SLC11A1 Polymorphisms Are Associated with the Risk of Chronic Obstructive Pulmonary Disease in a Korean Population

The solute carrier family 11 member 1 (SLC11A1) protein plays important roles in macrophage activation and displays pleiotropic effects on various macrophage functions, including the regulation of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and oxidative burst. Considering the important roles of macrophage in the pathogenesis of chronic obstructive pulmonary disease (COPD), we hypothesized that the SLC11A1 gene may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, we first examined the frequencies of 12 candidate polymorphisms in the SLC11A1 gene in 27 healthy Korean individuals, and then genotyped 3 haplotype-tagging polymorphisms [IVS4 + 14G > C (rs3731865), D543 N (rs17235409), and (*)86A > G (rs1059823)] in 83 COPD patients and 203 healthy controls. Individuals with at least one variant allele of the D543 N and (*)86A > G polymorphisms were at a significantly increased risk for COPD compared with carriers with each homozygous wild-type allele [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.24-4.02, P = 0.007; and adjusted OR = 1.92, 95% CI = 1.10-3.35, P = 0.022, respectively]. Consistent with the findings of the genotyping analysis, the 122 haplotype carrying both the 543 N and (*)86G alleles was associated with a significantly increased risk for COPD compared with the 111 haplotype with the 542D and (*)86A alleles (adjusted OR = 2.05, 95% CI = 1.19-3.51, P = 0.009 and Bonferroni corrected P = 0.027). These findings suggest that the SLC11A1 polymorphisms could be used as markers for genetic susceptibility to COPD. However, further studies with large numbers of subjects are needed to confirm our findings.     

Association Between Single-Nucleotide Polymorphisms in Interleukin-12A and Risk of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction due to chronic bronchitis, emphysema, and/or disease of small airways. It has been reported that the genetic variation may play a role in the development and severity of COPD. The purpose of this study was to investigate whether single-nucleotide polymorphisms (SNP) in interleukin (IL)-12A and IL-12B were associated with COPD in a Chinese population. The IL-12A rs2243115 and IL-12B rs3212227 polymorphisms were genotyped by performing polymerase chain reaction-restriction fragment length polymorphism in 298 patients with COPD and 346 healthy controls. We observed that the frequencies of GT and GT+GG of IL-12A rs2243115 were significantly different from TT in the COPD group and the control group (GT vs. TT: odds ratio [OR]=2.35, 95% confidence interval [CI]=1.55-3.57, p<0.001; GT+GG vs. TT: OR=2.46, 95% CI=1.63-3.71, p<0.001). These data suggest that the IL-12A rs2243115 polymorphism may contribute to genetic susceptibility to COPD in a Chinese population.     

Association of GNLY Genetic Polymorphisms with Chronic Liver Disease in a Korean Population

Granulysin (GNLY) is found in cytotoxic granules of cytolytic T lymphocytes and natural killer (NK) cells, which are critical for hepatitis B virus (HBV) clearance. GNLY cytotoxicity plays an important role in the defense against viruses or intracellular bacteria. We hypothesized that genetic variation in the GNLY gene could affect the resistance of hosts against HBV infection. We compared the distribution frequencies of GNLY polymorphisms between an HBV-induced chronic liver disease (CLD) group and a spontaneous recovery (SR) control group to determine whether GNLY polymorphisms play a role in HBV clearance. A total of 117 patients in the SR group and 230 patients in the CLD group were enrolled. Samples derived from complex infections, including hepatitis C and human immunodeficiency virus, and those associated with insufficient clinical information (10 samples in SR and 24 samples in CLD) were excluded from the study. The final analysis included 107 SR and 206 CLD samples. DNA was extracted from peripheral blood, and GNLY genotypes were determined by the GoldenGate(?) method. The genotype distribution of the single-nucleotide polymorphisms (SNPs) rs2886767 (C>T), rs1561285 (G>C), and rs11127 (T>C) were significantly different between the SR and CLD groups in a recessive model (p<0.015). These three SNPs were in a complete linkage disequilibrium (LD) block. Diplotype distributions of haplotype (HT) 1 (C-G-T) and HT2 (T-C-C) were significantly different between the SR and CLD groups in a recessive model (p=0.025) and a dominant model (p=0.008). All p-values remained significant after multiple comparisons. GNLY polymorphism genotypes and diplotypes were associated with the chronicity of HBV. These data suggested that genetic variation of GNLY may be an important factor in HBV clearance through the CD8+ T or NK cell-mediated removal of HBV-infected cells from the host.     

Genetic Polymorphisms of Cytochrome P450 and Matrix Metalloproteinase in Chronic Obstructive Pulmonary Disease

We investigated whether polymorphisms of cytochrome P450 (CYP) and matrix metalloproteinase (MMP) are associated with the development and severity of chronic obstructive pulmonary disease (COPD). Genotypes of 184 patients with COPD and 212 controls were determined by polymerase chain reaction, followed by restriction fragment length polymorphism. The homozygous T allele of MMP-9 was significantly higher in patients with COPD than in controls (14.7% vs. 7.5%). The odds ratio was 2.4 (95% CI 1.1–5.9). No differences were observed in the frequency of polymorphic genotypes in CYP1A1, 1A2, MMP-1 and -3. During combined analysis of these candidate genes, we found strong indicators for susceptibility to COPD (combined with homozygotes *2A for CYP1A1 and T alleles of MMP-9 versus others = 3.3, 95% CI 1.2–8.6). The frequency of the homozygous *2A allele of CYP1A1 was significantly higher in very severe COPD (P < 0.01). Combinations of genetic variants including *2A homozygotes of CYP1A1 and T alleles in MMP-9 are significant indicators for susceptibility to COPD. The homozygous *2A allele of CYP1A1 is an independent risk factor for very severe COPD.     

Cluster Analysis in Patients with GOLD 1 Chronic Obstructive Pulmonary Disease

Background

We hypothesized that heterogeneity exists within the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 spirometric category and that different subgroups could be identified within this GOLD category.

Methods

Pre-randomization study participants from two clinical trials were symptomatic/asymptomatic GOLD 1 chronic obstructive pulmonary disease (COPD) patients and healthy controls. A hierarchical cluster analysis used pre-randomization demographics, symptom scores, lung function, peak exercise response and daily physical activity levels to derive population subgroups.

Results

Considerable heterogeneity existed for clinical variables among patients with GOLD 1 COPD. All parameters, except forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC), had considerable overlap between GOLD 1 COPD and controls. Three-clusters were identified: cluster I (18 [15%] COPD patients; 105 [85%] controls); cluster II (45 [80%] COPD patients; 11 [20%] controls); and cluster III (22 [92%] COPD patients; 2 [8%] controls). Apart from reduced diffusion capacity and lower baseline dyspnea index versus controls, cluster I COPD patients had otherwise preserved lung volumes, exercise capacity and physical activity levels. Cluster II COPD patients had a higher smoking history and greater hyperinflation versus cluster I COPD patients. Cluster III COPD patients had reduced physical activity versus controls and clusters I and II COPD patients, and lower FEV₁/FVC versus clusters I and II COPD patients.

Conclusions

The results emphasize heterogeneity within GOLD 1 COPD, supporting an individualized therapeutic approach to patients.

Trial registration

www.clinicaltrials.gov. NCT01360788 and NCT01072396.     

Association of GSTM1 and GSTT1 with ageing in auto repair shop workers

We evaluated the possible influence of glutathione S-transferase mu (GSTM1) and glutathione S-transferase theta (GSTT1) genes on genetic damage due to occupational exposure, which contributes to accelerate ageing. This study was conducted on 120 car auto repair workshop workers exposed to occupational hazards and 120 controls without this kind of exposure. The null and non-null genotypes of GSTM1 and GSTT1 genes were determined by multiplex PCR. Micronucleus frequency, Comet tail length and relative telomere length differences between the null and non-null genotypes of the GSTM1 gene were significantly greater in the exposed group. Lack of GSTT1 did not affect the damage biomarkers significantly (P > 0.05), while lack of GSTM1 was associated with greater susceptibility to genomic damage due to occupational exposure. It was concluded that early ageing is under the influence of these genes and the environmental and socio-demographic factors. Duration of working time was significantly associated with micronucleus frequency, Comet tail length and relative telomere length.     

Association of PON1 and PON2 Polymorphisms with PON1 Activity and Significant Coronary Stenosis in a Tunisian Population

PON1 and PON2 have attracted considerable attention as candidate genes for coronary heart disease because their enzymes function as key factors in lipoprotein catabolism pathways. We studied the distribution of PON1 and PON2 polymorphisms, including genotyping, lipid profile, and PON1 activity, and their association with PON1 activity and significant coronary stenosis (SCS) in a Tunisian population. PON1 activity was lower in patients with SCS than in controls. It increased with the R allele (QQ < QR < RR) in PON1-192 genotypes and with the L allele (MM < ML < LL) in PON1-55 genotypes. In the presence of metabolic syndrome and diabetes, PON1-192RR and PON2-311CC were associated with an increased risk of SCS and PON1-55MM seems to have lower risk. This association was evident among nonsmokers for PON1-55MM and among smokers for PON1-192RR and PON2-311CC. The GTGC haplotype seemed to increase the risk of SCS compared with the wild haplotype in a Tunisian population.     

Systemic and Pulmonary Vascular Remodelling in Chronic Obstructive Pulmonary Disease

BackgroundChronic Obstructive Pulmonary Disease (COPD) is associated with subclinical systemic atherosclerosis and pulmonary vascular remodelling characterized by intimal hyperplasia and luminal narrowing. We aimed to determine differences in the intimal thickening of systemic and pulmonary arteries in COPD subjects and smokers. Secondary aims include comparisons with a non-smokers group; determining the clinical variables associated with systemic and pulmonary intimal thickening, and the correlations between systemic and pulmonary remodelling changes.MethodsAll consecutive subjects undergoing lung resection were included and divided into 3 groups: 1) COPD, 2) smokers, and 3) non-smokers. Sections of the 5th intercostal artery and muscular pulmonary arteries were measured by histo-morphometry. Four parameters of intimal thickening were evaluated: 1) percentage of intimal area (%IA), 2) percentage of luminal narrowing, 3) intimal thickness index, and 4) intima-to-media ratio.ResultsIn the adjusted analysis, the systemic arteries of COPD subjects showed greater intimal thickening (%IA) than those of smokers (15.6±1.5% vs. 14.2±1.6%, p = 0.038). In the pulmonary arteries, significant differences were observed for %IA between the 2 groups (37.3±2.2% vs. 29.3±2.3%, p = 0.016). Among clinical factors, metabolic syndrome, gender and COPD status were associated with the systemic intimal thickening, while only COPD status was associated with pulmonary intimal thickening. A correlation between the %IA of the systemic and pulmonary arteries was observed (Spearman’s rho = 0.46, p = 0.008).ConclusionsGreater intimal thickening in systemic and pulmonary arteries is observed in COPD patients than in smokers. There is a correlation between systemic and pulmonary vascular remodelling in the overall population.     

Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease

Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV(1) and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV(1) and accelerated decline of FEV(1) and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV(1) level. Eleven out of 17 SNPs were associated with FEV(1) decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.     

Associations of ABHD2 Genetic Variations with Risks for Chronic Obstructive Pulmonary Disease in a Chinese Han Population

The human α/β hydrolase domain-containing protein 2 gene (ABHD2) plays a critical role in pulmonary emphysema, a major subset of the clinical entity known as chronic obstructive pulmonary disease (COPD). Here, we evaluated genetic variation in the ABHD2 gene in a Chinese Han population of 286 COPD patients and 326 control subjects. The rs12442260 CT/CC genotype was associated with COPD (P < 0.001) under a dominant model. In the former-smoker group, the rs12442260 TT genotype was associated with a decreased risk of developing COPD after adjusting for age, gender and pack-years (P = 0.012). Rs12442260 was also associated with pre-FEV1 (the predicted bronchodilator forced expiratory volume in the first second) in controls (P = 0.027), but with FEV1/ forced vital capacity (FVC) ratios only in COPD patients (P = 0.012) under a dominant model. Results from the current study suggest that ABHD2 gene polymorphisms contribute to COPD susceptibility in the Chinese Han population.     

Functional Polymorphisms of CHRNA3 Predict Risks of Chronic Obstructive Pulmonary Disease and Lung Cancer in Chinese

Recently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, reflecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14–1.54) and lung cancer (OR = 1.57; 95% CI = 1.31–1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13–1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.     

Epicardial Adipose Tissue in Patients with Chronic Obstructive Pulmonary Disease

Rationale

Epicardial Adipose Tissue (EAT) volume as determined by chest computed tomography (CT) is an independent marker of cardiovascular events in the general population. COPD patients have an increased risk of cardiovascular disease, however nothing is known about the EAT volume in this population.

Objectives

To assess EAT volume in COPD and explore its association with clinical and physiological variables of disease severity.

Methods

We measured EAT using low-dose CT in 171 stable COPD patients and 70 controls matched by age, smoking history and BMI. We determined blood pressure, cholesterol, glucose and HbA1c levels, microalbuminuria, lung function, BODE index, co-morbidity index and coronary artery calcium score (CAC). EAT volume were compared between groups. Uni and multivariate analyses explored the relationship between EAT volume and the COPD related variables.

Results

COPD patients had a higher EAT volume [143.7 (P_25–75, 108.3–196.6) vs 129.1 (P_25–75, 91.3–170.8) cm³, p = 0.02)] and the EAT volume was significantly associated with CAC (r = 0.38, p<0.001) and CRP (r = 0.32, p<0.001) but not with microalbuminuria (r = 0.12, p = 0.13). In COPD patients, EAT volume was associated with: age, pack-years, BMI, gender, FEV₁%, 6 MWD, MMRC and HTN. Multivariate analysis showed that only pack-years (B = 0.6, 95% CI: 0.5–1.3), BMI (B = 7.8, 95% CI: 5.7–9.9) and 6 MWD (B = −0.2, 95% CI: −0.3–−0.1), predicted EAT volume.

Conclusions

EAT volume is increased in COPD patients and is independently associated with smoking history, BMI and exercise capacity, all modifiable risk factors of future cardiovascular events. EAT volume could be a non-invasive marker of COPD patients at high risk for future cardiovascular events.     

The Association of Health Literacy with Illness and Medication Beliefs among Patients with Chronic Obstructive Pulmonary Disease

Background

Low health literacy is associated with low adherence to self-management in many chronic diseases. Additionally, health beliefs are thought to be determinants of self-management behaviors. In this study we sought to determine the association, if any, of health literacy and health beliefs among elderly individuals with COPD.

Methods

We enrolled a cohort of patients with COPD from two academic urban settings in New York, NY and Chicago, IL. Health literacy was measured using the Short Test of Functional Health Literacy in Adults. Using the framework of the Self-Regulation Model, illness and medication beliefs were measured with the Brief Illness Perception Questionnaire (B-IPQ) and Beliefs about Medications Questionnaire (BMQ). Unadjusted analyses, with corresponding Cohen’s d effect sizes, and multiple logistic regression were used to assess the relationships between HL and illness and medication beliefs.

Results

We enrolled 235 participants, 29% of whom had low health literacy. Patients with low health literacy were more likely to belong to a racial minority group (p<0.001), not be married (p = 0.006), and to have lower income (p<0.001) or education (p<0.001). In unadjusted analyses, patients with low health literacy were less likely to believe they will always have COPD (p = 0.003, Cohen’s d = 0.42), and were more likely to be concerned about their illness ((p = 0.04, Cohen’s d = 0.17). In analyses adjusted for sociodemographic factors and other health beliefs, patients with low health literacy were less likely to believe that they will always have COPD (odds ratio [OR]: 0.78, 95% confidence interval [CI]: 0.65–0.94). In addition, the association of low health literacy with expressed concern about medications remained significant (OR: 1.20, 95% CI: 1.05–1.37) though the association of low health literacy with belief in the necessity of medications was no longer significant (OR: 0.92, 95% CI: 0.82–1.04).

Conclusions

In this cohort of urban individuals with COPD, low health literacy was prevalent, and associated with illness beliefs that predict decreased adherence. Our results suggest that targeted strategies to address low health literacy and related illness and medications beliefs might improve COPD medication adherence and other self-management behaviors.     

Association between Psoriasis and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis

Psoriasis is considered a systemic inflammatory disorder. Previous studies have reported conflicting positive or negative correlations between psoriasis and chronic obstructive pulmonary disease. We performed a meta-analysis to determine whether there is an associated risk between psoriasis and chronic obstructive pulmonary disease. We performed a complete 30-year literature search of MEDLINE, Embase, and Cochrane Central Register databases on this topic. Four observational studies with a total of 13,418 subjects were identified. The odds ratios of chronic obstructive pulmonary disease in subjects with psoriasis/mild-to-moderate psoriasis were analyzed using the random-effects model, while the odds ratios of chronic obstructive pulmonary disease in subjects with severe psoriasis and current smoking in subjects with psoriasis were analyzed using the fixed-effect model. We found that psoriasis patients were at a greater risk of developing chronic obstructive pulmonary disease than the general population (odds ratio, 1.90; 95% confidence interval, 1.36–2.65) and that the association between of psoriasis and with chronic obstructive pulmonary disease was stronger among patients with severe psoriasis (odds ratio, 2.15; 95% confidence interval, 1.26–3.67). Psoriasis patients should be advised to cease smoking to reduce their risk of COPD. Moreover, identification of this potential risk may enable earlier implementation of preventive measures for reduction comorbidity and mortality rates.     

Oxygen Therapy Use in Older Adults with Chronic Obstructive Pulmonary Disease

Rationale

Oxygen therapy improves survival and function in severely hypoxemic chronic obstructive pulmonary disease (COPD) patients based on two landmark studies conducted over 40 years ago. We hypothesize that oxygen users in the current era may be very different. We examined trends and subject characteristics associated with oxygen therapy use from 2001–2010 in the United States.

Methods

We examined Medicare beneficiaries with COPD who received oxygen from 2001 to 2010. COPD subjects were identified by: 1) ≥2 outpatient visits >30 days apart within one year with an encounter diagnosis of COPD; or 2) an acute care hospitalization with COPD as the primary or secondary discharge diagnosis. Oxygen therapy and sustained oxygen therapy were defined as ≥1 and ≥11 claims for oxygen, respectively, in the durable medical equipment file in a calendar year. Primary outcome measures were factors associated with oxygen therapy and sustained oxygen therapy over the study period.

Results

Oxygen therapy increased from 33.7% in 2001 to 40.5% in 2010 (p-value of trend <0.001). Sustained oxygen therapy use increased from 19.5% in 2001, peaked in 2008 to 26.9% and declined to 18.5% in 2010. The majority of subjects receiving oxygen therapy and sustained oxygen therapy were female. Besides gender, factors associated with any oxygen use or sustained oxygen therapy were non-Hispanic white race, low socioeconomic status and ≥2 comorbidities.

Conclusions

Any oxygen use among fee-for service Medicare beneficiaries with COPD is high. Current users of oxygen are older females with multiple comorbidities. Decline in sustained oxygen therapy use after 2008 may be related to reimbursement policy change.     

Predicting Daily Physical Activity in Patients with Chronic Obstructive Pulmonary Disease

Background

Objectively measuring daily physical activity (PA) using an accelerometer is a relatively expensive and time-consuming undertaking. In routine clinical practice it would be useful to estimate PA in patients with chronic obstructive pulmonary disease (COPD) with more simple methods.

Objectives

To evaluate whether PA can be estimated by simple tests commonly used in clinical practice in patients with COPD.

Methods

The average number of steps per day was measured for 7 days with a SenseWear Pro™ accelerometer and used as gold standard for PA. A physical activity level (PAL) of <1.4 was considered very inactive. Univariate and multivariate analyses were used to examine the relationship between the 6-minute walking distance (6MWD), the number of stands in the Sit-to-Stand Test (STST), hand-grip strength and the total energy expenditure as assessed by the Zutphen Physical Activity Questionnaire (TEE_ZPAQ). ROC curve analysis was used to identify patients with an extremely inactive lifestyle (PAL<1.4).

Results

In 70 patients with COPD (21 females) with a mean [SD] FEV₁ of 43.0 [22.0] %predicted, PA was found to be significantly and independently associated with the 6MWD (r = 0.69, 95% CI 0.54 to 0.80, p<0.001), STST (r = 0.51, 95% CI 0.31 to 0.66, p = 0.001) and TEEZPAQ (r = 0.50, 95% CI 0.30 to 0.66, p<0.001) but not with hand-grip strength. However, ROC curve analysis demonstrated that these tests cannot be used to reliably identify patients with an extremely inactive lifestyle.

Conclusions

In patients with COPD simple tests such as the 6-Minute Walk Test, the Sit-to-Stand Test and the Zutphen Physical Activity Questionnaire cannot be used to reliably predict physical inactivity.     

慢性阻塞性肺病大鼠模型的建立和比较评估

目的:动态观察运用不同方法建立的两种实验性大鼠慢性阻塞性肺疾病(COPD)模型并比较评估两组模型的特点.方法:分别采用单纯被动吸烟(单一组)和被动吸烟与细菌内毒素(LPS)气管注入的复合方法(复合组)制造大鼠COPD模型,运用HE染色及半定量图像分析法对比研究两组模型肺组织及小支气管的病理形态学改变.结果:建立的COPD大鼠模型均符合人类COPD的病理形态学特点;复合组的气道慢性炎症、重塑改变及气流阻塞情况均较单一组严重;单一组、复合组模型各时间段管壁及平滑肌层均较正常对照组显著增厚(P＜0.01),第20天时复合组管壁及平滑肌层均较单一组显著增厚(P＜0.01),而第40天及60天时复合组仅管壁较单一组显著增厚(P＜0.01).结论:COPD模型的形成是由于慢性气道炎症的反复刺激引起管壁纤维性增生增厚及平滑肌层增厚,即气道重塑,最终导致气流受限;复合组COPD模型的气道炎症及气道重塑均较单一组COPD模型显著.