[Show abstract][Hide abstract] ABSTRACT: To determine if nuclear factor-kappaB (NF-kappaB) activation may be a key factor in lung inflammation and respiratory dysfunction, we investigated whether NF-kappaB can be blocked by intratracheal administration of NF-kappaB decoy oligodeoxynucleotides (ODNs), and whether decoy ODN-mediated NF-kappaB inhibition can prevent smoke-induced lung inflammation, respiratory dysfunction, and improve pathological alteration in the small airways and lung parenchyma in the long-term smoke-induced mouse model system. We also detected changes in transcriptional factors. In vivo, the transfection efficiency of NF-kappaB decoy ODNs to alveolar macrophages in BALF was measured by fluorescein isothiocyanate (FITC)-labeled NF-kappaB decoy ODNs and flow cytometry post intratracheal ODN administration. Pulmonary function was measured by pressure sensors, and pathological changes were assessed using histology and the pathological Mias software. NF-kappaB and activator protein 1(AP-1) activity was detected by the electrophoretic motility shift assay (EMSA). Mouse cytokine and chemokine pulmonary expression profiles were investigated by enzyme-linked immunosorbent assay (ELISA) in bronchoalveolar lavage fluid (BALF) and lung tissue homogenates, respectively, after repeated exposure to cigarette smoke. After 24 h, the percentage of transfected alveolar macrophages was 30.00 +/- 3.30%. Analysis of respiratory function indicated that transfection of NF-kappaB decoy ODNs significantly impacted peak expiratory flow (PEF), and bronchoalveolar lavage cytology displayed evidence of decreased macrophage infiltration in airways compared to normal saline-treated or scramble NF-kappaB decoy ODNs smoke exposed mice. NF-kappaB decoy ODNs inhibited significantly level of macrophage inflammatory protein (MIP) 1alpha and monocyte chemoattractant protein 1(MCP-1) in lung homogenates compared to normal saline-treated smoke exposed mice. In contrast, these NF-kappaB decoy ODNs-treated mice showed significant increase in the level of tumor necrosis factor-alpha(TNF-alpha) and pro-MMP-9(pro-matrix metalloproteinase-9) in mice BALF. Further measurement revealed administration of NF-kappaB decoy ODNs did not prevent pathological changes. These findings indicate that NF-kappaB activation play an important role on the recruitment of macrophages and pulmonary dysfunction in smoke-induced chronic lung inflammation, and with the exception of NF-kappaB pathway, there might be complex mechanism governing molecular dynamics of pro-inflammatory cytokines expression and structural changes in small airways and pulmonary parenchyma in vivo.
Respiratory research 09/2009; 10(1):79. DOI:10.1186/1465-9921-10-79 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effects of oral appliance (OA) treatment upon systemic blood pressure (BP) in mild to moderate patients with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Forty-six consecutive patients diagnosed with OSAHS on polysomnography were divided into OA treatment group (OA group, 25 patients, 15 patients with hypertension) and non-tolerated OA treatment group (N-OA group, 21 patients, 13 patients with hypertension). Polysomnography and 24-hour ambulatory blood pressure monitoring (ABPM) were performed at baseline in two groups. Polysomnography and ABPM were repeated after a completion of 12 weeks of treatment in OA group and after a cessation of treatment for 12 weeks in N-OA group. Hypertensive patients in two groups continued taking the same kind and the same dose of antihypertensive agents during the period of study.
There was no significant difference between the two groups in age, body mass index, Epworth sleepiness score (ESS), apnoea-hypopnoea index (AHI), arousal index (AI) and minimum arterial oxygen saturation (MSaO2) at baseline. After a 12-week treatment, OA group showed significant improvement in AHI [(7.0 +/- 3.8) vs (21.0 +/- 6.5) per hour, P < 0.01], AI [(22.9 +/- 6.3) vs (32.2 +/- 9.3) per hour, P < 0.01] and MSaO2 (86.8% +/- 3.5% vs 80.0% +/- 5.2%, P < 0.01), while nocturnal mean systolic blood pressure (SBP) and diastolic blood pressure (DBP), 24-hour and diurnal SBP, and nocturnal mean artery pressure (MAP) were significantly reduced [(121.3 +/- 7.0) vs (125.3 +/- 9.3), (76.1 +/- 6.1) vs (78.8 +/- 6.8), (127.2 +/- 7.5) vs (129.4 +/- 8.8), (131.5 +/- 6.9) vs (133.6 +/- 8.1), and (91.2 +/- 6.4) vs (94.3 +/- 7.6) mm Hg respectively, all P < 0.01]. The reduction in nocturnal MAP was significantly correlated to improvement in AI(r = 0.37, P = 0.005) and AHI (r = 0.32, P = 0.011), to baseline nocturnal mean blood pressure (SBP: r = 0.39, P = 0.015; DBP: r = 0.30, P = 0.024). The N-OA group showed no differences in blood pressure variables between baseline and after a cessation of treatment for 12 weeks.
Oral appliance treatment for mild to moderate OSAHS may lead to a reduction in systemic blood pressure.
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoke-triggered inflammation is important in the pathophysiology of chronic obstructive pulmonary disease, and involves overexpression of many proinflammatory genes. Transcription factors regulating expression of inflammatory mediators may play a key role in characterizing the disease. To observe alterations in pulmonary function, observe pathological changes in lung tissues, and detect changes in transcriptional factors, mice were exposed to 30 days of cigarette smoke. Pulmonary function was measured by pressure sensors, and pathological changes were observed in lung tissue sections. Nuclear factor (NF)-kappaB and AP-1 activities were detected by electrophoretic mobility shift assay (EMSA). The levels of inflammatory mediators tumor necrosis factor (TNF)-alpha, interleukin(IL)-6, and IL-8 in bronchoalveolar lavage fluid (BALF) were measured using enzyme-linked immunosorbent assay (ELISA). Pulmonary function was not markedly decreased after 30 days of smoke exposure. Exposure to this regimen of cigarette smoke induced peribronchial and perivascular lymphocytic aggregates and parenchymal accumulation of macrophages in mice. EMSA demonstrated that smoke exposure enhanced activator protein (AP)-1 DNA binding activation, but only slightly changed NF-kappaB activation in mouse lung. Compared to the control group, smoke exposure induced a notable increase in TNF-alpha in BALF. These data demonstrated that subacute smoke-triggered lung inflammation was accompanied by inflammatory cell influx, AP-1 activation, and proinflammatory gene overexpression in mouse lungs.
[Show abstract][Hide abstract] ABSTRACT: To investigate whether obstructive sleep apnea/hypopnea syndrome (OSAHS) is independently associated with insulin resistance (IR).
We recruited 60 male obese patients with OSAHS [OSAHS group, age (42.3 +/- 2.6) years, body mass index (BMI) (28.3 +/- 2.1) kg/m2, waist/hip ratio (WHR) 0.95 +/- 0.05], 60 male weight-matched obese patients without OSAHS [OB group, age (41.5 +/- 3.1) years, BMI (27.7 +/- 1.5) kg/m2, WHR 0.94 +/- 0.04] and 60 male normal weight subjects [NW group, age (41.8 +/- 2.4) years, BMI (22.6 +/- 1.9) kg/m2, WHR 0.86 +/- 0.05]. The subjects underwent polysomnography and OSAHS was defined as an apnea-hypopnea index (AHI) > or = 5. The systolic blood pressure and diastolic blood pressure were measured. IR was evaluated by fasting serum true insulin (TI) level and IR index based on the homeostasis model assessment method (HOMA-IR). In the OSAHS group, multiple linear regression was used with either TI or HOMA-IR as the dependent variable, and the corresponding set of independent variables included age, BMI, WHR, AHI and minimum oxygen saturation (MSpO2).
After adjustment for age, BMI, and WHR, the OSAHS group was more insulin resistant, as indicated by the higher levels of TI and HOMA-IR. Multiple linear regression showed that the central obesity parameter (WHR) was the major determinant of IR of the OSAHS group, while sleep-disordered breathing parameters (AHI and MSpO2) were also independent determinants of IR of the group (TI: AHI P = 0.017, TI: MSpO2 P = 0.005; HOMA-IR: AHI P = 0.008, HOMA-IR: MSpO2 P = 0.003).
OSAHS may be independently associated with IR.
Zhonghua nei ke za zhi [Chinese journal of internal medicine] 04/2006; 45(3):184-7.
[Show abstract][Hide abstract] ABSTRACT: To investigate the changes of leukotriene B(4) (LTB(4)) in induced sputum and plasma of patients with chronic obstructive pulmonary disease (COPD) and the effects of theophylline.
The investigation was a prospective, randomized controlled trial. Forty stable COPD patients (group C) were randomized into a subgroup receiving oral theophylline 0.2 g twice a day for one month (group CA) and a subgroup receiving no theophylline (group CB). Fifteen age-matched healthy non-smokers (group H) were included as controls. The following measurements were performed at baseline for each group and one month later for group C: symptom and life quality scores, pulmonary function, cell counts and cell differentials in induced sputum, and concentrations of interleukin-8 (IL-8) and LTB(4) in both induced sputum and plasma by using enzyme linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA).
Concentrations of LTB(4) in induced sputum [(794 +/- 305) pg/mg x pro] and plasma [(5,219 +/- 1,185) ng/L] in group C were significantly higher than those in group H [(347 +/- 169) pg/mg x pro, (2,283 +/- 489) ng/L, all P < 0.05]. The level of LTB(4) in induced sputum was positively correlated with the percentage of neutrophil (r = 0.453, P = 0.018) and IL-8 (r = 0.364, P = 0.047). The pre-and post-therapy concentrations of LTB(4) in induced sputum and plasma in group CA were (812 +/- 592), (657 +/- 459) pg/mg x pro and (5,422 +/- 935), (4,589 +/- 1,057) ng/L, respectively; while in group CB the concentrations were (776 +/- 227), (860 +/- 194) pg/mg x pro and (5,074 +/- 1,850), (6,063 +/- 2,450) ng/L, respectively. There were no significant changes either in the level of LTB(4) in induced sputum or in plasma in both groups (all P > 0.05).
The results suggest that LTB(4) is involved in airway inflammation in COPD. Theophylline is not effective in decreasing the levels of LTB(4) in both induced sputum and plasma of COPD patients.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 07/2005; 28(7):441-4.
[Show abstract][Hide abstract] ABSTRACT: To investigate the association of polymorphisms in the beta(2) and beta(3) adrenergic receptor (beta(2)-ADR and beta(3)-ADR) genes with obstructive sleep apnea/hypopnea syndrome (OSAHS).
The genotypes and alleles of beta(2)-ADR and beta(3)-ADR genes were identified by polymerase chain reaction-restricted fragment length polymorphism assay in 318 unrelated subjects of North region Han population of China (including 165 male OSAHS subjects and 153 male non-OSAHS subjects). The genotypes and allele frequencies of the polymorphisms were compared between OSAHS group and non-OSAHS group. The effects of the polymorphisms in OSAHS group on body mass index (BMI), neck circumference (NC), waist/hip rate (WHR), apnea-hypopnea index (AHI), systolic blood pressure (SBP), diastolic blood pressure (DBP) were analyzed.
There were significant differences in genotypes distribution in beta(3)-ADR polymorphism between the two groups (chi(2) = 10.434, P = 0.006). Compared with the control group, OSAHS group had significantly higher Arg allele frequency in beta(3)-ADR polymorphism (chi(2) = 12.742, P = 0.004). There were independent effects of beta(3)-ADR polymorphism on BMI, NC, WHR in OSAHS group; carriers of the Arg allele of beta(3)-ADR polymorphism had greater BMI, NC, and WHR (P = 0.019, 0.025, 0.012), while the carriers of the Arg allele had greater AHI and SBP (P = 0.032, 0.035), but after adjusted for BMI, AHI and age, there were no differences in SBP between the carriers and non-carriers of Arg allele (P = 0.097). There were no significant differences in the genotypes and allele frequencies in beta(2)-ADR polymorphism between the two groups (chi(2) = 1.406 and 0.809, P = 0.465 and 0.382).
beta(3)-ADR polymorphism may be involved in the development of central obesity and may be related to OSAHS by the central obesity in male OSAHS subjects of North region Han population of China, and may be induce hypertension in OSAHS patients of the population indirectly through obesity and sleep apnea. On the contrary, beta(2)-ADR polymorphism may not be correlated with central obesity and OSAHS in the population.
Zhonghua nei ke za zhi [Chinese journal of internal medicine] 06/2005; 44(5):333-6.
[Show abstract][Hide abstract] ABSTRACT: The study aims to investigate the changes of interleukin (IL)-17 in induced sputum, and to observe the correlation between concentrations of IL-17 and the number of inflammatory cells in induced sputum in chronic obstructive pulmonary disease (COPD) and in asthma.
Induced sputum was obtained in patients with COPD both during acute exacerbation and stable stage and in asthma during acute attack. Healthy nonsmoking volunteers were included as controls. The concentrations of IL-17 in induced sputum were measured by enzyme-linked immunosorbent assay.
The concentrations of IL-17 both in patients with COPD during acute exacerbation and with asthma were significantly higher than that in the control subjects (P < 0.001). The levels of IL-17 in patients with COPD during acute exacerbation positively correlated with that of IL-8 (r = 0.381, P = 0.038) and with the percentage of neutrophils (r = 0.446, P = 0.010) respectively. There was also a positive correlation between the concentrations of IL-17 and the numbers of eosinophils in patients with asthma.
The concentrations of IL-17 in patients with acute exacerbation of COPD and in patients with asthma were significantly increased. IL-17 may play a role in the airway inflammation in both COPD and asthma.
Zhonghua nei ke za zhi [Chinese journal of internal medicine] 01/2005; 43(12):888-90.
[Show abstract][Hide abstract] ABSTRACT: To investigate the changes of interleukin-17 (IL-17) both in rat models of chronic obstructive pulmonary disease (COPD) and in asthma.
Male SD rats were randomly divided into COPD group, asthma group, smoking group and control group. The concentrations of IL-17 in lung tissues and in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). The expression of IL-17 in lung tissue was determined by immunohistochemical staining and photographic analysis.
The concentrations of IL-17 both in the lung tissue and in the BALF were significantly higher in the COPD group and the asthma group than in the controls and the smoking group (all P <0. 01). IL-17 was mainly expressed in airway epithelial cells of COPD rats and in T lymphocytes around the airway in rats with asthma. The levels of IL-17 were also higher both in the COPD group and in the asthma group than in the smoking group and the controls (all P < 0. 01) evaluated by immunohistochemical staining and photographic analysis. In the COPD group,IL-17 concentration of lung tissue was positively correlated with percentage of neutrophils in BALF; it also tended to be positively correlated with the level of intercellular adhesion molecule-1 (ICAM-1) in airway epithelial cells, and the concentration of IL-17 in BALF was positively correlated with the degree of smooth muscle proliferation as well. The concentration of IL-17 in the lung tissue of the asthma group was positively correlated with the number of eosinophils in BALF and with the number of CD3 T lymphocytes in lung tissues respectively.
The production of IL-17 in COPD and in asthma might be distinct. IL-17 probably recruits neutrophils into airways by enhancing the expression of ICAM-1 in airway epithelial cells, and it might play a role in pathological changes of small airways in COPD. The role of IL-17 in asthma maybe associated with the recruitment of eosinophils into airways.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 10/2004; 27(10):654-8.
[Show abstract][Hide abstract] ABSTRACT: To investigate the association of polymorphisms in the angiotensin system gene with obstructive sleep apnea-hypopnea syndrome (OSAHS).
The genotypes and alleles of angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genes were identified by polymerase chain reaction-restricted fragment length polymorphism assay in 221 unrelated subjects of the north region "Han" population of China (including 121 OSAHS subjects and 100 non-OSAHS subjects). The genotypes and allele frequencies of the polymorphisms were compared between OSAHS group and non-OSAHS group. The effects of the polymorphisms in OSAHS group on body mass index (BMI), neck circumference (NC), waist/hip rate (WHR), apnea-hypopnea index (AHI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were analysed.
There were significant differences in genotypes distribution in AGT polymorphism between the two groups (P = 0.009). Compared with the control group, OSAHS group had significantly higher T allele frequency in AGT polymorphism (P = 0.020). There were independent effects of AGT polymorphism on BMI, NC, WHR in OSAHS group, and carriers of the T allele of AGT polymorphism had greater BMI, NC, and WHR, while the carriers of the T allele had greater AHI, SBP, and DBP.
ACE polymorphism may not be correlated with central obesity and OSAHS in the population. AGT polymorphism may be involved in the development of central obesity and may be related to OSAHS and hypertension in OSAHS patients by the central obesity in male OSAHS subjects of North region "Han" population of China.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 09/2004; 27(8):507-10.
[Show abstract][Hide abstract] ABSTRACT: To investigate whether repeated arousals and hypoxia at the end of apnea contribute to nocturnal and diurnal elevation of blood pressure in obstructive sleep apnea syndrome (OSAS) patients with hypertension.
30 OSAS patients with hypertension and 30 OSAS patients without hypertension were studied. Movement arousal index (MAI), cortical arousal index (CAI), length of time during which nocturnal oxygen saturation decreased below 90% (OLT90%), apnea/hypopnea index (AHI), 24 h average systolic and diastolic blood pressure (ASBP and ADBP) were measured. Multiple stepwise regression analysis was performed to find the correlation between 24 h ASBP, ADBP and MAI, CAI, OLT90%, AHI, age, body mass index in OSAS patients with hypertension.
MAI made the most significant contribution to 24 h ASBP and ADBP in OSAS patients with hypertension (ASBP: r = 0.485, P < 0.01; ADBP: r = 0.407, P < 0.05). OLT90% was the second most important contributing factor (ASBP: r = 0.382, P < 0.05; ADBP: r = 0.369, P < 0.05).
Movement arousal and hypoxia may make an important contribution to circardian elevation of blood pressure in OSAS patients with hypertension. Both of them may contribute to the development of nocturnal and diurnal hypertension in patients with OSAS.
[Show abstract][Hide abstract] ABSTRACT: To study the correlation between the inflammatory mediators released by alveolar macrophages and the pulmonary ventilatory capacity in patients with chronic obstructive pulmonary disease (COPD).
Alveolar macrophages were collected by fiberoptic bronchoscopy from 8 patients with chronic bronchitis, 8 with COPD with a forced expiratory volume in one second (FEV(1)) < or = 70%, and 8 healthy nonsmokers. All patients were in the stable stage. The macrophages were cultured and stimulated with lipopolysaccharide (LPS, 10 microg/ml). IL-8, IL-1 beta, TNF-alpha and IL-6 in the supernatants were measured by ELISA. Pulmonary functions were tested in all three groups. The correlation between different cytokines was tested with Pearson's relevant analysis, and the correlation between lung functions and cytokines was tested with multiple reverse regression analysis.
(1) The concentrations of IL-8 released from macrophages in the COPD group were (43 +/- 27) microg/L and (57 +/- 41) microg/L (with LPS), higher than those from healthy controls [(13 +/- 10) microg/L and (20 +/- 13) microg/L] (P < 0.05), but not different from those in patients with chronic bronchitis [(29 +/- 21) microg/L and (32 +/- 23) microg/L] (P > 0.05). (2) The concentrations of IL-1 beta released from macrophages in the COPD group, the chronic bronchitis group and the control group were [(50 +/- 41) ng/L, (94 +/- 59) ng/L, (37 +/- 32) ng/L] before LPS, and [(225 +/- 108) ng/L, (153 +/- 175) ng/L, (70 +/- 37) ng/L] after LPS stimulation, which were positively correlated with the concentrations of IL-8 (P < 0.05). The concentrations of TNF-alpha released from macrophages in three groups were [(1,238 +/- 679) ng/L, (3,088 +/- 2,879) ng/L and (1,332 +/- 1,846)ng/L], which were positively correlated with the concentrations of IL-1 beta (P < 0.05). The concentrations of IL-6 released from macrophages in the three groups were [(7,959 +/- 8,458) ng/L, (5,317 +/- 10,112) ng/L and (6,480 +/- 4,982) ng/L, which were positively correlated with the concentrations of IL-8 (P < 0.05). (3) The values of FEV(1)/FVC, V(max50) and V(max25) measured in the COPD group were [(65.1 +/- 5.3)%, (43 +/- 8)% and (37 +/- 11)%, respectively, which were negatively correlated with the concentrations of IL-8 (P < 0.05), but negatively correlated with the concentrations of IL-1 beta only in the presence of LPS (P < 0.05).
IL-8 released by alveolar macrophages plays an important role in the process from chronic cough to chronic airflow obstruction. TNF-alpha, IL-1 beta and IL-6 released by alveolar macrophages are also involved in the airway inflammation in COPD.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 01/2003; 26(1):22-5.