Exhaled and sputum nitric oxide in bronchiectasis: correlation with clinical parameters.

STUDY OBJECTIVES: Although there has been tremendous attention on endogenous nitric oxide (NO) production in many respiratory and systemic diseases, little is known on NO production in bronchiectasis. DESIGN AND SETTING: We determined exhaled and sputum NO levels in 109 patients with stable bronchiectasis (71 women; mean +/- SD age, 58.2 +/- 14.1 years) and 78 control subjects (39 women; mean age, 56.7 +/- 12.1 years) by using an automatic chemiluminescence analyzer. MEASUREMENTS AND RESULTS: There was no significant difference in exhaled NO between patients with bronchiectasis and control subjects (p = 0.11). Bronchiectasis patients with Pseudomonas aeruginosa infection had a significantly lower exhaled, but not sputum, NO levels than their counterparts and control subjects (p = 0.04 and p = 0.009, respectively). Exhaled NO correlated with 24-h sputum volume in P aeruginosa-infected patients (r = - 0.36; p = 0.002). After adjustment for sputum volume and number of bronchiectatic lung lobes, P aeruginosa-infected patients still had lower exhaled NO levels than their counterparts (p = 0.01). There was no correlation between exhaled NO with FEV(1), FVC, and the number of bronchiectatic lung lobes (p > 0.05). Sputum NO levels were not different between patients and control subjects (p = 0.64), and had no correlation with clinical parameters. CONCLUSION: Exhaled NO appears to be reduced among bronchiectasis patients with P aeruginosa infection independent of other clinical parameters, and further studies on the potential mechanisms and pathogenetic implications of this reduction should be pursued.     

Endothelin-1 in stable bronchiectasis.

Endothelin (ET)-1 has been suggested to promote neutrophil adhesion to endothelium, migration to inflamed areas, and release of elastase. ET-1 might therefore play a role in the pathogenesis of bronchiectasis, a chronic inflammatory and infective airway disease which is still poorly understood. Thirty five patients with stable bronchiectasis (20 females, mean age+/-SD 49.1+/-15.0 yrs) and 18 control subjects (8 females, 49.4+/-11.3 yrs) were recruited prospectively. The ET-1 levels in serum and sputum were measured by commercially available enzyme linked immunosorbent assay (ELISA) kits. Patients with Pseudomonas aeruginosa in their sputum had a significantly higher serum level of ET-1 (median 25.8, interquartile range 13-43.9 pg x mL(-1)) than patients without P. aeruginosa (0, 0-10.5 pg x mL(-1); p=0.0004) and healthy control subjects (4.6, 0-16.3 pg x mL(-1); p=0.002). However, patients with and without P. aeruginosa infection had no significant difference in sputum ET-1 level (p=0.15). There was no correlation between serum or sputum ET-1 levels with the serum and sputum levels of the interleukin (IL)-1beta, IL-8 and tumour necrosis factor (TNF)-alpha; the number of bronchiectasis lung lobes; and spirometry. Serum ET-1 level correlated with 24 h sputum volume for the bronchiectasis patients (r=0.51, p=0.002). The results, therefore, suggest a significant pathogenic role for endothelin-1 among Pseudomonas aeruginosa-infected patients with bronchiectasis. Further studies should be performed to evaluate the clinico-pathological correlation and expression of endothelin-1 in bronchiectasis.     

Ciliary central microtubular orientation is of no clinical significance in bronchiectasis

It has been suggested that patients with bronchiectasis might have increased central microtubular orientation angle (CMOA), which leads to poor coordination of ciliary beating, and consequently impairment of airway defence. We have employed transmission electron microscopy to assess CMOA of ciliated nasal mucosa in a cohort of 133 (81F, 56.8+/-16.1yr) stable bronchiectasis and 59 healthy subjects (30F, 49.3+/-22.1yr). There was no significant difference in CMOA between bronchiectasis (13.2 degree) and control subjects (13.0 degree, P=0.82). There was no significant difference in CMOA among patients according to the etiology of bronchiectasis, presence of nasal symptoms, or sputum status of Pseudomonas aeruginosa infection. Patients with more severe bronchiectasis, i.e. those with FEV(1) <60%, FVC <60%, or more than 4 bronchiectatic lung lobes, had significantly lower CMOA than their counterparts (P<0.05). There was no correlation between CMOA with age, 24h sputum volume, exacerbation frequency, FEV(1), FVC, or the number of bronchiectatic lung lobes (P>0.05). CMOA correlated with ciliary beat frequency (negative), and the percent of cilia showing ultrastructural or microtubular defects (P<0.05). Central microtubular orientation angle does not correlate with clinically important parameters, in contrary to the results reported by previously published smaller scale studies.     

Up-regulation of circulating adhesion molecules in bronchiectasis.

Adhesion molecules are expressed on the surface of endothelial cells and leukocytes and are responsible for mediating the migration of intravascular leukocytes into inflamed tissue. Intensive recruitment of neutrophils into the airways occurs in bronchiectasis, although little is known about the role of adhesion molecules in this process. The authors, therefore, determined serum levels of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 in stable bronchiectasis patients (n=37) and healthy control subjects (n=17), and evaluated their relationship with clinical markers of disease severity in bronchiectasis. Serum levels of E-selectin, ICAM-1 and VCAM-1 in bronchiectasis patients were significantly higher than those in control subjects (p=0.02, <0.0001 and 0.0002 respectively). Both E-selectin and ICAM-1 levels were inversely related to forced expiratory volume in one second (FEV1)% predicted (r=-0.57, p<0.001; and r=-0.53, p=0.001 respectively), and FVC% predicted (r=-0.52, p=0.002; and r=-0.46, p=0.005). This was not the case for VCAM-1 levels. There was a correlation between serum ICAM-1 levels and 24 h sputum volume (r=0.34, p= 0.04). Serum E-selectin and ICAM-1, but not VCAM-1, levels showed correlation with the number of lung lobes affected by bronchiectasis (r=0.35, p=0.04 and r=0.34, p=0.04 respectively). These original observations strongly suggest that E-selectin, intercellular adhesion molecule-1 and Vascular adhesion molecule-1 could play a significant role in the pathogenesis of bronchiectasis.     

Tiotropium and simplified detection of dynamic hyperinflation

STUDY OBJECTIVE: To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium. METHODS: IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH. RESULTS: At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003). CONCLUSION: In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.     

Validation of the Hong Kong Chinese version of the St. George Respiratory Questionnaire in patients with bronchiectasis

STUDY OBJECTIVES: To validate the Hong Kong Chinese version of the St. George Respiratory Questionnaire (SGRQ-HK) in patients with bronchiectasis. DESIGN AND SETTING: Outpatients (93 patients; 61 women; mean age [+/- SD], 59.0 +/- 14.2 years) were assessed at baseline by the SGRQ-HK, the Hong Kong Chinese version of the 36-item short form health survey (SF-36-HK), and the hospital anxiety and depression scale (HADS). Forty randomly selected patients also were reassessed at 2 weeks for repeatability. Seventy-two patients were further reassessed at 6 months for responsiveness. Measurements and results: Cronbach alpha coefficients, which reflected internal consistency, were > 0.7 for all SGRQ-HK components except for symptoms (alpha = 0.59), and the intraclass correlation coefficients between baseline and the 2-week follow-up visits were between 0.80 and 0.94 (p > 0.05). SGRQ-HK component scores and total scores correlated with all the component scores of the SF-36-HK and the HADS (p < 0.02). SGRQ-HK component scores and total scores correlated with the scores of the SF-36-HK and the HADS, confirming the concurrent validity. All SGRQ-HK scores correlated negatively with FEV(1), FVC, and arterial oxygen saturation (p < 0.005), while the activity score correlated with the Karnofsky performance scale and the number of bronchiectatic lobes (p < 0.001). SGRQ-HK scores positively correlated with Borg scale scores, exacerbation frequency, and 24-h sputum volumes (p < 0.03). Patients with 24-h sputum volumes of > or = 10 mL or < 10 mL had significantly different SQRG-HK component scores and total scores (p < 0.002), although this sensitivity was not displayed by scores on the HADS or the SF-36-HK. Patients with 25% reductions in 24-h sputum volumes had significant improvements in SGRQ-HK activity scores, impact scores, and total scores (p < 0.02), but not in other quality-of-life measures or clinical parameters, indicating the responsiveness of the SGRQ-HK. CONCLUSION: The SGRQ-HK is a valid and sensitive instrument for determining quality of life in bronchiectasis patients.     

Assessing response to treatment of exacerbations of bronchiectasis in adults

The present study aimed to assess the effect of intravenous antibiotic therapy on clinical and laboratory end-points in exacerbations of noncystic fibrosis bronchiectasis and to determine whether the outcomes were influenced by the pathogenic organism isolated. A prospective cohort study was conducted from November 2006 to March 2008 of exacerbations requiring intravenous antibiotics. End-points included 24-h sputum volume, forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), incremental shuttle walk test, qualitative sputum microbiology, white cell count, erythrocyte sedimentation rate, C-reactive protein (CRP) and St George's Respiratory Questionnaire (SGRQ). Exacerbations due to Pseudomonas aeruginosa were compared with exacerbations due to other potential pathogenic organisms. In total, 32 exacerbations were studied. Following 14 days of intravenous antibiotics, all outcomes significantly improved independent of a pathogenic organism, except FEV(1) and FVC. The most responsive markers were: 24-h sputum volume (reduced in all patients and 80% had >/=50% reduction); sputum bacterial clearance (78.1%); CRP (>/=75% reduction in 62.5%) and SGRQ (>/=4 unit improvement in 89.7%). CRP, 24-h sputum volume and SGRQ improved independent of microbial clearance. In the current study, 24-h sputum volume, microbial clearance, C-reactive protein and St George's Respiratory Questionnaire were the most useful parameters to assess response to treatment of exacerbations of bronchiectasis. Outcomes were similar independent of the pathogenic organism with the exception of forced expiratory volume in one second and forced vital capacity.     

Centrilobular nodules correlate with air trapping in diffuse panbronchiolitis during erythromycin therapy.

BACKGROUND: Low-dose erythromycin therapy improves airflow limitation and airway inflammation in patients with diffuse panbronchiolitis (DPB). However, to our knowledge there has been no study to determine whether physiologic improvement during erythromycin therapy correlates with radiologic findings. Study objective: To clarify whether improvement in pulmonary function correlates with specific changes on chest CT. DESIGN: The relationship between five CT findings and five pulmonary function parameters was evaluated before and 3 months after low-dose erythromycin therapy in 24 patients with DPB retrospectively. RESULTS: After erythromycin therapy, the predicted percentage of vital capacity (%VC; 87.0 +/- 3.07% vs 98.9 +/- 3.39%; p = 0.00006) and 50% of the maximum midexpiratory flow rate of FVC (1.41 +/- 0.26 L/s vs 1.61 +/- 0.27 L/s; p = 0.03) significantly increased, and the residual volume/total lung capacity ratio (RV/TLC%; 44.5 +/- 1.93% vs 40.7 +/- 1.83%; p = 0.0019) significantly decreased, but the FEV(1) to FVC ratio and 25% of the maximum expiratory flow rate of FVC did not. In five CT findings, centrilobular nodules (3.7 +/- 0.4 vs 1.5 +/- 0.3; p = 0.0001), peripheral bronchiolar wall thickness (3.8 +/- 0.3 vs 2.6 +/- 0.4; p = 0.0007), and peripheral bronchiolectasis (2.8 +/- 0.3 vs 2.2 +/- 0.4; p = 0.0058) had significantly improved, whereas low attenuation area and central bronchiectasis had not. There were positive correlations of improved scores of centrilobular nodules with improved %VC (r = 0.58, p = 0.0062) and RV/TLC% (r = 0.64, p = 0.0022). CONCLUSIONS: Decreased air trapping in DPB correlates with an improvement of centrilobular nodules, which reflects the obstructive lesions of bronchioles during the erythromycin therapy.     

Increased arginase activity in cystic fibrosis airways

RATIONALE: Airway nitric oxide concentrations are reduced in cystic fibrosis (CF). Arginases compete for L-arginine, the substrate of nitric oxide synthesis. OBJECTIVES: We hypothesized that increased arginase activity may be one factor contributing to nitric oxide deficiency in CF. MEASUREMENTS: We therefore studied sputum arginase activity, exhaled nitric oxide, and pulmonary function in patients with cystic fibrosis. RESULTS: Mean (+/- SEM) sputum arginase activity was significantly higher in patients admitted for pulmonary exacerbation compared with patients with stable disease (1.032 +/- 0.148 vs. 0.370 +/- 0.091 U/mg protein, p = 0.004). Fourteen days of intravenous antibiotic treatment resulted in significantly decreased sputum arginase activity in all patients (p = 0.0002). However, arginase activity was still significantly (p = 0.0001) higher in CF sputum after treatment for exacerbation compared with induced sputum from healthy control subjects (0.026 +/- 0.006 U/mg protein). Negative correlations were found for sputum arginase activity at admission with FEV1 (r = -0.41, p = 0.01), as well as changes in arginase activity with percent change in FEV1 during antibiotic therapy (r = -0.4, p < 0.01) in CF. Exhaled nitric oxide in CF was positively correlated to FEV1 (r = 0.34, p = 0.007), and in patients admitted for pulmonary exacerbation negatively correlated to sputum arginase activity (r = -0.45, p = 0.03). CONCLUSIONS: These data suggest that increased sputum arginase activity contributes to nitric oxide deficiency in CF lung disease and may be relevant in the pathogenesis of CF airway disease.     

Relationship between sputum inflammatory markers,lung function,and lung pathology on high-resolution computed tomography in children with cystic fibrosis

High-resolution computed tomography (HRCT) is a sensitive technique for early visualisation and location of cystic fibrosis (CF) bronchopathology, and has been shown to detect acute reversible and chronic changes. It would be expected to correlate with markers of the underlying pathological processes, such as sputum cytokines and cytology, as well as with pulmonary function tests (PFTs). Our aim was to study the relationship between PFTs, sputum cytology, and sputum cytokine interleukin-8 (IL-8) and HRCT in CF patients. Prospective standardized collection of sputum samples was performed at the time of routine annual high-resolution CT scans. Forced expired volume in 1 sec (FEV(1)) and forced vital capacity (FVC) were recorded. Sputum processing was selective, with dispersal by the three-enzyme technique. IL-8 measurements were by kit assay. HRCT scans were scored by a pediatric radiologist, blinded to clinical condition, using a modified Bhalla score.Forty-three CT scans were performed on 34 children with CF between March 1998 and April 2000. Mean age was 12.3 years (range, 6-21 years), FEV(1) (% predicted) was 67% (range, 23-120%), and mean modified Bhalla score was 11.2 (range, 0-22). Sputum IL-8 concentration (mean, 86; range, 4-150 ng/mL) and total cell count (mean, 31.9 x 10(6)/mL; range, 21.8-42.0 x 10(6)/mL) were high. FEV(1) and FVC correlated with modified Bhalla score (r = -0.66, P < 0.0001 for both), and most individual components of the score, especially mosaic perfusion (r = -0.64, r = -0.61 respectively, P < 0.0001) and extent of bronchiectasis (r = -0.61, P < 0.0001 for both). The combination of these two predicted 58% of the variability in FEV(1) on analysis of variance (P < 0.0001). Sputum total cell count correlated weakly with modified Bhalla score (r = 0.38, P < 0.05) and with FEV(1) and FVC (r = -0.36, P < 0.05; and r = -0.46, P < 0.01). Differential cell counts, cell viability, and IL-8 did not correlate with modified Bhalla scores, or with reversible components such as mucus plugging, centrilobular nodules, or peribronchial thickening.In conclusion, pathological changes on HRCT correlated with lung function but not with sputum markers of inflammation.     

Elevated levels of transforming growth factor-beta(1) in serum of patients with stable bronchiectasis

Bronchiectasis is a chronic inflammatory and infective airway disease characterized by irreversible dilatation of the bronchi and persistent purulent sputum. Transforming growth factor-beta(1) (TGF-beta(1)) has been found to be increased in the lungs or bronchoalveolar lavage fluid of patients with inflammatory lung diseases. However, little is known on the serum TGF-beta(1) levels in patients with bronchiectasis. We aimed to determine the serum TGF-beta(1) concentrations in 95 patients with stable bronchiectasis (63 women; mean+/-sd age, 58.9+/-14.1 years) and 68 control subjects (23 women; 48.9+/-12.8 years) by ELISA, and to correlate with clinical parameters. The serum TGF-beta(1) levels were significantly higher in bronchiectatic patients compared with control subjects (median [range], 1812.5 pg/ml [1226.4-4114.5 pg/ml] vs. 1342.4 pg/ml [940.3-2371.7 pg/ml]; P<0.001). There was, however, no correlation between serum TGF-beta(1) levels with FEV(1) (% predicted), FVC (% predicted), 24h sputum volume, the number of bronchiectatic lung lobes or total white blood cell count (P>0.05). Our findings support previous indications that TGF-beta(1) may contribute to bronchiectatic airway inflammation. Further studies on the potential mechanisms and pathogenesis implications of this elevation should also be pursued in future.     

Lung structure abnormalities, but normal lung function in pediatric bronchiectasis

BACKGROUND: Bronchiectasis is not considered to be uncommon in children anymore. The relationship between pulmonary function and severity of bronchiectasis is still controversial. STUDY OBJECTIVES: To assess the extent and severity of bronchiectasis through high-resolution CT (HRCT) scan score, and to correlate it with clinical, microbiological, and functional data. PATIENTS AND METHODS: Forty-three white children with HRCT-diagnosed bronchiectasis were studied. Bronchiectasis extent, bronchial wall thickening severity, and bronchial wall dilatation severity were evaluated using the Reiff score. Clinical, microbiological, and spirometry results were related to total HRCT scan score and to subscores as well. RESULTS: The percentages of affected lobes were as follows: right lower lobe, 65%; middle lobe, 56%; left lower lobe, 51%; right upper lobe, 37%; lingula, 30%; and left upper lobe, 30% (chi(2) = 18.4; p = 0.002). The mean (+/- SEM) HRCT score was 20 +/- 2.6. Total score or subscores of bronchiectasis extent, bronchial wall thickening severity, and bronchial wall dilatation severity were not significantly related to FEV(1) and FVC. Seventy-four percent of patients had asthma. The age at the onset of cough correlated with age at the time of the HRCT scan (p = 0.004) and with the presence of asthma (p = 0.01). Positive findings of deep throat or sputum cultures were found more frequently in atopic patients (p = 0.02) and asthmatic (p < 0.01) patients, and in children who were < 2 years of age at the onset of cough (p < 0.01). CONCLUSIONS: Normal lung function may coexist with HRCT scan abnormalities and does not exclude damage to the bronchial structure. Pulmonary function is not an accurate method for assessing the severity of lung disease in children with bronchiectasis.     

Mucus properties in children with primary ciliary dyskinesia: comparison with cystic fibrosis

OBJECTIVE: It has been assumed that cystic fibrosis (CF) lung disease is due in part to abnormal airway mucus. Primary ciliary dyskinesia (PCD) is a form of bronchiectasis that is similar to CF in many ways but is caused by congenital defects in mucociliary clearance. Our objective was to compare the biophysical and transport properties of CF and PCD sputa in subjects matched for age and degree of lung function impairment. DESIGN, SETTING, PARTICIPANTS: PCD patients (n = 19; mean age, 9.5 +/- 3.0 years [+/- SD]; FEV1, 65.0 +/- 7.8 L) were recruited from the clinic at the Royal Brompton Hospital. Patients with CF (n = 30, mean age, 10.8 +/- 2.6 years; FEV1, 61.8 +/- 22.8 L) were identified from the Wake Forest University School of Medicine CF Center. Pulmonary function testing and sputum collection were performed as part of routine, scheduled clinic visits. MEASUREMENTS: Pulmonary function was measured by spirometry, and sputum was collected during the pulmonary function test maneuver. Some patients were longitudinally assessed at visits during the course of 3 years. Sputum properties measured were dynamic viscoelasticity, wettability, cohesivity, interfacial (surface) tension, solids composition, DNA and interleukin (IL)-8 concentration, in vitro mucociliary transportability, and cough transportability. RESULTS: Inflammation as measured by IL-8 concentration was three times greater in the PCD sputa (p < 0.0001). There were no significant differences in the sputum biophysical or transport properties comparing CF with PCD sputum. CONCLUSIONS: It is unlikely that established CF lung disease is principally due to abnormal sputum properties, and it is more likely that the biophysical and transport properties reflect disease severity regardless of whether bronchiectasis is due to CF or PCD.     

A pilot study of low-dose erythromycin in bronchiectasis.

Patients with bronchiectasis suffer from sputum production, recurrent exacerbations, and progressive airway destruction. Erythromycin is effective in diffuse panbronchiolitis, another suppurative airway disorder, although its efficacy is unknown in idiopathic bronchiectasis. A double-blind placebo-controlled study was therefore conducted to evaluate the effects of 8-week administration of low dose erythromycin (500 mg b.i.d.) in steady-state idiopathic bronchiectasis. Patients in the erythromycin group (n=11, 8 female, mean age 50+/-15 yrs), but not the placebo group (n=10, 8 female, mean age 59+/-16 yrs) had significantly improved forced expiratory volume in one second, forced vital capacity and 24-h sputum volume after 8 weeks (p<0.05). There was no parallel improvement in sputum pathogens, leukocytes, interleukin (IL)-1alpha and IL-8, tumour necrosis factor-alpha, or leukotriene B4. The results of this pilot study show that low-dose erythromycin improves lung function and sputum volume in bronchiectasis. Further studies are indicated to evaluate the efficacy of long-term erythromycin therapy in bronchiectasis.     

慢性阻塞性肺疾病患者环氧合酶2和基质金属蛋白酶2的表达及其与气流阻塞的关系

目的探讨慢性阻塞性肺疾病(COPD)患者诱导痰中环氧合酶2(COX-2)及基质金属蛋白酶2(MMP-2)的表达及其与气流阻塞的关系。方法COPD组55例(COPD稳定期患者,其中0级12例、Ⅰ级10例、ⅡA级12例、ⅡB级11例和Ⅲ级10例)和正常对照组10名行痰诱导,对痰悬液进行细胞分类计数,应用酶联免疫吸附测定(ELISA)法检测诱导痰上清液中前列腺素E2(PGE2)和MMP2浓度,Westernblot法测定诱导痰细胞中COX-2蛋白表达。结果(1)COPD组诱导痰中细胞总数、肺泡巨噬细胞(AM)数和中性粒细胞(Neu)数较正常对照组显著增高(P<0.05或P<0.01)。AM、Neu与第一秒用力呼气容积占预计值%(FEV1占预计值%)、一秒率(FEV1/FVC)分别呈负相关(r=-0.280、P<0.05,r=-0.345、P<0.01;r=-0.677,r=-0.773,P均<0.01)。(2)Westernblot显示COPD组患者诱导痰细胞中COX-2蛋白表达(57±8)显著高于正常对照组(83±10,P<0.05)。(3)COPD各组诱导痰PGE2浓度[分别为(111±17)、(117±23)、(118±29)、(153±24)、(194±28)ng/L]显著高于正常对照组[(81±18)ng/L,P均<0.01],且与FEV1占预计值%、FEV-1/FVC呈负相关(r=-0.748,r=-0.750,P均<0.01),与MMP-2浓度呈正相关(r=0.775,P<0.01)。COPD各组诱导痰MMP2浓度[(4.0±0.9)、(4.5±1.5)、(7.7±3.1)、(11.9±3.5)、(18.5±5.     

Pulmonary function is negatively correlated with sputum inflammatory markers and cough clearability in subjects with cystic fibrosis but not those with chronic bronchitis

BACKGROUND: Polymorphonuclear neutrophil (PMN)-dominated inflammation is prominent in the airways of subjects with cystic fibrosis (CF) and chronic bronchitis (CB). Interleukin (IL)-8, myeloperoxidase (MPO), and DNA are markers of neutrophilic inflammation. We hypothesized that sputum MPO, DNA, and IL-8 concentrations would negatively correlate with pulmonary function and sputum transportability. METHODS: We measured pulmonary function and analyzed sputum IL-8, MPO, and DNA concentrations, as well as the transport properties of sputum samples obtained from 16 subjects with CF and 15 subjects with CB. We also evaluated changes in these measurements in paired sputum samples from these subjects obtained 2 to 12 months apart. RESULTS: IL-8 and MPO concentrations in the sputum of CF subjects was inversely correlated with FEV(1) percent predicted (IL-8: r = -0.40; p = 0.003; MPO: r = -0.38; p = 0.003) and FVC percent predicted (IL-8: r = -0.4; p = 0.02; MPO: r = -0.4; p = 0.02). IL-8 and DNA concentrations were inversely correlated with sputum cough transportability (CTR) [IL-8: r = -0.4; p = 0.02; DNA: r = -0.36; p = 0.048]. Changes in DNA concentration in sputum samples from CF subjects over time were inversely correlated with changes in FEV(1) percent predicted (r = -0.58; p = 0.02), FVC percent predicted (r = -0.74; p = 0.002), and CTR (r = -0.59; p = 0.02). There was no correlation among pulmonary function, sputum properties, and inflammatory markers in the sputum from subjects with CB. CONCLUSIONS: The sputum concentrations of IL-8, MPO, and DNA appear to be closely associated with pulmonary function in subjects with CF but not in subjects with CB.     

Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease

Relationships between high-resolution computed tomography (HRCT) findings in chronic obstructive pulmonary disease (COPD) and bacterial colonization, airway inflammation, or exacerbation indices are unknown. Fifty-four patients with COPD (mean [SD]: age, 69 [7] years; FEV(1), 0.96 [0.33] L; FEV(1) [percent predicted], 38.1 [13.9]%; FEV(1)/forced vital capacity [percent predicted], 40.9 [11.8]%; arterial partial pressure of oxygen, 8.77 [1.11] kPa; history of smoking, 50.5 [33.5] smoking pack-years) underwent HRCT scans of the chest to quantify the presence and extent of bronchiectasis or emphysema. Exacerbation indices were determined from diary cards over 2 years. Quantitative sputum bacteriology and cytokine measurements were performed. Twenty-seven of 54 patients (50%) had bronchiectasis on HRCT, most frequently in the lower lobes (18 of 54, 33.3%). Patients with bronchiectasis had higher levels of airway inflammatory cytokines (p = 0.001). Lower lobe bronchiectasis was associated with lower airway bacterial colonization (p = 0.004), higher sputum interleukin-8 levels (p = 0.001), and longer symptom recovery time at exacerbation (p = 0.001). No relationship was seen between exacerbation frequency and HRCT changes. Evidence of moderate lower lobe bronchiectasis on HRCT is common in COPD and is associated with more severe COPD exacerbations, lower airway bacterial colonization, and increased sputum inflammatory markers.     

Lymphocyte glutathione levels in children with cystic fibrosis.

OBJECTIVE: Lung disease in cystic fibrosis (CF) is characterized by a neutrophilic inflammatory response. This can lead to the production of oxidants, and to oxidative stress in the lungs. Glutathione (GSH) represents the primary intracellular antioxidant, and provides an important defense in the epithelial lining fluid. Evidence suggests that lymphocyte GSH reflects lung GSH concentrations, and so could potentially serve as a peripheral marker of lung inflammation. METHODS: We assessed peripheral blood lymphocyte GSH concentrations in 20 children (13 boys) with CF who were in stable condition at the time of evaluation. Values were compared with nutritional status and lung function parameters. RESULTS: Patients were 11.7+/-3.03 years old (mean +/- SD). Their percentage of ideal body weight was 101.8+/-17.92%; FEV1, 79.5+/-19.22% predicted; FEV1/FVC, 75.0+/-10.08%; and residual volume (RV)/total lung capacity (TLC), 31.3+/-10.47%. For the group, the GSH concentration was 1.31+/-0.52 micromol/10(6) lymphocytes, which was not different from laboratory control values. GSH values were correlated with nutritional status (percentage of ideal body weight: r = 0.49, p < 0.03) and the degree of gas trapping (RV/TLC: r = 0.50, p < 0.03), and were correlated inversely with airflow limitation (FEV1, percent predicted: r = -0.45, p < 0.05; FEV1/FVC: r = -0.48, p < 0.04), but not with age, height, or weight (p > 0.1). CONCLUSIONS: We interpret the inverse correlation between lymphocyte GSH concentration and lung function as a reflection of upregulation of GSH production by lung epithelial tissue in response to oxidative stress. We interpret the correlation between lymphocyte GSH concentration and nutritional status as a reflection of the role of cysteine in hepatic glutamine metabolism. Peripheral blood lymphocyte GSH concentration may potentially serve as a convenient marker of lung inflammation. Furthermore, the increased demand for GSH production in the face of ongoing inflammation suggests a potential role for supplementation with cysteine donors.     

Spirometry in 3- to 6-year-old children with cystic fibrosis

Spirometry is routinely used to assess pulmonary function of older children and adults with cystic fibrosis (CF); however, few data exist concerning the preschool age group. We have reported normative spirometric data for 3- to 6-year-old children. The current study was designed to assess a similarly aged group of clinically stable patients with CF. Thirty-three of 38 children with CF were able to perform 2 or 3 technically acceptable maneuvers. These patients had significantly decreased FVC, FEV(1), FEV(1)/FVC, and FEF(25-75) when expressed as z scores (number of SD from predicted): -0.75 +/- 1.63, -1.23 +/- 1.97, -0.87 +/- 1.33, and -0.74 +/- 1.63, respectively. There were significant positive correlations of the Brasfield radiological score with FVC and FEV(1) z scores (r(2) = 0.26, p < 0.01 and r(2) = 0.24, p < 0.01). In addition, homozygous patients for the DeltaF508 mutation had lower z scores for FVC (-1.21 versus 0.47, p < 0.01) and FEV(1) (-1.38 versus 0.21, p < 0.05) than heterozygous patients. Of the 14 patients who had full flow-volume spirometric measurements during infancy, 10 had FEF(25-75) z scores greater than -2 at both evaluations. Our findings suggest that spirometry can successfully be used to assess lung function in preschool children with CF and has the potential for longitudinal assessment from infancy through adulthood.     

The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis

Decreased survival in patients with cystic fibrosis has been related to FEV1, BMI, and infection with Burkholderia cepacia complex (BCC). We have assessed the relationship of blood, sputum, and urine inflammatory markers to lung function, BMI, colonization with B cenocepacia (Bc), and patient survival. Thirty-nine stable cystic fibrosis (CF) patients (10 with Bc) were enrolled in a study to determine the effect of alpha-1-antitrypsin on airways inflammation. Pre-treatment measurements were used in this study. Demographics, sputum microbiology, heart rate, oxygen saturation, lung function were recorded. Blood samples were obtained for white blood count (WBC), C-Reactive Protein (CRP), and plasma neutrophil elastase/AAT complexes (pNEC). Neutrophil elastase (NE), neutrophil elastase/AAT complexes (sNEC), interleukin-8 (IL-8), TNF-receptor 1 (sTNFr), and myeloperoxidase (MPO) were measured in sputum and urinary desmosine concentration determined. Patients with Bc had significantly higher levels of pNEC, 332 +/- 91.4 ng/ml (mean +/- SEM) versus 106 +/- 18.2 ng/ml (P = 0.0005) and sNEC, 369 +/- 76.6 ng/ml versus 197 +/- 36.0 ng/ml compared to those who were not. Five deaths were reported at the end of 1 year, (four with Bc) (P = 0.011). Patients who subsequently died had significantly lower lung function FEV1, 1.2 +/- 0.2 L versus 2.0 +/- 0.1 L (P = 0.03) and FVC, 2 +/- 0.3 L versus 3.1 +/- 0.2 L (P = 0.01), compared to those that survived. There was significantly higher NE activity, 3.6 +/- 1.6 U/ml versus 1.5 +/- 0.6 U/ml (P = 0.03), pNEC, 274 +/- 99 ng/ml versus 142 +/- 30 ng/ml (P = 0.05), MPO, 163 +/- 62 mcg/ml versus 54 +/- 6.9 mcg/ml (P = 0.03), and urinary desmosines 108 +/- 19.9 pM/mg creatinine versus 51.1 +/- 3.3 pM/mg creatinine (P = 0.001), in those patients who subsequently died compared to those that survived. These data suggest there is increased neutrophil degranulation in patients infected with Bc and these patients have a poor outcome.