1.Correlation of pulmonary functions of COPD patients to those of their first-degree children.
Chinese Medical Journal 2003;116(7):991-995
OBJECTIVETo assess the risk factors correlating to the likelihood for airflow obstruction among first-degree children of chronic obstructive pulmonary disease (COPD) patients and whether familial aggregation of pulmonary function abnormality exists.
METHODSFifty-nine smokers with COPD and 28 smokers without COPD as control and all their children available were recruited into the study. Their history was recorded and a binary logistic regression analysis was carried out to ascertain the effects of their relationship to a proband with COPD, when other potential risk factors were controlled.
RESULTSChildren with COPD probands showed increased risk of FEV1 below the 70% predicted (OR = 1.987) after accounting for the effects of smoking, sex and clinical symptoms. The lower the pulmonary function of the COPD proband, the higher the risk to their children for FEV1 below the 70% predicted.
CONCLUSIONSOur finding demonstrates the presence of a household aggregation inclination of COPD and pulmonary function impairment. Genetic factors might act as the basis of the familial aggregation.
Aged ; Female ; Forced Expiratory Flow Rates ; Humans ; Lung ; physiopathology ; Male ; Pulmonary Disease, Chronic Obstructive ; genetics ; physiopathology ; Regression Analysis ; Smoking
2.Heme oxygenase-1 polymorphism associated with severity of chronic obstructive pulmonary disease.
Wei-Ping FU ; Zhi-Huan ZHAO ; Li-Zhou FANG ; Chang SUN ; Lin LIU ; Jian-Qin ZHANG ; Ya-Ping ZHANG ; Lu-Ming DAI
Chinese Medical Journal 2007;120(1):12-16
BACKGROUNDRecent studies have suggested that susceptibility to chronic obstructive pulmonary disease (COPD) might be related to the length polymorphism of (GT)(n) repeat in the 5'-flanking region of heme oxygenase-1 (HOX-1) gene. However, there has been no research about the relationship between the polymorphism of HOX-1 gene and severity of COPD.
METHODSThe polymorphism of HOX-1 gene in 452 patients with COPD from Han population in Southwest China was analysed by fragment analysis. The frequencies of the HOX-1 genotype were compared with the stage of COPD of each patient.
RESULTSThe HOX-1 genotypes were classified into two groups: group I were individuals with class L allele (the number of GT = 32 repeats), and group II were those without class L allele (the number of GT < 32 repeats). The genotypic frequency of the HOX-1 group I was significantly higher than group II in the very severe COPD patients (36.8% vs 22.4%, P < 0.01, OR = 2.0, 95% CI 1.3 - 3.1), while the genotypic frequency of the HOX-1 group II was lower in the mild COPD (16.0% vs 26.0%, P = 0.02, OR = 0.5, 95% CI 0.3 - 0.9). However, in moderate and severe stages COPD, there were similar genotypic frequencies between HOX-1 group I and group II.
CONCLUSIONSGenetic polymorphism in HOX-1 is associated with the severity of COPD in Southwest China. COPD patients with class L allele may be susceptible to develop very severe COPD. Conversely, the COPD patients without class L allele may be more easily stabilized on mild COPD.
Adult ; Aged ; Female ; Forced Expiratory Volume ; Genotype ; Heme Oxygenase-1 ; genetics ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Pulmonary Disease, Chronic Obstructive ; enzymology ; genetics ; physiopathology
3.Effect of polymorphisms in the β2-adrenergic receptor on the susceptibility and pulmonary function of patients with chronic obstructive pulmonary disease: a meta analysis.
Li-Ming NIU ; Ying LIANG ; Ming XU ; You-Yi ZHANG ; Yuan ZHANG ; Bei HE
Chinese Medical Journal 2012;125(12):2213-2218
BACKGROUNDChronic obstructive pulmonary disease (COPD) is a heterogeneous and complex disease of which the pathogenesis remains largely unknown. Many factors could influence COPD development and progression. One of them is the genetic risk factor. A severe hereditary deficiency of alpha-1 antitrypsin is the best genetic proof. Four single nucleotide polymorphisms (SNPs) of beta2-adrenergic receptor (β(2)AR) result in single amino acid substitution. Two loci had been extensively studied and found that they could change the function of β(2)AR. Two SNPs consist of substitutions of glycine for arginine at amino acid position 16, glutamic acid for glutamine at position 27. Many studies proved that polymorphisms at position 16 and 27 altered the lung function of COPD patients or the patient's susceptibility to the development of COPD. However, there was no exclusive conclusion. Therefore, a meta analysis was done to investigate the effect of polymorphisms in the β2-adrenergic receptor (ADRB2) gene on the risk of COPD and lung function.
METHODSComprehensive searches of MEDLINE, Embase, Ovid, HighWire, Cochrane Library, and Chinese databases (CBMdisc, VIP, CNKI, and Wanfang data) from January 1980 to September 2011 were performed, using the keywords: COPD OR chronic obstructive pulmonary disease AND adrenoreceptor OR adrenergic receptor AND polymorphism OR mutation OR variation. Case-control research or cross sectional studies in which diagnosis of COPD met the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines; all the studies reported the ADRB2 genotype at position 16 or 27. Outcomes measured were genotype frequency and forced expiratory volume in the first second (FEV(1)%) in both the case and control.
RESULTSTwelve case-control studies and eight cross-sectional studies were included. Compared to the control (n = 1225), neither Gly/Gly (n = 527) nor Arg/Arg (n = 422) homozygotes at position 16 demonstrated increased susceptibility to COPD, with odds ratios (ORs) of 0.95 (95%CI (0.68, 1.31), z = 0.33, P = 0.740) and 0.82 (95%CI (0.52, 1.28), z = 0.88, P = 0.381), respectively. Similar results were obtained for position 27, with ORs of 0.97 (95%CI (0.77, 1.23), z = 0.21, P = 0.833) for Glu/Glu homozygotes (n = 357) and 0.82 (95%CI (0.53, 1.29), z = 0.85, P = 0.393) for Gln/Gln homozygotes (n = 704) (control = 1183). In patients with COPD, Arg/Arg homozygotes (n = 41) had a similar FEV1% compared with Gly/Gly homozygotes (n = 102) (standardized mean difference (SMD) = 0.88, 95%CI (-0.85, 2.62), z = 1.00, P = 0.319). The genotype distribution was different between Caucasian and Asian populations (all P < 0.05 except the genotype Arg/Gly) for both position 16 and 27.
CONCLUSIONSPolymorphisms of ADRB2 at positions 16 and 27 did not change the risk of COPD nor affect lung function or disease severity. The genotype distribution for these polymorphisms was different between Caucasian and Asian populations.
Case-Control Studies ; Cross-Sectional Studies ; Forced Expiratory Volume ; physiology ; Genetic Predisposition to Disease ; genetics ; Humans ; Polymorphism, Genetic ; genetics ; Pulmonary Disease, Chronic Obstructive ; genetics ; physiopathology ; Receptors, Adrenergic, beta-2 ; genetics ; Respiratory Function Tests
4.Electroacupuncture at Feishu (BL13) and Zusanli (ST36) down-regulates the expression of orexins and their receptors in rats with chronic obstructive pulmonary disease.
Xin-fang ZHANG ; Ji ZHU ; Wen-ye GENG ; Shu-jun ZHAO ; Chuan-wei JIANG ; Sheng-rong CAI ; Miao CHENG ; Chuan-yun ZHOU ; Zi-bing LIU ; E-mail: ZIBINGLIU@163.COM.
Journal of Integrative Medicine 2014;12(5):417-424
OBJECTIVEInflammation and lung function decline are the main pathophysiological features of chronic obstructive pulmonary disease (COPD). Acupuncture can improve lung function in patients with COPD, but the underlying mechanisms are not well understood. Orexins (OXs), which are found in peripheral plasma, are neuropeptides that regulate respiration and their levels are related to COPD. Therefore, we hypothesized that acupuncture might alter OXs, reduce lung inflammation and improve lung function in COPD.
METHODSCOPD was induced in rats by exposure to cigarette smoke for 8 weeks and injecting with lipopolysaccharide twice. Electroacupuncture (EA) was performed at Feishu (BL13) and Zusanli (ST36) for 30 min/d for 2 weeks. Rat lung function and morphology were assessed after EA. The levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF) and orexin A and B levels in the lung tissue were detected by enzyme-linked immunosorbent assay. OX receptor mRNA levels and immunopositive cells were assessed with real-time polymerase chain reaction and immunohistochemical methods, respectively. The relationships among lung function, cell factors, and OX levels were analyzed by Pearson correlation analyses.
RESULTSCompared with the control group, lung function was significantly decreased in the rats with COPD (P<0.05). There were increases in TNF-α and IL-1β levels in BALF (P<0.05 and P<0.01, respectively), orexin A level in lung tissue (P<0.01; but not orexin B) and mRNA expressions of OX (OXR1) and OX 2 (OXR2) in lung tissue (P<0.05 and P<0.01, respectively); the integrative optical densities (IODs) of both receptors were greater in the COPD group (P<0.05). For rats with COPD subjected to EA, lung function was improved (P<0.05). There were notable decreases in TNF-α and IL-1β levels (P<0.05 and <0.01, respectively) in BALF. Orexin A, but not orexinB, levels in lung tissue also decreased (P<0.01), as did mRNA expression of OX1R and OX2R in lung tissue (P<0.05 and P<0.01, respectively). Receptor IODs were also reduced after EA treatment (P<0.05). Furthermore, orexin A levels and ratio of forced expiratory volume in 0.3 s to forced vital capacity were strongly negatively correlated (P<0.01), and orexin A was positively correlated with TNF-α and IL-1β (P<0.001 and P<0.05, respectively).
CONCLUSIONEA at Zusanli and Feishu improved lung function of rats with COPD and had an anti-inflammatory effect, which may be related to down-regulation of OXA and its receptors.
Animals ; Down-Regulation ; Electroacupuncture ; Interleukin-1beta ; analysis ; Intracellular Signaling Peptides and Proteins ; analysis ; genetics ; Lung ; physiopathology ; Male ; Neuropeptides ; analysis ; genetics ; Orexin Receptors ; analysis ; genetics ; Orexins ; Pulmonary Disease, Chronic Obstructive ; physiopathology ; therapy ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; analysis
5.Relationship of Vitamin D Binding Protein Polymorphisms and Lung Function in Korean Chronic Obstructive Pulmonary Disease.
Ji Ye JUNG ; Dong Pil CHOI ; Sungho WON ; Young LEE ; Ju Hye SHIN ; Young Sam KIM ; Se Kyu KIM ; Yeon Mok OH ; Il SUH ; Sang Do LEE
Yonsei Medical Journal 2014;55(5):1318-1325
PURPOSE: Multiple genetic factors are associated with chronic obstructive pulmonary disease (COPD). The association of gene encoding vitamin D binding protein (VDBP, GC) with COPD has been controversial. We sought to investigate the types of GC variants in the Korean population and determine the association of GC variants with COPD and lung function in the Korean population. MATERIALS AND METHODS: The study cohort consisted of 203 COPD patients and 157 control subjects. GC variants were genotyped by the restriction fragment-length polymorphism method. Repeated measures of lung function data were analyzed using a linear mixed model including sex, age, height, and pack-years of smoking to investigate the association of GC genetic factors and lung function. RESULTS: GC1F variant was most frequently observed in COPD (46.1%) and controls (42.0%). GC1S variant (29.0% vs. 21.4%; p=0.020) and genotype 1S-1S (8.3% vs. 3.4%; p=0.047) were more commonly detected in control than COPD. According to linear mixed model analysis including controls and COPD, subjects with genotype 1S-1S had 0.427 L higher forced expiratory volume in 1 second (FEV1) than those with other genotypes (p=0.029). However, interaction between the genotype and smoking pack-year was found to be particularly significant among subjects with genotype 1S-1S; FEV1 decreased by 0.014 L per smoking pack-year (p=0.001). CONCLUSION: This study suggested that GC polymorphism might be associated with lung function and risk of COPD in Korean population. GC1S variant and genotype 1S-1S were more frequently observed in control than in COPD. Moreover, GC1S variant was more common in non-decliners than in rapid decliners among COPD.
Aged
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Female
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Forced Expiratory Volume
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Genetic Predisposition to Disease
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Genotype
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Humans
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Male
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Middle Aged
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*Polymorphism, Genetic
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Pulmonary Disease, Chronic Obstructive/*genetics/physiopathology
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Respiratory Function Tests
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Smoking
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Vitamin D-Binding Protein/chemistry/*genetics
6.A Functional Polymorphism in the CHRNA3 Gene and Risk of Chronic Obstructive Pulmonary Disease in a Korean Population.
Jae Yeon LEE ; Seung Soo YOO ; Hyo Gyoung KANG ; Guang JIN ; Eun Young BAE ; Yi Young CHOI ; Jin Eun CHOI ; Hyo Sung JEON ; Jaehee LEE ; Shin Yup LEE ; Seung Ick CHA ; Chang Ho KIM ; Jae Yong PARK
Journal of Korean Medical Science 2012;27(12):1536-1540
A genome-wide association study has identified the 15q25 region as being associated with the risk of chronic obstructive pulmonary disease (COPD) in Caucasians. This study intended as a confirmatory assessment of this association in a Korean population. The rs6495309C > T polymorphism in the promoter of nicotinic acetylcholine receptor alpha subunit 3 (CHRNA3) gene was investigated in a case-control study that consisted of 406 patients with COPD and 394 healthy control subjects. The rs6495309 CT or TT genotype was associated with a significantly decreased risk of COPD when compared to the rs6495309 CC genotype (adjusted odds ratio = 0.69, 95% confidence interval = 0.50-0.95, P = 0.023). The effect of the rs6495309C > T on the risk of COPD was more evident in moderate to very severe COPD than in mild COPD under a dominant model for the variant T allele (P = 0.024 for homogeneity). The CHRNA3 rs6495309C > T polymorphism on chromosome 15q25 is associated with the risk of COPD in a Korean population.
Adult
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Aged
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Alleles
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Asian Continental Ancestry Group/*genetics
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Case-Control Studies
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Female
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Forced Expiratory Volume
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Genotype
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Humans
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Male
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Middle Aged
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Odds Ratio
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*Polymorphism, Single Nucleotide
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Pulmonary Disease, Chronic Obstructive/*genetics/physiopathology
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Receptors, Nicotinic/*genetics
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Republic of Korea
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Risk Factors
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Smoking
7.Inflammatory airway features and hypothalamic-pituitary-adrenal axis function in asthmatic rats combined with chronic obstructive pulmonary disease.
Cui CAI ; Hong-Ying ZHANG ; Jing-Jing LE ; Jing-Cheng DONG ; Yan CUI ; Chang-Qing XU ; Bao-Jun LIU ; Jin-Feng WU ; Xiao-Hong DUAN ; Yu-Xue CAO
Chinese Medical Journal 2010;123(13):1720-1726
BACKGROUNDBronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) are both inflammatory airway diseases with different characteristics. However, there are many patients who suffer from both BA and COPD. This study was to evaluate changes of inflammatory airway features and hypothalamic-pituitary-adrenal (HPA) axis function in asthmatic rats combined with COPD.
METHODSBrown Norway (BN) rats were used to model the inflammatory airway diseases of BA, COPD and COPD + BA. These three models were compared and evaluated with respect to clinical symptoms, pulmonary histopathology, airway hyperresponsiveness (AHR), inflammatory cytokines and HPA axis function.
RESULTSThe inflammatory airway features and HPA axis function in rats in the COPD + BA model group were greatly influenced. Rats in this model group showed features of the inflammatory diseases BA and COPD. The expression of inflammatory cytokines in this model group might be up or downregulated when both disease processes are present. The levels of corticotrophin releasing hormone mRNA and corticosterone in this model group were both significantly decreased than those in the control group (P < 0.05).
CONCLUSIONSBN rat can be used as an animal model of COPD + BA. By evaluating this animal model we found that the features of inflammation in rats in this model group seem to be exaggerated. The HPA axis functions in rats in this model group have been disturbed or impaired, which is prominent at the hypothalamic level.
Animals ; Asthma ; immunology ; pathology ; physiopathology ; Corticotropin-Releasing Hormone ; genetics ; Enzyme-Linked Immunosorbent Assay ; Hypothalamo-Hypophyseal System ; pathology ; Inflammation ; physiopathology ; Male ; Pituitary-Adrenal System ; pathology ; Pulmonary Disease, Chronic Obstructive ; immunology ; Rats ; Rats, Inbred BN
8.Increased expression of human calcium-activated chloride channel 1 is correlated with mucus overproduction in the airways of Chinese patients with chronic obstructive pulmonary disease.
Ke WANG ; Yu-Ling FENG ; Fu-Qiang WEN ; Xue-Rong CHEN ; Xue-Mei OU ; Dan XU ; Jie YANG ; Zhi-Pin DENG
Chinese Medical Journal 2007;120(12):1051-1057
BACKGROUNDChronic obstructive pulmonary disease (COPD) is usually complicated with mucus overproduction in airway. Recently the increased expression of the human calcium-activated chloride channel 1 (CaCC(1)) was found to play an important role in mucus overproduction in the asthmatic airways. To investigate the relationship of CaCC(1) and mucus overproduction in the airway of Chinese patients with COPD, the expressions of CaCC(1), MUC5AC and mucus in bronchial tissues were examined.
METHODSBronchial tissues were obtained from fiberoptic bronchoscopy and bronchial biopsy in West China Hospital from April to July in 2004. Twenty-five patients were diagnosed as the patients with COPD overproduction, and other 20 were the control subjects. The expressions of CaCC(1), MUC5AC and mucin in bronchial tissues were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization with digoxigenin (DIG)-labeled RNA probe, immunohistochemical and alcian blue-periodic acid Schiff (AB-PAS) staining, respectively.
RESULTSCompared with the control group, the stronger expressions of CaCC(1) were further detected throughout the bronchial tissues from patients with COPD (P < 0.01). Furthermore, the stronger expressions of the CaCC(1) mRNA were related to the severity of airflow obstruction. Samples from COPD showed a stronger staining for MUC5AC than those in control subjects (P < 0.01) and AB-PAS staining revealed more mucins in COPD patients' submucosal gland comparing with that in control subjects (P < 0.01). Expression levels of the CaCC(1) mRNA were respectively negatively correlated with the patients' forced expiratory volume in one second (FEV(1))/forced vital capacity (FVC) data, FEV(1)% predicted data, V(50)% predicted data, V(25)% predicted data (r = -0.43, r = -0.43, r = -0.35, r = -0.36, P < 0.01, P < 0.01, P < 0.05, P < 0.05). While the expression levels of the CaCC(1) mRNA were well correlated with the expression levels of the MUC5AC mRNA of airway epithelium and the PAS-AB stained area of submucosal glands (r = 0.39, r = 0.46, P < 0.05, P < 0.01). Expression levels of the MUC5AC mRNA were negatively correlated with the patients' FEV(1)/FVC data (P = 0.01), FEV(1)% pred data (P = 0.01), V(50)% predicted data, V(25)% predicted data (r = -0.53, r = -0.53, r = -0.48, r = -0.43, P < 0.01, P < 0.01, P < 0.01, P < 0.01). While the expression levels of the MUC5AC mRNA were well correlated with the positively PAS-AB stained area of submucosal gland (P < 0.05), and the correlation coefficients were 0.43.
CONCLUSIONThese results suggest that the stronger gene expression of CaCC(1) exists, complicated with mucus overproduction in the airway of Chinese patients with COPD.
Adult ; Aged ; Bronchi ; metabolism ; Chloride Channels ; genetics ; Female ; Forced Expiratory Volume ; Gene Expression Regulation ; Humans ; Male ; Middle Aged ; Mucin 5AC ; Mucins ; genetics ; Mucus ; physiology ; Pulmonary Disease, Chronic Obstructive ; metabolism ; physiopathology ; RNA, Messenger ; analysis ; Vital Capacity
9.Pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease and therapeutic effects of glucocorticoids and N-acetylcysteine in rats.
Ling XU ; Bai-Qiang CAI ; Yuan-Jue ZHU
Chinese Medical Journal 2004;117(11):1611-1619
BACKGROUNDT lymphocytes and matrix metalloproteinase (MMP) play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the details of the mechanisms involved are unclear. The aims of this study were to investigate the changes in interferon-gamma (IFN-gamma), interleukin-4 (IL-4), MMP-9, MMP-12 and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels in a smoke-induced COPD rat model and the therapeutic effects of glucocorticoids and N-acetylcysteine.
METHODSMale Wistar rats were exposed to cigarette smoke for 3.5 months. Budesonide or N-acetylcysteine was given in the last month. Lung function was measured at the end of the study. IL-4 and IFN-gamma levels were then determined in bronchoalveolar lavage fluid and lung tissue samples by enzyme-linked immunosorbent assay. The expression of MMP-9, MMP-12 and TIMP-1 mRNA in lung tissue was determined by RT-PCR.
RESULTSIn comparison with the control group, rats exposed to smoke had a significant increase in IL-4 and MMP-12 levels and a significant decrease in IFN-gamma levels. In addition, the IL-4/IFN-gamma ratio and MMP-12/TIMP-1 ratio were both higher. At the same time, the ratio of forced expiratory volume in 0.3 second to forced vital capacity (FEV(0.3)/FVC) and dynamic compliance (C(dyn)) decreased and expiratory resistance (Re) increased. By measuring pulmonary mean linear intercept and mean alveolar numbers, obvious emphysematous changes were observed in the smoke exposed group. After treatment with budesonide, IL-4 and MMP-12 decreased and IFN-gamma increased. The IL-4/IFN-gamma ratio returned to normal, though the MMP-12/TIMP-1 ratio remained unchanged. FEV(0.3)/FVC was significantly higher and Re was significantly lower than that in untreated smoke exposed rats. No significant differences were found in pulmonary mean linear intercept and mean alveolar numbers. After treatment with N-acetylcysteine, IFN-gamma increased and the IL-4/IFN-gamma ratio decreased. The MMP-12/TIMP-1 ratio remained unchanged. Re and C(dyn) both improved obviously. No significant differences were found in pulmonary mean linear intercept and mean alveolar numbers. Correlation analysis indicated that IL-4 levels in lung tissue correlated negatively with FEV(0.3)/FVC (r = -0.53, P = 0.001), IFN-gamma levels in lung tissue correlated negatively with Re (r = -0.63, P = 0.000) and positively with C(dyn) (r = 0.44, P = 0.009), and that the IL-4/IFN-gamma ratio correlated negatively with FEV(0.3)/FVC (r = -0.44, P = 0.010) and C(dyn) (r = -0.42, P = 0.015) and positively with Re (r = 0.58, P = 0.000). Finally, MMP-12 correlated negatively with FEV(0.3)/FVC (r = -0.36, P = 0.026).
CONCLUSIONSCigarette smoke exposure increases IL-4 levels and decreases IFN-gamma levels. This may be the result of smoke-induced changes in lung function. Budesonide can mitigate the changes in IL-4 and IFN-gamma levels induced by smoke exposure. N-acetylcysteine has no effect on IL-4, but increases IFN-gamma levels and brings the IL-4/IFN-gamma ratio back to normal. Cigarette smoke can also promote MMP-12 gene expression and elevate the MMP-12/TIMP-1 ratio. This effect may play a role in smoke-induced emphysema. Budesonide and N-acetylcysteine do not alter the MMP-12/TIMP-1 ratio in this study when given in the late phase of smoke exposure.
Acetylcysteine ; therapeutic use ; Animals ; Forced Expiratory Volume ; Glucocorticoids ; therapeutic use ; Interferon-gamma ; analysis ; physiology ; Interleukin-4 ; analysis ; physiology ; Lung ; pathology ; physiopathology ; Male ; Matrix Metalloproteinase 12 ; Metalloendopeptidases ; genetics ; Pulmonary Disease, Chronic Obstructive ; drug therapy ; etiology ; physiopathology ; Rats ; Rats, Wistar ; Smoking ; adverse effects ; Tissue Inhibitor of Metalloproteinase-1 ; genetics ; Vital Capacity