Predictors of longitudinal changes in body weight, muscle and fat in patients with and ever-smokers at risk of COPD.

BACKGROUND AND OBJECTIVE: Weight and muscle loss are predictors of poor outcomes in chronic obstructive pulmonary disease. However, to our knowledge, no study has investigated the predictors of longitudinal weight loss or its composition from functional and morphological perspectives. METHODS: This longitudinal observational study with a median follow-up period of 5 years (range: 3.0-5.8 years) included patients with COPD and ever-smokers at risk of COPD. Using chest computed tomography (CT) images, airway and emphysematous lesions were assessed as the square root of the wall area of a hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10) and the percentage of low attenuation volume (LAV%). Muscle mass was estimated using cross-sectional areas (CSAs) of the pectoralis and erector spinae muscles, and fat mass was estimated using the subcutaneous fat thickness at the level of the 8th rib measured using chest CT images. Statistical analyses were performed using the linear mixed-effects models. RESULTS: In total, 114 patients were enrolled. Their body mass index remained stable during the study period while body weight and muscle CSA decreased over time and the subcutaneous fat thickness increased. Reduced forced expiratory volume in 1 s and peak expiratory flow (PEF) at baseline predicted the future decline in muscle CSA. CONCLUSION: Severe airflow limitation predicted future muscle wasting in patients with COPD and ever-smokers at risk of COPD. Airflow limitation with a PEF slightly below 90% of the predicted value may require intervention to prevent future muscle loss.

The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD.

RATIONALE: Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. METHODS: Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling. RESULTS: Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and <1000 µm, which we have termed a "hot spot". Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes. INTERPRETATION: The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.

Risk factors for pneumonitis in advanced extrapulmonary cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune-mediated pneumonitis has a high mortality rate; however, information regarding the related risk factors remains limited. This study aimed to analyze risk factors for pneumonitis, including smoking and lung metastasis (LM), in patients with extrapulmonary primary tumors. METHODS: Data of 110 patients treated with immune checkpoint inhibitors (ICIs) (nivolumab/pembrolizumab) for treating extrapulmonary primary tumors at the Shiga University of Medical Science Hospital between January 2015 and December 2019 were retrospectively collected. The association between the onset of pneumonitis and treatment-related factors was analyzed by logistic regression. The severity of pneumonitis was graded according to the Common Terminology Criteria for Adverse Events version 5.0. Risk factors, such as the absence or presence of interstitial lung disease (ILD) and LM, or other clinical factors, including smoking status before ICI administration, were analyzed. RESULTS: Multivariate analyses indicated that the amount of smoking was significantly associated with an increase in the development of all-grade pneumonitis types (odds ratio (OR) = 20.33, 95% confidence interval (CI) = 20.03-20.66; p = 0.029). LM and ILD were significantly related to an increase in the development of symptomatic pneumonitis (≥ Grade 2) (OR = 10.08, 95% CI = 1.69-199.81; p = 0.076, and OR = 6.76, 95% CI = 1.13-40.63; p = 0.037, respectively). CONCLUSIONS: Pre-screening for ILD and LM and recognizing patients' smoking history is important for determining the risk of ICI-induced pneumonitis and allowing safe ICI administration.

Analysis of airway pathology in COPD using a combination of computed tomography, micro-computed tomography and histology.

The small conducting airways are the major site of obstruction in chronic obstructive pulmonary disease (COPD). This study examined small airway pathology using a novel combination of multidetector row computed tomography (MDCT), micro-computed tomography (microCT) and histology.Airway branches visible on specimen MDCT were counted and the dimensions of the third- to fifth-generation airways were computed, while the terminal bronchioles (designated TB), preterminal bronchioles (TB-1) and pre-preterminal bronchioles (TB-2) were examined with microCT and histology in eight explanted lungs with end-stage COPD and seven unused donor lungs that served as controls.On MDCT, COPD lungs showed a decrease in the number of 2-2.5 mm diameter airways and the lumen area of fifth-generation airways, while on microCT there was a reduction in the number of terminal bronchioles as well as a decrease in the luminal areas, wall volumes and alveolar attachments to the walls of TB, TB-1 and TB-2 bronchioles. The combination of microCT and histology showed increased B-cell infiltration into the walls of TB-1 and TB-2 bronchioles, and this change was correlated with a reduced number of alveolar attachments in COPD.Small airways disease extends from 2 mm diameter airways to the terminal bronchioles in COPD. Destruction of alveolar attachments may be driven by a B-cell-mediated immune response in the preterminal bronchioles.

Micro-Computed Tomography Comparison of Preterminal Bronchioles in Centrilobular and Panlobular Emphysema.

RATIONALE: Very little is known about airways that are too small to be visible on thoracic multidetector computed tomography but larger than the terminal bronchioles. OBJECTIVES: To examine the structure of preterminal bronchioles located one generation proximal to terminal bronchioles in centrilobular and panlobular emphysema. METHODS: Preterminal bronchioles were identified by backtracking from the terminal bronchioles, and their centerlines were established along the entire length of their lumens. Multiple cross-sectional images perpendicular to the centerline were reconstructed to evaluate the bronchiolar wall and lumen, and the alveolar attachments to the outer airway walls in relation to emphysematous destruction in 28 lung samples from six patients with centrilobular emphysema, 20 lung samples from seven patients with panlobular emphysema associated with alpha-1 antitrypsin deficiency, and 47 samples from seven control (donor) lungs. MEASUREMENTS AND MAIN RESULTS: The preterminal bronchiolar length, wall volume, total volume (wall + lumen), lumen circularity, and number of alveolar attachments were reduced in both centrilobular and panlobular emphysema compared with control lungs. In contrast, thickening of the wall and narrowing of the lumen were more severe and heterogeneous in centrilobular than in panlobular emphysema. The bronchiolar lumen was narrower in the middle than at both ends, and the decreased number of alveolar attachments was associated with increased wall thickness in centrilobular emphysema. CONCLUSIONS: These results provide new information about small airways pathology in centrilobular and panlobular emphysema and show that these changes affect airways that are not visible with thoracic multidetector computed tomography scans but located proximal to the terminal bronchioles in chronic obstructive pulmonary disease.

Association of gut microbiome with COPD in Japanese male residents: the SESSA study.

Background: Altered gut microbiota may contribute to COPD development or progression. Herein, we investigated the association of gut microorganisms with COPD, taking into account the impact of smoking status. Methods: This cross-sectional observational study was a part of the Shiga Epidemiological Study of Subclinical Atherosclerosis, a population-based cohort study of Japanese men aged 46-76 years, conducted from 2010 to 2016. The gut microbiome, determined using 16S rRNA gene sequencing, was compared among 99 never-smokers, 306 non-COPD ever-smokers and 76 patients with COPD while adjusting for age, body mass index, ethanol consumption and treatment for type 2 diabetes mellitus. Results: The abundance of phylum Firmicutes was comparable between patients with COPD and non-COPD ever-smokers but tended to be higher in never-smokers. Similarly, the α- and ß-diversity analysis showed similarity between patients with COPD and non-COPD ever-smokers, which tended to differ from never-smokers. Discriminant analysis identified the genus [Prevotella] to be more prevalent in patients with COPD than in never-smokers or non-COPD ever-smokers. Post hoc analysis confirmed similarity of gut microbiome between COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) I and non-COPD ever-smokers, which was different from GOLD II. Conclusion: Smoking may alter the overall gut microbial composition, but gut microbial composition itself may not play a role in the development of COPD. Rather, specific gut bacteria, such as [Prevotella], could be a risk factor for the development of COPD; this may be a potential therapeutic target.

Inspiratory and Expiratory Computed Tomography Imaging Clusters Reflect Functional Characteristics in Chronic Obstructive Pulmonary Disease.

Purpose: Disease probability measure (DPM) is a useful voxel-wise imaging assessment of gas-trapping and emphysematous lesions in patients with chronic obstructive pulmonary disease (COPD). To elucidate the progression of COPD, we performed a cluster analysis using the following DPM parameters: normal (DPMNormal), gas-trapping (DPMGasTrap), and emphysematous lesions (DPMEmph). Our findings revealed the characteristics of each cluster and the 3-year disease progression using imaging parameters. Patients and Methods: Inspiratory and expiratory chest computed tomography (CT) images of 131 patients with COPD were examined, of which 84 were followed up for 3 years. The percentage of low attenuation volume (LAV%) and the square root of the wall area of a hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10) were quantitatively measured using inspiratory chest CT. A hierarchical cluster analysis was performed using the DPM parameters at baseline. Five clusters were named according to the dominant DPM parameters: normal (NL), normal-GasTrap (NL-GT), GasTrap (GT), GasTrap-Emphysema (GT-EM), and Emphysema (EM). Results: Women were predominantly diagnosed with GT. Forced expiratory volume in 1 s gradually decreased in the following order: NL, NL-GT, GT, GT-EM, and EM. DPMEmph correlated well with LAV%. Four clusters other than NL showed significantly higher values of √Aaw at Pi10 than NL; however, no significant differences were observed among them. In all clusters, DPMEmph increased after 3 years. DPMNormal only increased in the GT cluster. Conclusion: Clusters using DPM parameters may reflect the characteristics of COPD and help understand the pathophysiology of the disease.

Autobullectomy with COVID-19 in a patient with chronic obstructive pulmonary disease.

A 72-year-old man with chronic obstructive pulmonary disease (COPD) was admitted for coronavirus disease 2019 (COVID-19). He was discharged on day 30; however, he was readmitted 6 days later due to a left lung organizing pneumonia secondary to COVID-19. After methylprednisolone treatment, the patient was discharged on day 15. One year later, computed tomography showed shrinkage of emphysematous lesions, and both total lung capacity measured using computed tomography and fraction of low attenuation volume decreased in the left lung compared to that before COVID-19. Here, we report a rare case of autobullectomy with COVID-19 in a patient with COPD.

Oxidative stress induced interleukin-32 mRNA expression in human bronchial epithelial cells.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and persistent inflammation in the airways and lung parenchyma. Oxidative stress contributes to the pathogenesis of COPD. Interleukin (IL)-32 expression has been reported to increase in the lung tissue of patients with COPD. Here, we show that IFNγ upregulated IL-32 expression and that oxidative stress augmented IFNγ-induced-IL-32 expression in airway epithelial cells. We further investigated transcriptional regulation responsible for IFNγ induced IL-32 expression in human airway epithelial cells. METHODS: Human bronchial epithelial (HBE) cells were stimulated with H2O2 and IFNγ, and IL-32 expression was evaluated. The cell viability was confirmed by MTT assay. The intracellular signaling pathways regulating IL-32 expression were investigated by examining the regulatory effects of MAPK inhibitors and JAK inhibitor after treatment with H2O2 and IFNγ, and by using a ChIP assay to identify transcription factors (i.e. c-Jun, CREB) binding to the IL-32 promoter. Promoter activity assays were conducted after mutations were introduced into binding sites of c-Jun and CREB in the IL-32 promoter. IL-32 expression was also examined in HBE cells in which the expression of either c-Jun or CREB was knocked out by siRNA of indicated transcription factors. RESULTS: There were no significant differences of cell viability among groups. After stimulation with H2O2 or IFNγ for 48 hours, IL-32 expression in HBE cells was increased by IFNγ and synergistically upregulated by the addition of H2O2. The H2O2 augmented IFNγ induced IL-32 mRNA expression was suppressed by a JNK inhibitor, but not by MEK inhibitor, p38 inhibitor, and JAK inhibitor I. Significant binding of c-Jun and CREB to the IL-32 promoter was observed in the IFNγ + H2O2 stimulated HBE cells. Introducing mutations into the c-Jun/CREB binding sites in the IL-32 promoter prominently suppressed its transcriptional activity. Further, knocking down CREB expression by siRNA resulted in significant suppression of IL-32 induction by IFNγ and H2O2 in HBE cells. CONCLUSION: IL-32 expression in airway epithelium may be augmented by inflammation and oxidative stress, which may occur in COPD acute exacerbation. c-Jun and CREB are key transcriptional factors in IFNγ and H2O2 induced IL-32 expression.

Emphysema distribution and annual changes in pulmonary function in male patients with chronic obstructive pulmonary disease.

BACKGROUND: The progression of chronic obstructive pulmonary disease (COPD) considerably varies among patients. Those with emphysema identified by quantitative computed tomography (CT) are associated with the rapid progression assessed by forced expiratory volume in one second (FEV1). However, whether the rate of the decline in lung function is independently affected by the regional distribution or the severity of emphysema in the whole lung is unclear. METHODS: We followed up 131 male patients with COPD for a median of 3.7 years. We measured wall area percent (WA%) in right apical segmental bronchus, total lung volume, percent low attenuation volume (LAV%), and the standard deviation (SD) of LAV% values from CT images of 10 isovolumetric partitions (SD-LAV) as an index of cranial-caudal emphysema heterogeneity. Annual changes in FEV1 were then determined using a random coefficient model and relative contribution of baseline clinical parameters, pulmonary function, and CT indexes including LAV%, SD-LAV, and WA% to annual changes in FEV1 were examined. RESULTS: The mean (SD) annual change in FEV1 was -44.4 (10.8) mL. Multivariate random coefficient model showed that higher baseline FEV1, higher LAV%, current smoking, and lower SD-LAV independently contributed to an excessive decline in FEV1, whereas ratio of residual volume to total lung capacity, ratio of diffusing capacity to alveolar ventilation, and WA% did not, after adjusting for age, height, weight, and ratio of CT-measured total lung volume to physiologically-measured total lung capacity. CONCLUSIONS: A more homogeneous distribution of emphysema contributed to an accelerated decline in FEV1 independently of baseline pulmonary function, whole-lung emphysema severity, and smoking status. In addition to whole-lung analysis of emphysema, CT assessment of the cranial-caudal distribution of emphysema might be useful for predicting rapid, progressive disease and for developing a targeted strategy with which to prevent disease progression.

A NOD2 gene polymorphism is associated with the prevalence and severity of chronic obstructive pulmonary disease in a Japanese population.

BACKGROUND AND OBJECTIVE: Genetic background is thought to be one of the risk factors for development of COPD. Recently, it has been proposed that the innate immune system is involved in the pathophysiology of COPD. We hypothesized that polymorphisms in the nucleotide-binding and oligomerization domain (NOD)1 and NOD2 genes would be associated with the pathogenesis of COPD. In addition, the associations between these single nucleotide polymorphisms (SNPs) and phenotypes of COPD were analysed. METHODS: Japanese COPD patients (n = 228) and non-COPD smokers (n = 101) were recruited from the outpatient clinic at Kyoto University Hospital, Kyoto, Japan. At entry into the study, a blood sample was taken and a pulmonary function test was performed. Genotyping was performed for 6 selected tag SNPs of NOD1 and 5 tag SNPs of NOD2. Further investigations were performed for SNP that were associated with COPD, including baseline gene expression, the relative proportions of splicing variants in whole blood, responses to ligand and enhancement of gene expression in peripheral blood neutrophils stimulated with pro-inflammatory cytokines. RESULTS: The distribution of NOD2 rs1077861 genotypes differed between Japanese COPD patients and non-COPD smokers (P = 0.036). This SNP was also associated with a lower FEV(1) % predicted (57.2 ± 1.8 for TT vs 50.8 ± 2.3 for TA/AA, P = 0.03) and DL(CO) /V(A) (2.89 ± 0.1 in TT vs 2.53 ± 0.14 in TA/AA, P = 0.036) in COPD patients. NOD2 gene expression after stimulation with 10 ng/mL of tumour necrosis factor-α for 4 h, was increased to a greater extent in TA/AA genotype than in TT genotype peripheral blood neutrophils (P = 0.015). CONCLUSIONS: The NOD2 rs1077861 SNP may influence the development and progression of COPD in Japanese subjects.

Peri-diaphragmatic lung volume assessed by computed tomography correlates with quality of life in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Health-related quality of life (HRQoL) is important in the management of chronic obstructive pulmonary disease (COPD). In patients with emphysema, lung hyperinflation identified radiologically as shortening and flattening of the diaphragm is associated with impaired HRQoL. It remains unclear whether shortening of the diaphragm and/or alteration in chest wall shape are associated with reduced pulmonary function and HRQoL. METHODS: Pulmonary function testing and chest computed tomography (CT) were performed, and the St. George's Respiratory Questionnaire (SGRQ) was administered to 123 patients with COPD. Using CT images, the ratio of volume of lung region adjacent to the diaphragm dome to total lung volume (DLV%) was evaluated as a novel CT index, and conventional indices, including percent low attenuation volume (LAV%), wall area percent (WA%), total lung volume and diaphragm length (Ldi) were calculated. RESULTS: DLV% was significantly correlated with Ldi. DLV% and Ldi were inversely correlated with lung hyperinflation, assessed as the ratio of residual volume to total lung capacity, independent of LAV% and WA%. Unlike Ldi, DLV% was inversely associated with all components and total scores for the SGRQ, independent of the severity of emphysema and airflow limitation. CONCLUSIONS: Reduced lung volume around the diaphragm correlated with lung hyperinflation and HRQoL, independent of emphysema severity. This needs to be verified in additional studies.

Impact of exacerbations on emphysema progression in chronic obstructive pulmonary disease.

RATIONALE: Low-attenuation areas assessed by computed tomography reflect the extent of pathological emphysema and correlate with airflow limitation and mortality in patients with chronic obstructive pulmonary disease. The cumulative size distribution of low-attenuation area clusters follows a power law characterized by an exponent, D. The values of D reflect the complexity of the terminal airspace geometry and sensitively detect alveolar structural changes. Exacerbations of chronic obstructive pulmonary disease have a negative impact on lung function and prognosis. However, the impact on emphysema progression remains unclear. OBJECTIVES: We investigated the relationship between exacerbation and emphysema progression assessed by computed tomography in patients with chronic obstructive pulmonary disease. METHODS: Exacerbations were prospectively recorded for 2 years. Annual changes in computed tomography parameters of emphysema were compared between patients with and without a history of exacerbations. MEASUREMENTS AND MAIN RESULTS: In patients with exacerbations, increases in the percentage of low-attenuation areas and decreases in D were greater than in patients without exacerbations. To interpret these results, we established a novel simulation model and found that not only enlargement of preexisting low-attenuation areas but also coalescence of adjoining low-attenuation areas due to alveolar wall destruction caused emphysema progression in patients with exacerbations. CONCLUSIONS: This is the first longitudinal study to demonstrate that exacerbations are involved in emphysema progression in patients with chronic obstructive pulmonary disease. Emphysema progression should be evaluated as part of the outcomes of exacerbations in the management of chronic obstructive pulmonary disease.

Impact of COPD exacerbations on osteoporosis assessed by chest CT scan.

BACKGROUND: COPD pathology involves not only the lungs but also extrapulmonary abnormalities. Osteoporosis is one of the most important abnormalities because it may cause vertebral compression fractures and deteriorate pulmonary function. COPD patients have many risk factors for osteoporosis, such as low BMI, decreased activity, systemic inflammation, and use of corticosteroids. Some of these factors have been shown to deteriorate with COPD exacerbations. We previously demonstrated the correlation between emphysema and osteoporosis and between emphysema progression and COPD exacerbations. Thus, the hypothesis that exacerbation causes osteoporosis progression in COPD patients was investigated. METHODS: Forty-two COPD patients not on osteoporosis treatment for over 2 years were recruited. During follow-up, exacerbations had been prospectively recorded. Thoracic vertebral bone mineral density (BMD) was measured using chest CT, and the annual change in BMD was calculated. The change was compared between patients with and without a history of exacerbations. RESULTS: The decrease in thoracic vertebral BMD was greater in patients with than in those without a history of exacerbations (median ΔBMD mg/ml·year: -3.78 versus -0.30, p = 0.02). Moreover, multivariate regression analysis showed that exacerbations and baseline PaO2 were independent predictors of the BMD decrease (R² = 0.20, p = 0.007, and R² = 0.09, p = 0.03, respectively) after adjustment for baseline age, smoking status, and airflow limitation. CONCLUSIONS: This is the first longitudinal study to demonstrate that COPD exacerbations are independently associated with osteoporosis progression. Osteoporosis progression should be evaluated in COPD patients, especially in those with a history of frequent exacerbations.

Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD.

Pharmacological lung volume reduction in COPD is an important goal in treatment with long-acting bronchodilators because in addition to airflow limitation, lung hyperinflation considerably affects COPD symptoms. Quantitative computed tomography (CT) simultaneously provides structural information about airway dimensions, emphysematous changes, and lung volumes, some of which are difficult to be evaluated by pulmonary function. Here, we evaluated changes in CT parameters and pulmonary function in 30 patients with COPD who underwent CT scans before and one year after starting tiotropium treatment and in 12 patients with COPD who were not treated with long-acting bronchodilators. Baseline pulmonary function and CT parameters did not differ between the two groups. One-year tiotropium therapy improved physiological-indices including residual volume (RV) and ratio of RV to total lung capacity (RV/TLC) (-235 mL, p = 0.005, and -2.9%, p = 0.0001, respectively), and CT-indices including wall area percent (WA%) and inner luminal area in right upper lobe apical and lower lobe basal segmental bronchi (-1.59%, p = 0.01, 2.27 mm(2), p = 0.0005; and -1.33%, p = 0.0008, 3.42 mm(2), p < 0.0001, respectively), low attenuation volume (LAV) and total lung volume (CT-TLV) (-92 mL, p = 0.0003, and -211 mL, p = 0.002, respectively). Changes in LAV, CT-TLV, RV, and RV/TLC were significantly greater in the tiotropium, than the non-bronchodilator group. The tiotropium-induced reduction in LAV correlated with the decrease in RV (ρ = 0.45, p = 0.01). Our findings not only indicate the value of the comprehensive CT measurements in assessing the effects of bronchodilators, including pharmacological lung volume reduction, but also further understanding of the structural changes underlying physiological improvements induced by bronchodilators.

Two cases of cancer-associated retinopathy combined with small-cell lung cancer.

Cancer-associated retinopathy is a rare paraneoplastic syndrome that is often associated with small-cell lung cancer. It is caused by an autoantibody to the 23 kDa photoreceptor protein, recoverin. A small number of reports have described effective treatment for the disease. We report two cases of cancer-associated retinopathy with small-cell lung cancer whose visual symptom preceded the diagnosis of cancer. Their visual acuity and visual field were slightly improved after steroid and anticancer therapy. Steroid therapy was effective, although the period from visual symptom onset to therapy was comparative longer. When cancer-associated retinopathy is suspected, a comparatively large quantity of steroids and anticancer treatment should be combined immediately.

The transition from normal lung anatomy to minimal and established fibrosis in idiopathic pulmonary fibrosis (IPF).

BACKGROUND: The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition. METHODS: Pre-operative thoracic Multidetector Computed Tomography (MDCT) scans of patients with severe IPF (n = 9) were used to identify regions of minimal(n = 27) and established fibrosis(n = 27). MDCT, Micro-CT, quantitative histology, and next-generation sequencing were used to compare 24 samples from donor controls (n = 4) to minimal and established fibrosis samples. FINDINGS: The present results extended earlier reports about the transition from normal lung anatomy to minimal and established fibrosis by showing that there are activations of TGFBI, T cell co-stimulatory genes, and the down-regulation of inhibitory immune-checkpoint genes compared to controls. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming lymphoid follicles. Moreover, fibrosis pathways, mucin secretion, surfactant, TLRs, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis. INTERPRETATION: The transition from normal lung anatomy to minimal and established fibrosis is associated with genes that are involved in the tissue repair processes, the activation of immune responses as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events correlate with the development of structural abnormality of IPF and probably contribute to its pathogenesis.

Lipopolysaccharide induced connective tissue growth factor gene expression in human bronchial epithelial cells.

BACKGROUND AND OBJECTIVE: Connective tissue growth factor (CTGF) is up-regulated in the lungs of patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke and repeated bacterial infections, both of which are rich sources of LPS, are major causes of COPD. The high levels of LPS in lung epithelial lining fluid also suggest that it may have a considerable impact on the airway epithelium, in terms of cytokine and growth factor production. The aim of this study was to clarify the mechanism of LPS-induced CTGF expression in bronchial epithelial cells. METHODS: The expression and transcriptional regulation of the CTGF gene were assessed using the cultured human bronchial epithelial cell line, BEAS-2B. RESULTS: LPS significantly up-regulated CTGF mRNA expression in a dose-dependent fashion, with 100 microg/mL LPS causing a twofold increase after 2 h. CTGF protein expression was also up-regulated by LPS after 8 h. Transforming growth factor-beta1 mRNA expression was not changed by LPS treatment. A pharmacological inhibitor of nuclear factor (NF)-kappaB, MG132, inhibited LPS-induced CTGF mRNA expression. Furthermore, luciferase assays demonstrated that deletion of base pairs -253 to -53 from the CTGF promoter, where the Smad and proximal NF-kappaB binding sites are located, decreased the induction of CTGF by LPS. After stimulation with LPS, the p65 subunit of NF-kappaB was shown to be bound to the CTGF promoter in vitro and in situ. CONCLUSIONS: LPS directly induced CTGF expression in bronchial epithelial cells, independently of transforming growth factor-beta1, suggesting a possible mechanism for airway remodelling in COPD that is induced by smoking and repeated bacterial infections.

Relationship between peripheral airway function and patient-reported outcomes in COPD: a cross-sectional study.

BACKGROUND: Health status, dyspnea and psychological status are important clinical outcomes in chronic obstructive pulmonary disease (COPD). However, forced expiratory volume in one second (FEV1) measured by spirometry, the standard measurement of airflow limitation, has only a weak relationship with these outcomes in COPD. Recently, in addition to spirometry, impulse oscillometry (IOS) measuring lung resistance (R) and reactance (X) is increasingly being used to assess pulmonary functional impairment. METHODS: We aimed to identify relationships between IOS measurements and patient-reported outcomes in 65 outpatients with stable COPD. We performed pulmonary function testing, IOS, high-resolution computed tomography (CT), and assessment of health status using the St. George's Respiratory Questionnaire (SGRQ), dyspnea using the Medical Research Council (MRC) scale and psychological status using the Hospital Anxiety and Depression Scale (HADS). We then investigated the relationships between these parameters. For the IOS measurements, we used lung resistance at 5 and 20 Hz (R5 and R20, respectively) and reactance at 5 Hz (X5). Because R5 and R20 are regarded as reflecting total and proximal airway resistance, respectively, the fall in resistance from R5 to R20 (R5-R20) was used as a surrogate for the resistance of peripheral airways. X5 was also considered to represent peripheral airway abnormalities. RESULTS: R5-R20 and X5 were significantly correlated with the SGRQ and the MRC. These correlation coefficients were greater than when using other objective measurements of pulmonary function, R20 on the IOS and CT instead of R5-R20 and X5. Multiple regression analyses showed that R5-R20 or X5 most significantly accounted for the SGRQ and MRC scores. CONCLUSIONS: IOS measurements, especially indices of peripheral airway function, are significantly correlated with health status and dyspnea in patients with COPD. Therefore, in addition to its simplicity and non-invasiveness, IOS may be a useful clinical tool not only for detecting pulmonary functional impairment, but also to some extent at least estimating the patient's quality of daily life and well-being.