METHODS: This study included a lung cancer screening CT cohort of asymptomatic never smokers aged ≥40 years from two institutions (n = 364 and 419) to validate and optimize the MESA equation and a COPD cohort (n = 199) to test its applicability. RESULTS: In all asymptomatic never smokers, the variance explained by the predicted values (R2) based on the original MESA equation was 0.60. The original equation was optimized to minimize the root mean squared error (RMSE) by adjusting the scaling factor but not the age, sex, height, or body mass index terms of the equation. The RMSE changed from 714 ml in the original equation to 637 ml in the optimized equation. In the COPD cohort, lung hyperexpansion, defined based on the 95th percentile of the ratio of measured lung volume to predicted lung volume in never smokers (122 %), was observed in 60 (30 %) patients and was associated with centrilobular emphysema and air trapping on inspiratory/expiratory CT. CONCLUSIONS: The MESA equation was optimized for Japanese middle-aged and elderly adults.

Chronic obstructive pulmonary disease features in patients visiting primary respiratory clinic and tertiary hospital in Japan.

Pulmonologists in primary care clinics are positioned between those in tertiary hospitals and general practitioners in clinics and are anticipated to promote hospital-clinic collaboration for patients with chronic obstructive pulmonary disease (COPD). However, the clinical features of patients in primary respiratory clinics are unclear. This multicenter study cross-sectionally compared the characteristics of patients with COPD in a respiratory clinic (n = 69) with those in a university hospital (n = 124). More patients visited the clinic for symptom relief without a referral, whereas more visited the hospital for consultation of abnormal spirometry/computed tomography (CT). The patients in the clinic showed female predilection, higher prevalence of current smokers, severe dyspnea, and concomitant heart failure, and higher CT-measured cross-sectional area ratio of pectoralis muscle to adjacent subcutaneous adipose tissue compared to those in the hospital (all p < 0.05). The observed differences between the two groups suggest the need to establish the role of primary pulmonologists in hospital-clinic collaboration for better COPD management.

Subtyping emphysematous COPD by respiratory volume change distributions on CT.

BACKGROUND: There is considerable heterogeneity among patients with emphysematous chronic obstructive pulmonary disease (COPD). We hypothesised that in addition to emphysema severity, ventilation distribution in emphysematous regions would be associated with clinical-physiological impairments in these patients. OBJECTIVE: To evaluate whether the discordance between respiratory volume change distributions (from expiration to inspiration) in emphysematous and non-emphysematous regions affects COPD outcomes using two cohorts. METHODS: Emphysema was quantified using a low attenuation volume percentage on inspiratory CT (iLAV%). Local respiratory volume changes were calculated using non-rigidly registered expiratory/inspiratory CT. The Ventilation Discordance Index (VDI) represented the log-transformed Wasserstein distance quantifying discordance between respiratory volume change distributions in emphysematous and non-emphysematous regions. RESULTS: Patients with COPD in the first cohort (n=221) were classified into minimal emphysema (iLAV% <10%; n=113) and established emphysema with high VDI and low VDI groups (n=46 and 62, respectively). Forced expiratory volume in 1 s (FEV1) was lower in the low VDI group than in the other groups, with no difference between the high VDI and minimal emphysema groups. Higher iLAV%, more severe airway disease and hyperventilated emphysematous regions in the upper-middle lobes were independently associated with lower VDI. The second cohort analyses (n=93) confirmed these findings and showed greater annual FEV1 decline and higher mortality in the low VDI group than in the high VDI group independent of iLAV% and airway disease on CT. CONCLUSION: Lower VDI is associated with severe airflow limitation and higher mortality independent of emphysema severity and airway morphological changes in patients with emphysematous COPD.

The prevalence and physiological impacts of centrilobular and paraseptal emphysema on computed tomography in smokers with preserved ratio impaired spirometry.

Centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are observed in smokers with preserved ratio impaired spirometry (PRISm, defined as the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ≥0.7 and FEV1 <80%), but their prevalence and physiological impacts remain unestablished. This multicentre study aimed to investigate its prevalence and to test whether emphysema subtypes are differently associated with physiological impairments in smokers with PRISm. Both never- and ever-smokers aged ≥40 years who underwent computed tomography (CT) for lung cancer screening and spirometry were retrospectively and consecutively enrolled at three hospitals and a clinic. Emphysema subtypes were visually classified according to the Fleischner system. Air-trapping was assessed as the ratio of FVC to total lung capacity on CT (TLCCT). In 1046 never-smokers and 772 smokers with ≥10 pack-years, the prevalence of PRISm was 8.2% and 11.3%, respectively. The prevalence of PSE and CLE in smokers with PRISm was comparable to that in smokers with normal spirometry (PSE 43.7% versus 36.2%, p=1.00; CLE 46.0% versus 31.8%, p=0.21), but higher than that in never-smokers with PRISm (PSE 43.7% versus 1.2%, p<0.01; CLE 46% versus 4.7%, p<0.01) and lower than that in smokers with airflow limitation (PSE 43.7% versus 71.0%, p<0.01; CLE 46% versus 79.3%, p<0.01). The presence of CLE, but not PSE, was independently associated with reduced FVC/TLCCT in smokers with PRISm. Both PSE and CLE were common, but only CLE was associated with air-trapping in smokers with PRISm, suggesting different physiological roles of these emphysema subtypes.

Associations of pulmonary and extrapulmonary computed tomographic manifestations with impaired physical activity in symptomatic patients with chronic obstructive pulmonary disease.

In patients with chronic obstructive pulmonary disease (COPD), emphysema, airway disease, and extrapulmonary comorbidities may cause various symptoms and impair physical activity. To investigate the relative associations of pulmonary and extrapulmonary manifestations with physical activity in symptomatic patients, this study enrolled 193 patients with COPD who underwent chest inspiratory/expiratory CT and completed COPD assessment test (CAT) and the Life-Space Assessment (LSA) questionnaires to evaluate symptom and physical activity. In symptomatic patients (CAT ≥ 10, n = 100), emphysema on inspiratory CT and air-trapping on expiratory CT were more severe and height-adjusted cross-sectional areas of pectoralis muscles (PM index) and adjacent subcutaneous adipose tissue (SAT index) on inspiratory CT were smaller in those with impaired physical activity (LSA < 60) than those without. In contrast, these findings were not observed in less symptomatic patients (CAT < 10). In multivariable analyses of the symptomatic patients, severe air-trapping and lower PM index and SAT index, but not CT-measured thoracic vertebrae bone density and coronary artery calcification, were associated with impaired physical activity. These suggest that increased air-trapping and decreased skeletal muscle and subcutaneous adipose tissue quantity are independently associated with impaired physical activity in symptomatic patients with COPD.

Genetic Homology between Bacteria Isolated from Pulmonary Abscesses or Pyothorax and Bacteria from the Oral Cavity.

Pulmonary abscesses and pyothorax are bacterial infections believed to be caused primarily by oral microbes. However, past reports addressing such infections have not provided genetic evidence and lack accuracy, as they used samples that had passed through the oral cavity. The aim of this study was to determine whether genetically identical bacterial strains exist in both the oral microbiota and pus specimens that were obtained percutaneously from pulmonary abscesses and pyothorax, without oral contamination. First, bacteria isolated from pus were identified by 16S rRNA gene sequencing. It was then determined by quantitative PCR using bacterial-species-specific primers that DNA extracted from paired patient oral swab sample suspensions contained the same species. This demonstrated sufficient levels of bacterial DNA of the targeted species to use for further analysis in 8 of 31 strains. Therefore, the whole-genome sequences of these eight strains were subsequently determined and compared against an open database of the same species. Five strain-specific primers were synthesized for each of the eight strains. DNA extracted from the paired oral swab sample suspensions of the corresponding patients was PCR amplified using five strain-specific primers. The results provided strong evidence that certain pus-derived bacterial strains were of oral origin. Furthermore, this two-step identification process provides a novel method that will contribute to the study of certain pathogens of the microbiota. IMPORTANCE We present direct genetic evidence that some of the bacteria in pulmonary abscesses and pyothorax are derived from the oral flora. This is the first report describing the presence of genetically homologous strains both in pus from pulmonary abscesses and pyothorax and in swab samples from the mouth. We developed a new method incorporating quantitative PCR and next-generation sequencing and successfully prevented contamination of pus specimens with oral bacteria by percutaneous sample collection. The new genetic method would be useful for enabling investigations on other miscellaneous flora; for example, detection of pathogens from the intestinal flora at the strain level.

Linguistic Validation of the Japanese Version of the Multidimensional Dyspnea Profile and Relation to Physical Activity in Patients with COPD.

PURPOSE: This study aimed to develop a linguistically validated Japanese translation of the multidimensional dyspnea profile (MDP) and assess whether worsening of dyspnea's sensory and affective domains during exercise had detrimental effects on physical activity in stable outpatients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: The Japanese version of the MDP was prepared in collaboration with Mapi Research Trust (Lyon, France) after the approval of the developer. Physical activity was assessed using a 3-axis accelerometer. Dyspnea upon exertion was investigated using a 3-minute step test. RESULTS: The Japanese version of the MDP was obtained and validated linguistically. Air-hunger was significantly associated with total calories from walking (r = - 0.47, p < 0.05), while anxiety and depression were significantly correlated with both the amount and intensity of physical activity (r = - 0.49, p < 0.05, and r = - 0.46, p < 0.05, respectively). CONCLUSION: The Japanese version of the MDP was suggested to reflect both pulmonary functions, ventilatory response during exercise, and intensity and amount of physical activity in patients with COPD.

l-Menthol - a new treatment for breathlessness?

PURPOSE OF REVIEW: In patients with advanced chronic obstructive pulmonary disease (COPD), it is challenging to treat breathlessness. In addition, novel palliative interventions are required for multiple perspectives of breathlessness that may still be present after disease-specific therapies. This review provides an overview of the mechanisms and effects of l-menthol on breathlessness by covering the latest relevant papers. RECENT FINDINGS: A literature review identified one randomized controlled trial assessing the effect of l-menthol on relieving breathlessness in patients with COPD. It has been reported that the mechanism of relieving breathlessness partly involves stimulation of the trigeminal nerve by the cooling sensation of l-menthol, which gives a cognitive illusion of inspiratory flow perception. The effect of l-menthol on breathlessness caused by exertion has been reported in healthy subjects but not yet in patients with breathlessness. SUMMARY: The effect of l-menthol on the sensory-emotional dimensions of laboratory-induced breathlessness in patients with COPD has been described in a clinical trial. Further studies are warranted to investigate its application to inspiratory muscle training and its effects in combination with exercise training.

Exertional multidimensional dyspnoea predicts exacerbation in stable outpatients with COPD.

This study assessed the sensory and emotional aspects of breathlessness under the same exercise load in patients with COPD. Breathing discomfort with constant exercise predicted exacerbations within 1 year. https://bit.ly/3l2oA4A.

Expiratory central airway collapse and symptoms in smokers.

BACKGROUND: The prevalence and clinical impacts of expiratory central airway collapse (ECAC) in smokers remain controversial. Although studies have shown associations of ECAC with airflow limitation and symptoms, others have shown that higher tracheal collapsibility is associated with lower expiratory-to-inspiratory ratio of lung volume (E/I-LV), but not airflow limitation. This study tested whether ECAC of the trachea and main bronchi could occur exclusively in smokers with lower E/I-LV and affect their symptoms independent of emphysema and intrapulmonary airway disease. METHODS: ECAC was defined as the expiratory-to-inspiratory ratio of cross-sectional lumen area <0.5 for at least one of the three locations, including the trachea, right and left main bronchi on static full-inspiratory, and end-tidal expiratory CT. Symptoms were assessed using the chronic obstructive pulmonary disease (COPD) assessment test (CAT) and modified MRC scale (mMRC). RESULTS: Out of 241 smokers with and without COPD (n = 189 and 52, respectively), ECAC was found in 21 (9%) smokers. No ECAC was found in smokers with E/I-LV ≥0.75. CAT and mMRC in smokers with ECAC were higher than in non-ECAC smokers with E/I-LV <0.75, but comparable to those in non-ECAC smokers with E/I-LV ≥0.75. In the multivariable analysis of smokers with E/I-LV <0.75, ECAC was associated with increased mMRC and CAT independent of CT-emphysema severity, wall area percent of segmental airways, and forced expiratory volume in 1 s CONCLUSIONS: ECAC is associated with worsening of symptoms independent of emphysema and segmental airway disease in smokers with a lower expiratory-to-inspiratory lung volume ratio.

Central airway and peripheral lung structures in airway disease-dominant COPD.

The concept that the small airway is a primary pathological site for all COPD phenotypes has been challenged by recent findings that the disease starts from the central airways in COPD subgroups and that a smaller central airway tree increases COPD risk. This study aimed to examine whether the computed tomography (CT)-based airway disease-dominant (AD) subtype, defined using the central airway dimension, was less associated with small airway dysfunction (SAD) on CT, compared to the emphysema-dominant (ED) subtype. COPD patients were categorised into mild, AD, ED and mixed groups based on wall area per cent (WA%) of the segmental airways and low attenuation volume per cent in the Kyoto-Himeji (n=189) and Hokkaido COPD cohorts (n=93). The volume per cent of SAD regions (SAD%) was obtained by nonrigidly registering inspiratory and expiratory CT. The AD group had a lower SAD% than the ED group and similar SAD% to the mild group. The AD group had a smaller lumen size of airways proximal to the segmental airways and more frequent asthma history before age 40 years than the ED group. In multivariable analyses, while the AD and ED groups were similarly associated with greater airflow limitation, the ED, but not the AD, group was associated with greater SAD%, whereas the AD, but not the ED, group was associated with a smaller central airway size. The CT-based AD COPD subtype might be associated with a smaller central airway tree and asthma history, but not with peripheral lung pathologies including small airway disease, unlike the ED subtype.

Effects of Sarcopenia on Ventilatory Behavior and the Multidimensional Nature of Dyspnea in Patients With Chronic Obstructive Pulmonary Disease.

OBJECTIVES: This study tested the hypothesis that sarcopenia, a common extrapulmonary feature of chronic obstructive pulmonary disease (COPD), can affect ventilatory behavior, and worsen the multidimensional nature of dyspnea in patients with COPD. DESIGN: Cross-sectional survey study. SETTING: and Participants: Stable outpatients with COPD encountered in general practice and respiratory clinic. METHOD: Sarcopenia was diagnosed according to an appendicular skeletal muscle mass index based on measurements of electrical impedance and handgrip strength. Exertional dyspnea was tested using a 3-minute Step Test and a 6-minute Walk Test. The dimensions of dyspnea were assessed by a multidimensional dyspnea profile. RESULTS: Of 60 stable patients with COPD, 16 met the criteria for sarcopenia. During the 3-minute Step Test, minute ventilation as a proportion of exercise time, tidal volume as a proportion of inspiratory capacity, the change in inspiratory capacity, and ventilation as a proportion of maximal voluntary ventilation did not differ between patients with and without sarcopenia. Patients with sarcopenia exhibited lower evolution of tidal volume, higher evolution of respiratory frequency versus ventilation and breathing discomfort on the 3-minute Step Test, as well as increased physical breathing effort on the 6-minute Walk Test, compared with those without sarcopenia. In a multivariable model adjusted using inverse probability weighting, sarcopenia was independently associated with breathing discomfort during the 3-minute Step Test and physical breathing effort during the 6-minute Walk Test. CONCLUSIONS AND IMPLICATIONS: Sarcopenia may be associated with shallow breathing and diverse sensory and affective components of exertional dyspnea in patients with COPD. The study indicates that improvement of the rapid breathing pattern may offer unique ways to alleviate dyspnea in older patients with COPD and sarcopenia.

Effect of Olfactory Stimulation by L-Menthol on Laboratory-Induced Dyspnea in COPD.

BACKGROUND: Inhalation of L-menthol as a transient receptor potential melastatin 8 agonist induces a cooling sensation in the airway. This cooling sensation induced through olfactory stimulation by L-menthol (OSM) alleviates dyspnea in healthy humans. Therefore, we investigated effects of OSM on the neural respiratory drive (NRD) and multidimensional aspects of dyspnea induced by inspiratory resistive loaded breathing in COPD. METHODS: In total, 28 patients with COPD and 14 control participants were included in this randomized, single-blinded, placebo-controlled, crossover study. OSM was administered using an L-menthol-scented patch, whereas placebo was administered using olfactory stimulation by strawberry-scented patch: placebo (OSP). Sham condition was measured by breathing through a face mask without a OSP. Dyspnea was evoked by breathing through the inspiratory resistance of 20 or 30 cm H2O/L/s and measured using the Multidimensional Dyspnea Profile. NRD was estimated using the electromyogram activities of the parasternal intercostal muscles. RESULTS: Compared with sham and OSP, OSM did not alter the breathing pattern/timing and NRD during inspiratory resistive loading; however, it significantly alleviated the physical and mental breathing effort, air hunger, breathing discomfort, anxiety, and fear during inspiratory resistive loaded breathing in patients with COPD. However, although OSM reduced the air hunger, mental breathing effort, and unpleasantness, no significant improvement on affective dimension of dyspnea by OSM was observed in control participants. CONCLUSIONS: Our findings suggest that OSM activated the sense of inspiratory flow that achieved dyspnea relief in patients with COPD. TRIAL REGISTRY: UMIN Clinical Trials Registry (UMIN-CTR); No.: UMIN000033822; URL: https://www.umin.ac.jp/ctr/index.htm.

Association between chemical components of PM2.5 and children's primary care night-time visits due to asthma attacks: A case-crossover study.

BACKGROUND: Few papers have examined the association between the chemical components of PM2.5 and health effects. The existence of an association is now under discussion. METHODS: This case-crossover study aimed to examine the association between the chemical components of PM2.5 and night-time primary care visits (PCVs) due to asthma attacks. The subjects were 1251 children aged 0-14 years who received medical care for asthma at a municipal emergency clinic. We measured daily average concentrations of hydrogen ion, sulfate ion, nitrate ion and water-soluble organic compounds (WSOCs), which are components of PM2.5. We estimated the odds ratios (ORs) of PCVs per unit increment (inter quartile ranges) in each chemical component of PM2.5 for the subgroups of warmer months and colder months separately. RESULTS: No association was seen between PCVs and PM2.5 mass concentrations the day before the PCVs in either warmer or colder months. In the warmer months, an association was seen with the concentrations of WSOCs and hydrogen ion the day before the PCVs (OR = 1.33; 95% CI: 1.00-1.76, OR = 1.18; 95% CI: 1.02-1.36, respectively). Furthermore, a negative association was seen between sulfate ion and PCVs (OR = 0.85; 95%CI: 0.74-0.98). No associations were observed in the colder months. CONCLUSIONS: We observed a positive association between PCVs and certain concentrations of WSOCs and hydrogen ions in warmer months. In contrast, sulfate ion showed a negative association.

Relationship between periodontitis-related antibody and frequent exacerbations in chronic obstructive pulmonary disease.

BACKGROUND: To identify patients with chronic obstructive pulmonary disease (COPD) who are susceptible to frequent exacerbations is important. Although periodontitis aggravated by poor oral hygiene might increase the risk of lower respiratory tract infection, the relationship between periodontitis and COPD exacerbations remains unknown. This prospective cohort study investigates the relationship between periodontitis-related antibody and exacerbation frequency over a one-year period. METHODS: We assessed an IgG antibody titer against Porphyromonas gingivalis, which is a major pathogen of periodontitis, and then prospectively followed up 93 individuals over one year to detect exacerbations. RESULTS: The numbers of exacerbations and the rate of individuals with frequent exacerbations (at least two per year) were significantly lower in patients with higher IgG titer than those with normal IgG titer (0.8 vs. 1.2 per year, p= 0.045 and 14.3 vs. 38.6%, p= 0.009, respectively). Multivariate logistic regression analysis showed that being normal-IgG titer for periodontitis-related antibody significantly increased the risk of frequent exacerbations (relative risk, 5.27, 95% confidence interval, 1.30-25.7; p = 0.019) after adjusting for other possible confounders, such as a history of exacerbations in the past year, disease severity, COPD medication and smoking status. CONCLUSIONS: Normal-IgG titer for periodontitis-related antibody can be an independent predictor of frequent exacerbations. Measuring periodontitis-related antibody titers might be useful to identify patients with susceptibility to frequent exacerbations so that an aggressive prevention strategy can be designed.

Sputum YKL-40 levels and pathophysiology of asthma and chronic obstructive pulmonary disease.

BACKGROUND: Recent evidence suggests that YKL-40, also called chitinase-3-like-1 protein, is involved in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Details of sputum YKL-40 in asthma and COPD, however, remain unknown. OBJECTIVES: To clarify associations of sputum YKL-40 levels with clinical indices in asthma and COPD. METHODS: Thirty-nine patients with asthma, 14 age-matched never-smokers as controls, 45 patients with COPD, and 7 age-matched smokers as controls were recuited for this study. Sputum YKL-40 levels were measured and YKL-40 expression in sputum cells was evaluated by immunocytochemistry. RESULTS: Sputum YKL-40 levels were higher in patients with COPD (346 ± 325 ng/ml) than in their smoker controls (125 ± 122 ng/ml; p < 0.05), but were not significantly different between patients with asthma (117 ± 170 ng/ml) and their controls (94 ± 44 ng/ml; p = 0.15). In patients with asthma only, sputum YKL-40 levels were positively correlated with disease severity (r = 0.34, p = 0.034) and negatively correlated with pre- and postbronchodilator %FEV(1) (r = -0.47 and -0.42, respectively; p < 0.01) and forced mid-expiratory flow (r = -0.48 and -0.46, respectively, p < 0.01). Sputum YKL-40 levels were positively correlated with sputum neutrophil counts in asthma (r = 0.55, p < 0.001) and with neutrophil and macrophage counts in COPD (r = 0.45 and 0.65, respectively, p < 0.01). YKL-40 was expressed in the cytoplasm of sputum neutrophils and macrophages in all groups. CONCLUSIONS: Elevated sputum YKL-40 reflects airflow obstruction in asthma whereas the roles of YKL-40 in the proximal airways in COPD remain to be elucidated.

Copper incorporation into ceruloplasmin is regulated by Niemann-Pick C1 protein.

AIM: Wilson disease is a genetic disorder of copper metabolism characterized by impaired biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. Our previous study showed the late endosome localization of ATP7B and described the copper transport pathway from the late endosome to trans-Golgi network (TGN). However, the cellular localization of ATP7B and copper metabolism in hepatocytes remains controversial. The present study was performed to evaluate the role of Niemann-Pick type C (NPC) gene product NPC1 on intracellular copper transport in hepatocytes. METHODS: We induced the NPC phenotype using U18666A to modulate the vesicle traffic from the late endosome to TGN. Then, we examined the effect of NPC1 overexpression on the localization of ATP7B and secretion of holo-Cp, a copper-binding mature form of Cp. RESULTS: Overexpression of NPC1 increased holo-Cp secretion to culture medium of U18666A-treated cells, but did not affect the secretion of albumin. Manipulation of NPC1 function affected the localization of ATP7B and late endosome markers, but did not change the localization of a TGN marker. ATP7B co-localized with the late endosome markers, but not with the TGN marker. CONCLUSION: These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via an NPC1-dependent pathway and incorporated into Cp.