[Show abstract][Hide abstract] ABSTRACT: Background: Small airway remodeling is an important cause of the airflow limitation in chronic obstructive pulmonary disease (COPD). A large population of patients with COPD also have pulmonary hypertension. Krüppel-like factor 5 (KLF5) is a zinc-finger transcription factor that contributes to tissue remodeling in cardiovascular diseases. Here, we evaluate the possible involvement of KLF5 in the remodeling of small airways and pulmonary vessels in COPD. Methods: Lung tissues were obtained from 23 control never-smokers, 17 control ex-smokers and 24 ex-smokers with COPD. The expression of KLF5 in the lung tissues was investigated by immunohistochemistry. We investigated whether oxidative/nitrosative stress, which is a major cause of the pathogenesis in COPD, could augment the production of KLF5. We examined the role of KLF5 in the stress-mediated tissue remodeling responses. We also investigated the susceptibility of KLF5 expression to nitrosative stress using bronchial fibroblasts isolated from the lung tissues. Results: The expression of KLF5 was up-regulated in the small airways and pulmonary vessels of the COPD patients and it was mainly expressed in bronchial fibroblasts and cells of the pulmonary vessels. The extent of the KLF5 expression in the small airway of the COPD group had a significant correlation with the severity of the airflow limitation. Oxidative/nitrosative stress augmented the production of KLF5 in lung fibroblasts as well as the translocation of KLF5 into the nuclei. Silencing of KLF5 suppressed the stress-augmented differentiation into myofibroblasts, the release of collagens and metalloproteinases. Bronchial fibroblasts from the patients with COPD highly expressed KLF5 compared to those from the control subjects under basal condition and were more susceptible to the induction of KLF5 expression by nitrosative stress compared to those from the control subjects. Conclusion: We provide the first evidence that the expression of KLF5 is up-regulated in small airways and pulmonary vessels of patients with COPD and may be involved in the tissue remodeling of COPD.
Preview · Article · Dec 2016 · Respiratory research
[Show abstract][Hide abstract] ABSTRACT: Improvement in the daily physical activity (PA) is important for the management of chronic obstructive pulmonary disease (COPD). However, the effects of pharmacologic treatment on PA are not well understood. We evaluated the effects of additional medications, including bronchodilator with or without inhaled corticosteroid, based on airflow limitation and breathlessness on the PA in COPD patients and the factors that could predict or affect the improvement in PA.
A prospective non-randomized observational study was employed. Twenty-one COPD subjects without any other diseases that might reduce PA were recruited. The PA was measured with a triaxial accelerometer for 2 weeks, and pulmonary function tests and incremental shuttle walking tests were administered before and after 4-week treatment with an additional medication.
Bronchodilation was obtained by additional medication. The mean values of PA evaluated by metabolic equivalents (METs) at ≥3.0 METs and the duration of PA at ≥3.0 METs and ≥3.5 METs were improved by medication. The % change in the duration of PA at ≥3.5 METs was significantly correlated with the baseline functional residual capacity (FRC), residual volume, and inspiratory capacity/total lung capacity. However, the % change in the duration of PA at any intensity was not correlated with the % changes of any values of the pulmonary function tests or incremental shuttle walking test except the PA at ≥2.5 METs with FRC.
Medication could improve the PA in patients with COPD, especially at a relatively high intensity of activity when medication was administered based on airflow limitation and breathlessness. The improvement was seen in the patients with better baseline lung volume, but was not correlated with the improvements in the pulmonary function tests or exercise capacity.
Full-text · Article · Jul 2015 · International Journal of COPD
[Show abstract][Hide abstract] ABSTRACT: Background:
A predominant feature of asthma is an accelerated rate of decline in forced expiratory volume in 1 s (FEV1), but data on the variability and factors associated with this change in patients with controlled asthma are largely unknown.
140 patients with controlled asthma were enrolled based on the Global Initiative for Asthma guidelines. We examined the data of a prospective analysis of the association between asthma control and change in FEV1 over time.
A 3-year follow-up assessment was completed in 128 patients. The mean rate of change in FEV1 was a decline of 22.2 mL yr(-1), with significant variation in the levels of change. The between patient standard deviation for the rate of decline was 34.1 mL yr(-1). We next classified the subjects of less than the 25th percentile as rapid decliners, and greater than the 25th percentile as non-rapid decliners. The decrease in the Asthma Control Test score over a 3-year period was higher for rapid decliners than that for non-rapid decliners (p < 0.001). The rapid decliner was more likely to be older, to have higher levels of FeNO, and to have had severe exacerbations during the study. Patients with severe exacerbations had a greater annual decline in FEV1 compared to patients with no exacerbations (-13.6 vs. -53.2 mL yr(-1), p < 0.0001).
Among patients with controlled asthma at baseline, the rate of change in FEV1 is highly variable. Severe exacerbations are strongly associated with a rapid loss of lung function.
No preview · Article · May 2014 · Respiratory Medicine
[Show abstract][Hide abstract] ABSTRACT: Viral infection often triggers asthma exacerbation and contributes to airway remodeling. Cell signaling in viral infection is mainly mediated through TLR3. Many mediators are involved in airway remodeling, but matrix metalloproteinases (MMPs) are key players in this process in asthma. However, the role of TLR3 activation in production of MMPs is unknown. In this study, we examined the effects of polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3, on production of MMPs in human lung fibroblasts, with a focus on nitrosative stress in TLR3 modulation of MMP production. After lung fibroblasts were treated with poly(I:C), production of MMP-1, -2, and -9 and inducible NO synthase (iNOS) was assessed. The roles of NF-κB and IFN regulatory factor-3 (IRF-3) in the poly(I:C)-mediated production of MMPs and the responsiveness to poly(I:C) of normal lung fibroblasts and asthmatic lung fibroblasts were also investigated. Poly(I:C) augmented production of MMPs and iNOS in fibroblasts, and an iNOS inhibitor diminished this production of MMPs. Poly(I:C) stimulated translocation of NF-κB and IRF-3 into the nucleus in fibroblasts and inhibition of NF-κB or IRF-3 abrogated the poly(I:C)-induced increase in both iNOS expression and release of MMPs. Poly(I:C)-induced production of iNOS and MMPs was greater in asthmatic fibroblasts than in normal fibroblasts. We conclude that viral infection may induce nitrosative stress and subsequent MMP production via NF-κB- and IRF-3-dependent pathways, thus potentiating viral-induced airway remodeling in asthmatic airways.
Full-text · Article · Apr 2014 · The Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: There is increasing interest in the quantification of physical activity (PA) with an accelerometer for the management of chronic obstructive pulmonary disease (COPD). However, a detailed understanding of the PA in Japanese patients with COPD is lacking. We evaluated the levels of PA in terms of intensity in Japanese patients with COPD and evaluated the factors, which could influence the PA.
Forty-three outpatients with COPD and 21 age-matched healthy subjects were monitored with a triaxial accelerometer, and their PA was compared. Furthermore, the effects of pulmonary function, ADO index (age, dyspnea, and airflow obstruction) and modified BODE index (body mass index, airflow obstruction, dyspnea, and exercise capacity) on the PA were evaluated.
The PA in COPD was significantly reduced at all intensities. The reduced levels of PA in COPD were 23.1% at ≥2.0 metabolic equivalents (METs), 33.0% at ≥2.5 METs, 50.9% at ≥3.0 METs, and 66.9% at ≥3.5 METs, compared with that of healthy subjects, and the reduction was significant at GOLD stage III. The values of FVC, FEV1.0, and DLCO/VA were correlated with that of the PA, but the lung volume parameters were not. The ADO and modified BODE indices were also well correlated with the PA.
The reduced levels of PA in Japanese patients with COPD were objectively demonstrated in terms of intensity that could provide us a new target for the management of COPD.
[Show abstract][Hide abstract] ABSTRACT: Nitrative stress is thought to be involved in the inflammatory process in COPD airways, and the alveolar nitric oxide concentration (CAlv) has been reported to be increased. However, the CAlv levels are also regulated by gas diffusion at alveolar sites. The aim of the study was to assess the relationship between the CAlv and pulmonary function in COPD patients, while taking into account the lung diffusion capacity. Twenty stable COPD patients (GOLD stage1/2/3/4 = 6/8/6/0) and 16 healthy subjects took part in this cross-sectional study. Fractional exhaled nitric oxide (FENO), CAlv, and pulmonary functions were measured. Pulmonary function, including single nitrogen washout curve (dN2) and diffusion capacity for carbon monoxide (DLCO), was also evaluated in patients with COPD. The mean FENO levels (20.7 ppb versus 16.3 ppb, p < 0.05) and the mean CAlv levels (6.4 ppb versus 4.2 ppb, p < 0.01) in COPD patients were significantly increased compared to those in HS. The CAlv level in COPD was significantly correlated with dN2, %DLCO/alveolar volume (VA). Using the standard entry method of multivariate analysis to adjust for dN2 and %DLCO/VA, dN2 (β = 0.54, p = 0.005) and %DLCO/VA (β = -0.44, p = 0.018) still showed significant correlations with the CAlv levels. These results suggest that the CAlv could be a useful marker for the small airway dysfunction in COPD. Airway inflammation, including excess nitric oxide generation in the peripheral airways, might be related to the pathophysiology of COPD.
Full-text · Article · Oct 2013 · Journal of Breath Research
[Show abstract][Hide abstract] ABSTRACT: Background:
Recently, correlations of peak expiratory flow (PEF) variation have been shown to facilitate the prediction of later asthma symptoms and exacerbations. However, it has not been fully examined whether or not any patient characteristics are associated with the residual airway lability in treated asthmatics. The objective of this study is to examine a predictive marker for increased variation of PEF in patients with clinically stable asthma.
We studied 297 asthmatic patients who were monitored for PEF twice a day. Asthma Control Questionnaire (ACQ), spirometry, and exhaled nitric oxide fraction (FENO) were measured. After the assessment of baseline values, PEF measuring was continued and associations between these clinical markers and later variation of PEF over a week (Min%Max) were investigated.
17.5% of the subjects showed increased PEF variability (Min%Max < 80%). ACQ, forced expiratory volume in 1 s % of predicted (%FEV1), and FENO were identified as independent predictors of Min%Max < 80%. An ACQ ≥ 0.4 yielded 96% sensitivity and 59% specificity, a %FEV1 ≤ 85% yielded 62% sensitivity and 89% specificity, and a FENO ≥ 40 ppb yielded 75% sensitivity and 90% specificity for identifying the subjects with high variability in PEF. When we combine %FEV1 ≤ 85% and FENO ≥ 40 ppb, this index showed the highest specificity (98%) for increased PEF variability.
These results indicate that ACQ, %FEV1 and FENO can stratify the risk for increased variation in airway caliber among patients with stable asthma. This may help identify subjects in whom further monitoring of lung function fluctuations is indicated.
Full-text · Article · Jul 2013 · Allergology International
[Show abstract][Hide abstract] ABSTRACT: Persistent airway inflammation, detected by fractional exhaled nitric oxide (FENO), is occasionally observed in asthmatic patients, even in those treated with inhaled corticosteroids (ICS). However, improvement in residual airway inflammation and pulmonary function through modification of corticosteroid therapy has not been proven.
Thirteen asthmatic patients whose FENO levels were over 40 parts per billion (ppb), despite dry-powder ICS therapy, were enrolled. A 3-step change in steroid treatment was undertaken until FENO was less than 40ppb. In the first step, the powder formula was changed to an ultra-fine particle compound as an equipotent ICS dose. In the second step, the ICS dose was doubled. In the third step, oral corticosteroids were added. We measured pulmonary function and FENO and alveolar NO concentrations (CAlvNO).
Doubling the ICS dose and changing the ICS formula significantly improved FVC (p<0.001), FEV1 (p<0.05), the slope of the single nitrogen washout curve (dN2) (p<0.01), FENO (p<0.001), and CAlvNO (p<0.05), relative to baseline. The reductions in FENO were significantly associated with the improvement in airflow limitation assessed by dN2 (r=0.73, p=0.007). The remaining FENO elevation, even after doubling the ICS dose, did not decrease after oral corticosteroid administration.
These results suggest that modification of ICS therapy can suppress residual FENO elevation, and that reduction in FENO levels is associated with improvement in airflow limitation. However, steroid-resistance mechanisms may exist in some asthmatic patients with sustained FENO elevations.
[Show abstract][Hide abstract] ABSTRACT: Abnormal structural alterations termed remodeling, including fibrosis and alveolar wall destruction, are important features of the pathophysiology of chronic airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma. 25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase (CH25H) in macrophages and is reported to be involved in the formation of arteriosclerosis. We previously demonstrated that the expression of CH25H and production of 25HC were increased in the lungs of COPD. However, the role of 25-HC in lung tissue remodeling is unknown. In this study, we investigated the effect of 25-HC on fibroblast-mediated tissue remodeling using human fetal lung fibroblasts (HFL-1) in vitro. 25-HC significantly augmented α-smooth muscle actin (SMA) (P<0.001) and collagen I (P<0.001) expression in HFL-1. 25-HC also significantly enhanced the release and activation of matrix metallaoproteinase (MMP)-2 (P<0.001) and MMP-9 (P<0.001) without any significant effect on the production of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. 25-HC stimulated transforming growth factor (TGF)-β1 production (P<0.01) and a neutralizing anti-TGF-β antibody restored these 25-HC-augmented pro-fibrotic responses. 25-HC significantly promoted the translocation of nuclear factor (NF)-κB p65 into the nuclei (P<0.01), but not phospholylated-c-jun, a complex of activator protein-1. Pharmacological inhibition of NF-κB restored the 25-HC-augmented pro-fibrotic responses and TGF-β1 release. These results suggest that 25-HC could contribute to fibroblast-mediated lung tissue remodeling by promoting myofibroblast differentiation and the excessive release of extracellular matrix protein and MMPs via an NF-κB-TGF-β dependent pathway.
Full-text · Article · Feb 2013 · Experimental Cell Research
[Show abstract][Hide abstract] ABSTRACT: The relationship between allergic rhinitis and asthma is well accepted; however, little is known about the mechanism that underlies the interactions between the upper and lower airways.
To investigate the symptomatic and inflammatory linkages between allergic rhinitis and asthma in patients with atopy.
We enrolled 520 patients with asthma who were taking inhaled corticosteroids, and examined them by using the Asthma Control Questionnaire, spirometry, exhaled nitric oxide fraction (FENO), visual analog scale for nasal symptoms, allergic rhinitis questionnaire, and serum specific IgE (study 1). The symptomatic and inflammatory marker responses to nasal corticosteroids in patients with incompletely controlled asthma (Asthma Control Questionnaire > 0.75) and moderate-to-severe persistent allergic rhinitis were also observed (study 2).
A total of 348 patients (66.9%) had atopy and allergic rhinitis. There was a striking difference in the proportion of patients with incomplete asthma control, depending on the presence as well as the activity of rhinitis (no rhinitis, 11.0%; mild intermittent, 20.4%; moderate-to-severe intermittent, 44.6%; mild persistent, 53.1%; moderate-to-severe persistent, 65.7%). The FENO levels were increased with the activity of rhinitis, and the nasal visual analog scale was positively correlated with the FENO levels (r = 0.31; P < .0001). The additive treatment with nasal corticosteroids improved the nasal visual analog scale, Asthma Control Questionnaire, and FENO levels, and the changes in these variables were correlated with each other in all parameters (all P < .001).
This observational study of patients with atopy indicates that the ongoing allergic rhinitis is related to worsening of asthma by enhancing the lower airway inflammation.
[Show abstract][Hide abstract] ABSTRACT: 25-hydroxycholesterol (25-HC) is one of the oxysterols, which are oxidized derivatives of cholesterol, and has been reported to be involved in the pathogenesis of atherosclerosis and Alzheimer's disease. In lung, the possible involvement of 25-HC in airway diseases has been revealed. In the present study, we examined whether 25-HC affects the release of cytokines and also modulates the responses of toll-like receptor 3 (TLR3) in airway epithelial cells.
The effect of 25-HC on the release of cytokines from primary human bronchial epithelial cells after stimulation with or without polyinosine-polycytidylic acid [poly(I:C)], a ligand for TLR3, and the signal transduction were examined.
25-HC significantly potentiated the release of interleukin-8 (IL-8) and IL-6 from the cells. This effect was more potent compared with that of other oxysterols, 22-HC and 27-HC. GW3965 and TO901317, synthetic agonists of liver X receptors that are receptors for oxysterols, did not augment the IL-8 release. 25-HC enhanced the nuclear factor-kappa B (NF-κB) DNA binding activity and translocation of phosphorylated c-Jun into the nucleus. The release of IL-8 was inhibited by the NF-κB inhibitor, caffeic acid phenethyl ester (CAPE), an inhibitor of nuclear factor kappa-B alpha (IκBα) inhibitor, BAY 11-7085, and an inhibitor of nuclear factor kappa-B kinase-2 (IKK-2) inhibitor, SC-514, but not by a c-Jun N-terminal kinase (JNK) inhibitory peptide, L-JNKi1. 25-HC significantly potentiated IL-8 release in poly(I:C)-treated cells and the augmentation was inhibited by CAPE, BAY 11-7085, and SC-514. Furthermore, 25-HC potentiated the translocation of interferon regulatory factor 3 into the nucleus and the release of interferon-beta (IFN-β) in poly(I:C)-treated cells.
These data demonstrated that 25-HC augments the release of IL-8 and IL-6 via NF-κB signalling pathway and enhances the release of IL-8 and IFN-β after stimulation of TLR3 in airway epithelial cells. 25-HC may be involved in the neutrophilic airway inflammation through the stimulant effect of IL-8 and IL-6 release and also potentiate the TLR3-mediated innate immunity in airway diseases.
Full-text · Article · Jul 2012 · Respiratory research
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD). Recently, toll-like receptor 3 (TLR3) was shown to recognize pathogen-associated molecular patterns, especially viral-derived double-stranded RNA, and to be involved in immune responses. However, the effects of cigarette smoke on TLR3 remain unclear. In this study, it was examined whether cigarette smoke affects the expression and responses of TLR3 in human macrophages.
The expression of TLR3 in alveolar macrophages from human lung tissues was analysed by immunohistochemistry, and the correlation of TLR3 expression with smoking history and lung function was evaluated. In addition, the effect of cigarette smoke on the expression and responses of TLR3 in macrophage lineage cells was investigated.
TLR3-positive alveolar macrophage numbers were significantly increased in smokers and COPD patients compared with non-smoking control subjects, but there was no difference between smokers and COPD patients. TLR3-positive macrophage numbers were positively correlated with smoking history and inversely correlated with corrected carbon monoxide diffusing capacity, but were not correlated with % predicted forced expiratory volume in 1 s. Furthermore, cigarette smoke extract potentiated the expression of TLR3 in monocyte-derived macrophages and significantly augmented the release of interleukin-8, as well as total matrix metalloproteinase-9 activity, in cells treated with TLR3 ligand.
These data suggest that cigarette smoke augments the expression and responses of TLR3 in human macrophages, and this may contribute to neutrophilic airway inflammation and parenchymal destruction in the lungs of smokers and patients with COPD.
[Show abstract][Hide abstract] ABSTRACT: The fraction of exhaled nitric oxide (FENO) is reduced by anti-inflammatory treatment in asthma. However, the FENO level is also regulated by individual demographics and there is considerable variation among clinically stable patients.
We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma.
This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expiratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12-weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were examined (Study 2).
A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identifying the patients with poorly controlled asthma. The persistent high FENO group (≥ 40 p.p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups.
These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma.
[Show abstract][Hide abstract] ABSTRACT: 25-Hydroxycholesterol (25-HC) is produced from cholesterol by the enzyme cholesterol 25-hydroxylase and is associated with atherosclerosis of vessels. Recently, 25-HC was reported to cause inflammation in various types of tissues. The aim of this study was to assess the production of 25-HC in the airways and to elucidate the role of 25-HC in neutrophil infiltration in the airways of patients with chronic obstructive pulmonary disease (COPD).
Eleven control never-smokers, six control ex-smokers without COPD and 13 COPD patients participated in the lung tissue study. The expression of cholesterol 25-hydroxylase in the lung was investigated. Twelve control subjects and 17 patients with COPD also participated in the sputum study. The concentrations of 25-HC in sputum were quantified by liquid chromatography/mass spectrometry/mass spectrometry analysis. To elucidate the role of 25-HC in neutrophilic inflammation of the airways, the correlation between 25-HC levels and neutrophil counts in sputum was investigated.
The expression of cholesterol 25-hydroxylase was significantly enhanced in lung tissue from COPD patients compared with that from control subjects. Cholesterol 25-hydroxylase was localized in alveolar macrophages and pneumocytes of COPD patients. The concentration of 25-HC in sputum was significantly increased in COPD patients and was inversely correlated with percent of predicted forced vital capacity, forced expiratory volume in 1 s and diffusing capacity of carbon monoxide. The concentrations of 25-HC in sputum were significantly correlated with sputum interleukin-8 levels and neutrophil counts.
25-HC production was enhanced in the airways of COPD patients and may play a role in neutrophilic inflammation.
[Show abstract][Hide abstract] ABSTRACT: The anti-inflammatory effects of theophylline have been reported to include inhibition of the release of proinflammatory mediators from macrophages and neutrophils. Overproduction of reactive nitrogen species (RNS) has been reported in the airways of patients with chronic obstructive pulmonary disease (COPD), and this causes tissue inflammation and injury. We investigated whether peroxynitrite stimulated the release of matrix metalloproteinases 2 and 9 (MMP-2 and -9; gelatinases) from human fetal lung fibroblasts (HFL-1 cell line) and whether theophylline inhibited the peroxynitrite-augmented release of MMPs. HFL-1 cells and primary lung fibroblasts were treated with peroxynitrite (an RNS), and gelatinases levels were evaluated by gelatin zymography. The inhibitory effect of theophylline on the peroxynitrite-augmented release of MMP-2 and MMP-9 was also investigated. To explore the cell signaling pathways involved in the peroxynitrite-induced gelatinases release and the inhibitory effect of theophylline, transforming growth factor-β(1) (TGF-β(1)), nuclear factor-κB (NF-κB), and histone deacetylase (HDAC) were measured. Peroxynitrite significantly augmented the release of MMP-2 and MMP-9 by fibroblasts (P < 0.01), as well as TGF-β(1) release (P < 0.01), NF-κB activation (P < 0.01), and HDAC2 inactivation (P < 0.01). An NF-κB inhibitor diminished the RNS-augmented release of MMPs and TGF-β(1) (P < 0.01), and a neutralizing TGF-β antibody also diminished MMP release (P < 0.01). Theophylline significantly inhibited the peroxynitrite-augmented release of MMP-2 and MMP-9 in HFL-1 cells and normal adult lung fibroblasts, and it also inhibited the peroxynitrite-mediated HDAC2 inactivation, NF-κB activation, and TGF-β(1) release in HFL-1 cells (all P < 0.01). These results suggest that peroxynitrite can influence tissue remodeling by promoting gelatinases release, while theophylline suppresses peroxynitrite-induced tissue remodeling via pathways involving NF-κB/TGF-β(1) and/or HDAC in the HFL-1 cell line.
No preview · Article · Jan 2012 · AJP Lung Cellular and Molecular Physiology
[Show abstract][Hide abstract] ABSTRACT: 27-Hydroxycholesterol (27-OHC) is produced from cholesterol by sterol 27-hydroxylase as an intermediate in the biosynthesis pathway of bile acid. Recently, 27-OHC was reported to cause inflammation and apoptosis in various types of cells. The aim of this study was to assess the production of 27-OHC in the airways of patients with COPD and to elucidate the possible role of 27-OHC in the tissue fibrosis of COPD.
Lung tissues were obtained from six control subjects and six patients with COPD, and sputum samples were obtained from 11 healthy subjects and 15 patients with COPD. The expression of sterol 27-hydroxylase in the lung was investigated by immunohistochemistry. The amounts of 27-OHC in the sputum were quantified by the liquid chromatography-tandem mass spectrometry method. Because peribronchial fibrosis in peripheral airways is involved in the airflow limitation of COPD, we investigated the profibrotic effects of 27-OHC in vitro.
The expression of sterol 27-hydroxylase was significantly enhanced in the lung tissues of patients with COPD compared with control subjects. The amounts of 27-OHC in the sputum were significantly increased in the patients with COPD (P < .01), and the degree of 27-OHC production was negatively correlated with lung function (P < .01). 27-OHC augmented the differentiation of lung fibroblasts into myofibroblasts and the production of extracellular matrix protein through activation of nuclear factor-κB and subsequent transforming growth factor-β(1) upregulation.
27-OHC production is enhanced in the airways of patients with COPD and might be involved in the pathogenesis of COPD.