Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations

BACKGROUND: Although it is presumed that exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased airway inflammation, there is little information available on inflammatory markers during an exacerbation and the relationship with severity or time course of recovery. A study was undertaken to investigate the sputum cell and cytokine characteristics of COPD when stable and during an exacerbation. METHODS: Induced sputum samples from 57 patients with moderate to severe COPD were analysed (44 samples were taken during a stable period and 37 during an exacerbation). The patients recorded daily symptoms on diary cards. Cell counts and sputum levels of interleukin (IL)-6 and IL-8 were measured. RESULTS: Patients with >/=3 exacerbations/year had higher median stable sputum levels of IL-6 (110 (95% CI 11 to 215) pg/ml) and IL-8 (6694 (95% CI 3120 to 11995) pg/ml) than those with 相似文献   

Relationship between bacterial colonisation and the frequency,character, and severity of COPD exacerbations

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are prone to frequent exacerbations which are a significant cause of morbidity and mortality. Stable COPD patients often have lower airway bacterial colonisation which may be an important stimulus to airway inflammation and thereby modulate exacerbation frequency. METHODS: Twenty nine patients with COPD (21 men, 16 current smokers) of mean (SD) age 65.9 (7.84) years, forced expiratory volume in 1 second (FEV(1)) 1.06 (0.41) l, FEV(1) % predicted 38.7 (15.2)%, FEV(1)/FVC 43.7 (14.1)%, inhaled steroid dosage 1.20 (0.66) mg/day completed daily diary cards for symptoms and peak flow over 18 months. Exacerbation frequency rates were determined from diary card data. Induced sputum was obtained from patients in the stable state, quantitative bacterial culture was performed, and cytokine levels were measured. RESULTS: Fifteen of the 29 patients (51.7%) were colonised by a possible pathogen: Haemophilus influenzae (53.3%), Streptococcus pneumoniae (33.3%), Haemophilus parainfluenzae (20%), Branhamella catarrhalis (20%), Pseudomonas aeruginosa (20%). The presence of lower airway bacterial colonisation in the stable state was related to exacerbation frequency (p=0.023). Patients colonised by H influenzae in the stable state reported more symptoms and increased sputum purulence at exacerbation than those not colonised. The median (IQR) symptom count at exacerbation in those colonised by H influenzae was 2.00 (2.00-2.65) compared with 2.00 (1.00-2.00) in those not colonised (p=0.03). The occurrence of increased sputum purulence at exacerbation per patient was 0.92 (0.56-1.00) in those colonised with H influenzae and 0.33 (0.00-0.60) in those not colonised (p=0.02). Sputum interleukin (IL)-8 levels correlated with the total bacterial count (rho=0.459, p=0.02). CONCLUSION: Lower airway bacterial colonisation in the stable state modulates the character and frequency of COPD exacerbations.     

Atrial natriuretic peptide in stable and decompensated chronic obstructive pulmonary disease.

BACKGROUND--Plasma levels of atrial natriuretic peptide (ANP) are elevated in patients with chronic obstructive pulmonary disease (COPD) and may have a role in preventing oedema formation in these patients. METHODS--Plasma ANP levels were measured in 60 patients with COPD and these measurements were related to pulmonary haemodynamics, response to treatment during exacerbations, and clinical patterns of the stable disease. RESULTS--Plasma ANP levels did not correlate significantly with right atrial or pulmonary arterial pressures but did correlate significantly with both the right ventricular end diastolic volume and right ventricular wall volume measured by magnetic resonance imaging. Oxygen (2 1/min by nasal prongs for 30 minutes) did not change the mean pulmonary arterial pressure or the level of plasma ANP. In 20 patients with an acute exacerbation of COPD plasma ANP levels were higher in those with oedema (302 (185) pg/ml) than in those without oedema (87 (43) pg/ml). Oxygen given for one hour had no effect on plasma levels of ANP. However, plasma ANP levels fell over the first three days during treatment in those with oedema, the fall correlating with the change in body weight. In a further 20 stable patients with hypoxic COPD, those with hypercapnia and previous episodes of oedema had higher levels of plasma ANP (120 (50) pg/ml) than normocapnic patients with no previous oedema (54 (15) pg/ml). CONCLUSIONS--The level of ANP is high in the plasma of patients with COPD, particularly during exacerbations in those with oedema. The association of a high plasma ANP level and volume overload is shown by the fall in ANP levels with treatment of the oedema, and the correlation between levels of ANP and right ventricular end diastolic or wall volumes.     

Endothelin-1 levels in induced sputum samples from asthmatic and normal subjects

BACKGROUND: Endothelin-1 (ET-1) is a potent bronchoconstrictor which may have a role in the pathogenesis of asthma. The levels of ET-1 in saliva, induced sputum, and plasma from asthmatic and non-asthmatic subjects were compared. METHODS: Sputum induction was performed on 28 asthmatic subjects and nine normal volunteers. ET-1 levels were measured in plasma, saliva, and sputum samples and reversed phase high performance liquid chromatography (RP-HPLC) was performed on saliva and sputum samples. RESULTS: ET-1 was present in the following order of concentration in both normal and asthmatic subjects: saliva > sputum > plasma (saliva, median 30.1 and 23.9 pg/ ml, respectively; sputum, median 15.5 and 11.2 pg/ml; plasma, median 3.1 and 3.6 pg/ ml). There were no differences between asthmatic and normal subjects in the levels of ET-1 in each fluid. The levels of ET-1 in asthmatic subjects were not influenced by whether or not they were taking inhaled steroids. RP- HPLC of sputum and saliva confirmed the presence of ET-1 in these fluids. CONCLUSIONS: Levels of ET-1 can be measured in saliva and sputum obtained by sputum induction in asthmatic and healthy subjects and, although no difference was found in basal levels of ET-1 in sputum, saliva and plasma between normal subjects and asthmatics without bronchoconstriction, it is apparent that ET-1 is produced or released locally within the respiratory tract in concentrations higher than those in plasma.


     

Bronchoscopic validation of the significance of sputum purulence in severe exacerbations of chronic obstructive pulmonary disease

BACKGROUND: Antibiotics are commonly prescribed in exacerbations of chronic obstructive pulmonary disease (COPD). However, the role of bacteria in these exacerbations is controversial. OBJECTIVE: To identify clinical predictors of bacterial infection as a cause of exacerbation, considering the protected specimen brush (PSB) as the gold standard. METHODS: Clinical data, sputum and PSB samples were collected from 40 patients with COPD requiring hospitalisation due to severe exacerbations who had not received previous antibiotic treatment. RESULTS: Quantitative cultures of PSB samples (n = 40) yielded 23 potential pathogenic microorganisms (PPMs) at concentrations of > or =10(2) colony-forming units/ml in 18 (45%) patients. Sputum samples were obtained from all 40 patients. Culture of good-quality sputum samples (n = 18) yielded 16 PPMs corresponding to 14 (35%) patients. The concordance between the PSB and sputum rate was high (kappa = 0.85, p < 0.002). The self-reporting patient observation of sputum purulence (odds ratio (OR) 27.20 (95% confidence interval (CI) 4.60 to 60.69), p = 0.001), the percentage predicted forced expiratory volume in 1 s (FEV(1)%) <50 (OR 2.27 (95% CI 1.55 to 3.21), p = 0.014), >4 exacerbations in the past year (OR 6.9 (95% CI 0.08 to 1.08), p = 0.028) and previous hospitalisations due to COPD (OR 4.13 (95% CI 1.02 to 16.07), p = 0.041) were associated with the presence of PPMs in the distal airways. The operative characteristics for predicting distal airway infection when patients presented with purulent exacerbation were as follows: sensitivity 89.5%, specificity 76.2%, positive predicted value 77.3% and negative predicted value 88.9%. CONCLUSIONS: The self-reporting presence of purulence in the sputum, as well as common previous exacerbations and hospitalisations due to COPD in patients with severe airflow obstruction (FEV1% <50) predict the presence of bacterial infection in the distal airways. The use of these clinical variables may help in selecting candidates to receive antibiotic treatment.     

Neutrophilic inflammation and IL-8 levels in induced sputum of alpha-1-antitrypsin PiMZ subjects

BACKGROUND: Severe alpha-1-antitrypsin deficiency (AATD), due to homozygosity for the protease inhibitor (Pi) Z allele, is a genetic risk factor for chronic obstructive pulmonary disease (COPD). In a previous study the sputum of severe AATD subjects with airflow obstruction showed a pattern of cellular inflammation similar to COPD patients. It is uncertain whether heterozygotes for the Z allele or intermediate deficiency (PiMZ) have an increased risk of developing COPD. METHODS: Sputum cell counts and the supernatant level of the neutrophil chemoattractant interleukin (IL)-8 were investigated by sputum induction in 10 non-smoker asymptomatic PiMZ subjects with normal pulmonary function, 10 patients with stable COPD, and 10 age matched normal subjects. Data are expressed as mean (SD). RESULTS: The mean (SD) number of neutrophils was significantly higher (p<0.01) in the sputum of PiMZ subjects (84.5 (22.2) x10(4)/ml) and patients with COPD (126.9 (18.8) x10(4)/ml) than in matched normal subjects (55.0 (8.7) x10(4)/ml). IL-8 levels were increased in PiMZ subjects (828.5 (490.6) ng/ml; median 1003.0 ng/ml; range 1260-100 ng/ml) and in COPD patients (882.5 (524.3) ng/ml; median 934.9 ng/ml; range 1506-258 mg/ml) compared with normal subjects (3.5 (0.5) ng/ml; median 3.5 ng/ml; range 4.5-2.5 ng/ml). There was a significant positive correlation between IL-8 supernatant concentration and neutrophil count in PiMZ subjects (p = 0.036; r = 0.66). An inverse correlation was observed between the percentage of neutrophils and forced expiratory volume in 1 second (% predicted) in patients with COPD (p = 0.04; r = -0.43). CONCLUSIONS: These findings indicate that PiMZ subjects without airflow obstruction may have an IL-8 related neutrophilic inflammation in the airways, similar to stable COPD patients, suggesting an increased risk of developing pulmonary changes.     

Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is often associated with peripheral muscle weakness, which is caused by several factors. Acute exacerbations may contribute, but their impact on muscle force remains unclear. Correlations between peripheral muscle force and inflammatory and anabolic markers have never been studied in COPD. The effect of an acute exacerbation on quadriceps peak torque (QPT) was therefore studied in hospitalised patients, and the aforementioned correlations were examined in hospitalised and in stable patients. METHODS: Lung function, respiratory and peripheral muscle force, and inflammatory and anabolic markers were assessed in hospitalised patients on days 3 and 8 of the hospital admission and 90 days later. The results on day 3 (n=34) were compared with those in clinically stable outpatients (n=13) and sedentary healthy elderly subjects (n=10). RESULTS: Hospitalised patients had lowest mean (SD) QPT (66 (22)% predicted) and highest median (IQR) levels of systemic interleukin-8 (CXCL8, 6.1 (4.5 to 8.3) pg/ml). Insulin-like growth factor I (IGF-I) tended to be higher in healthy elderly subjects (p=0.09). QPT declined between days 3 and 8 in hospital (mean -5% predicted (95% CI -22 to 8)) and partially recovered 90 days after admission to hospital (mean 6% predicted (95% CI -1 to 23)). QPT was negatively correlated with CXCL8 and positively correlated with IGF-I and lung transfer factor in hospitalised and in stable patients. CONCLUSIONS: Peripheral muscle weakness is enhanced during an acute exacerbation of COPD. CXCL8 and IGF-I may be involved in the development of peripheral muscle weakness in hospitalised and in stable patients with COPD.     

Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations

BACKGROUND: Exacerbations represent an important feature of the clinical manifestation and natural history of chronic obstructive pulmonary disease (COPD). Nuclear localisation of p65 is a signal of nuclear factor-kappaB (NF-kappaB) activation. A study was undertaken to evaluate whether NF-kappaB activation is modified in sputum cells during COPD exacerbations. METHODS: Total and nuclear p65 immunoreactivity was measured by immunocytochemistry in the sputum cells of 11 smokers with moderate COPD during an exacerbation and after 6-8 weeks of clinical stability. RESULTS: Total sputum cell count was significantly increased during exacerbations from a median (IQR) of 880 (510-1865) to 1914.5 (1065-3205) x 10(3)/ml (p<0.05). The main inflammatory cells in the sputum were neutrophils (83.2 (75.4-92.3)%) and macrophages (14.7 (2.6-21.6)%) and their relative proportion did not change during exacerbations. Nuclear staining for p65 was absent in sputum neutrophils, both during exacerbations and in the stable phase. In contrast, the percentage of macrophages expressing nuclear p65 increased significantly during exacerbations from a median (IQR) of 16 (7-24)% to 41.4 (6-69)% (p<0.05). CONCLUSIONS: NF-kappaB appears to be activated in sputum macrophages but not in sputum neutrophils during exacerbations of COPD     

Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD

BACKGROUND: Exacerbations are an important feature of chronic obstructive pulmonary disease (COPD), accounting for a large proportion of health care costs. They are associated with increased airway inflammation and oxidative stress. METHODS: Concentrations of leukotriene B4 (LTB4), a marker of inflammation, and 8-isoprostane, a marker of oxidative stress, were measured in the exhaled breath condensate of 21 patients (11 M) with COPD during an exacerbation and 2 weeks after treatment with antibiotics. In 12 patients who had no further exacerbations these markers were also measured after 2 months. RESULTS: LTB4 concentrations were raised during the COPD exacerbation (mean (SE) 15.8 (1.1) pg/ml and fell after treatment with antibiotics to 9.9 (0.9) pg/ml (p<0.0001). In 12 patients the level of LTB4 fell further from 10.6 (1.1) pg/ml to 8.5 (0.8) pg/ml (p<0.005) after 2 months. In 12 normal age matched subjects the LTB4 levels were 7.7 (0.5) pg/ml. Concentrations of 8-isoprostane were also increased during the exacerbation (13.0 (0.9) pg/ml) and fell after antibiotic treatment to 9.0 (0.6) pg/ml (p<0.0001). In 12 patients there was a further fall from 9.3 (0.7) pg/ml to 6.0 (0.7) pg/ml (p<0.001) after 2 months compared with normal subjects (6.2 (0.4) pg/ml). CONCLUSIONS: Non-invasive markers of inflammation and oxidative stress are increased during an infective exacerbation of COPD and only slowly recover after treatment with antibiotics.     

Plasma endothelin and big endothelin concentrations and serum endothelin-converting enzyme activity following aneurysmal subarachnoid hemorrhage

OBJECT: Pathogenesis of delayed ischemia after aneurysmal subarachnoid hemorrhage (SAH) seems to be complex. An important mediator of chronic vasospasm may be endothelin (ET)-1 with its powerful and long-lasting vasoconstricting activity. In this prospective study the author investigated the correlations between serial plasma concentrations of ET-1 and big ET-1 as well as the ET-1/big ET-1 molar concentration ratio and serum endothelin-converting enzyme (ECE)-1 activity, and ischemic complications after SAH. METHODS: To measure plasma ET-1 (51 patients), big ET-1 immunoreactivity (22 patients), and serum ECE-1 activity (13 patients), blood samples were obtained on admission, in the morning after aneurysm surgery, and during the 2nd week after hemorrhage in 51 consecutive patients (28 men and 23 women, with a mean age of 50.8 years) with aneurysmal SAH. Mean plasma concentrations of ET-1 in patients with SAH (mean +/- standard deviation: on admission, 4.2 +/- 2 pg/ml; after surgery, 4.3 +/- 2.2 pg/ml; and during the 2nd week after SAH, 3.7 +/- 1.9 pg/ml) differed from those in healthy volunteers (2.9 +/- 1.2 pg/ml; p < 0.01). Plasma concentrations of ET-1 and big ET-1 as well as the ET-1/big ET-1 ratio did not change significantly with elapsed time following SAH; however, serum ECE-1 activity during the 2nd week after SAH was higher in patients with SAH than that in controls (162 +/- 43 compared with 121 +/- 56 pg/ml, respectively; p = 0.028). Plasma ET-1 concentrations (p < 0.05) and the ET-1/big ET-1 ratios (p = 0.063) were higher but plasma big ET-1 concentrations were lower (p < 0.05) in patients who experienced symptomatic delayed cerebral ischemia, compared with other patients with SAH. In addition, in cases in which follow-up computerized tomography scans or magnetic resonance images demonstrated permanent ischemic lesions attributable to vasospasm, patients had higher ET-1 concentrations than did other patients with SAH. CONCLUSIONS: The plasma ET-1 concentration correlates with delayed cerebral ischemia after SAH, suggesting that an increased ET conversion rate in the endothelium predicts ischemic symptoms. Increased serum ECE-1 activity during the 2nd week may reflect the severity of endothelial injury to cerebral arteries.     

Angiogenic cytokines in patients with idiopathic interstitial pneumonia

BACKGROUND: Angiogenesis has been implicated in the pathogenesis of idiopathic interstitial pneumonia (IIP). The aim of this study was to examine the relationship between plasma concentrations of the angiogenic cytokines interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1) and clinical parameters of disease progression over a 6 month period to identify potential aetiological mediators and prognostic markers of disease activity in patients with IIP. METHODS: Forty nine patients with IIP (40 men) were recruited to the study. Plasma cytokine measurements, pulmonary function tests, and high resolution computed tomography (HRCT) scans were performed on recruitment and after 6 months. Plasma cytokine measurements were also performed in 15 healthy volunteers for control purposes. RESULTS: Patients with IIP had significantly higher median (IQR) baseline concentrations of IL-8 and ET-1 than controls (155 (77-303) pg/ml v 31 (0-100) pg/ml, p<0.001) and (1.21 (0.91-1.88) pg/ml v 0.84 (0.67-1.13) pg/ml, p<0.01), respectively. Baseline concentrations of IL-8, ET-1, and VEGF were significantly related to the baseline HRCT fibrosis score (r = 0.42, p<0.005; r = 0.39, p<0.01; and r = 0.42, p<0.005, respectively). Patients with IIP who developed progressive disease had significantly higher baseline levels of IL-8 (345 (270-497) pg/ml v 121 (73-266) pg/ml, p = 0.001) and VEGF (1048 (666-2149) pg/ml v 658 (438-837) pg/ml, p = 0.019). Over 6 months the change in VEGF was significantly related to the change in HRCT fibrosis score (r = 0.565, p = 0.035) and negatively related to the change in forced vital capacity (r = -0.353, p = 0.035).     

Correlation of CD4:CD8 ratio and tumour necrosis factor (TNF)alpha levels in induced sputum with bronchoalveolar lavage fluid in pulmonary sarcoidosis

BACKGROUND: An increased CD4:CD8 lymphocyte ratio and raised cytokine levels in bronchoalveolar lavage (BAL) fluid are characteristic of pulmonary sarcoidosis. Sputum induction has been used as a non-invasive tool for investigating the airways and may be useful in investigating inflammation in patients with sarcoidosis in whom endobronchial, peribronchial, and parenchymal inflammation is present. This study aimed to correlate the total and differential cell counts, CD4:CD8 ratio, and tumour necrosis factor (TNF)alpha levels between induced sputum and BAL fluid in patients with pulmonary sarcoidosis. METHODS: Fourteen patients with newly diagnosed biopsy proven sarcoidosis and six healthy controls were investigated. Sputum induction and BAL was carried out at the initial visit and repeated following six months of treatment with oral prednisone. RESULTS: There was no correlation of differential cell counts between induced sputum and BAL fluid. The CD4:CD8 ratio in induced sputum correlated strongly with that in BAL fluid (5.5 (0. 4:1) versus 4.4 (0.2:1); r = 0.8, p<0.001) and the fall in the ratio following six months of treatment in sputum paralleled that in BAL fluid (3.4 (0.2:1) versus 2.4 (0.2:1)). The TNF alpha levels in sputum also correlated with levels in the BAL fluid (11.9 (1.5) pg/ml versus 17.6 (2.7) pg/ml; r = 0.8, p<0.001). The fall in sputum TNF alpha levels following six months of treatment paralleled the fall in BAL fluid levels (6.7 (0.9) pg/ml versus 11.6 (1.3) pg/ml). CONCLUSIONS: The CD4:CD8 ratio and TNF alpha levels in induced sputum correlated with those in BAL fluid and paralleled changes with treatment. Induced sputum may therefore be a non-invasive surrogate for certain parameters in BAL fluid in patients with sarcoidosis.     

Imbalance between levels of nitrogen oxides and peroxynitrite inhibitory activity in chronic obstructive pulmonary disease

BACKGROUND: The prevalent theory concerning the pathogenesis of chronic obstructive pulmonary disease (COPD) is of an imbalance between oxidants and antioxidants in the lung. It has recently been reported that the production of peroxynitrite, an extremely potent oxidant, is increased in the airways of patients with COPD. A study was undertaken of the imbalance between the levels of nitrogen oxides and antioxidant activity against peroxynitrite in the airways of patients with COPD. METHODS: Sputum induction was performed in 30 patients with COPD and 15 normal control subjects. Levels of nitrogen oxides, percentage of neutrophils, and interleukin 8 (IL-8) levels were measured in sputum samples, and peroxynitrite inhibitory activity was assayed by monitoring rhodamine formation. RESULTS: Nitrite and nitrate levels in induced sputum were significantly higher in patients with COPD than in normal controls (949 (133) microM v 621 (89) microM, p<0.001). In contrast, peroxynitrite inhibitory activity in induced sputum was significantly lower in patients with COPD than in normal controls (47.4 (12.7)% v 92.9 (3.9)%, p<0.001). There was a negative correlation between nitrite and nitrate levels and peroxynitrite inhibitory activity in induced sputum (r=-0.775, p<0.001). Peroxynitrite inhibitory activity was also significantly correlated with forced expiratory volume in 1 second (FEV(1)) % predicted (r=0.539, p=0.004), FEV(1)/FVC (r=0.512, p=0.006), and carbon monoxide transfer factor (TLCO) (r=0.486, p=0.009). Moreover, there was a significant negative correlation between peroxynitrite inhibitory activity and the degree of neutrophilic inflammation (percentage of neutrophils: r=-0.754, p<0.001; IL-8 levels: r=-0.497, p=0.007). CONCLUSIONS: Reduced peroxynitrite inhibitory activity and increased levels of nitrogen oxides are found in induced sputum from patients with COPD. An imbalance in nitrogen oxides and antioxidant defence may contribute to the pathogenesis of COPD.     

Molecular Mechanisms of Inflammation During Exacerbations of Chronic Obstructive Pulmonary Disease

IntroductionExacerbations of chronic obstructive pulmonary disease (COPD) are characterised by an inflammatory and systemic response that persists for some time after their clinical resolution. The mechanisms of this inflammatory process are not well known.ObjectivesTo explore the inflammatory changes and possible mechanisms during COPD exacerbation.MethodsWe determined the inflammatory cell concentrations in blood and sputum, nitric oxide in exhaled air (FeNO), C-reactive protein (CRP) in plasma, cytokines (IL-6, 8, 1β, 10, 12, TNF-α) and SLPI (leukocyte protease inhibitor) and total antioxidant status (TAS) in blood and sputum, the activity of nuclear kappa B factor (NF-κ B) and of the histone deacetylase enzyme (HDAC) in 17 patients during COPD exacerbation and in stable phase, as well as in 17 smoker and 11 non-smoker controls.ResultsCOPD exacerbations are characterised by high levels of FeNO (p<0.05), plasma CRP (p<0.001) and IL-8, IL-1B, IL-10 in sputum (p<0.05) greater activation of NF-κ appaB in sputum macrophages compared with stable COPD and controls. During the stable phase, there continue to be high levels of oxidative stress, SLPI, IL-8, IL-6 and TNF-alfa, with no observed changes in either HDAC activity or in the amount of neutrophils in sputum, despite presenting a significant improvement (p<0.05) in lung function.ConclusionsChanges were observed in different pulmonary and systemic inflammatory markers during COPD exacerbation, which did not completely resolve during stable phase. However, current treatment does not allow for HDAC activity to be modified, which limits its anti-inflammatory effects.     

The role of plasma endothelin in the Fontan circulation

BACKGROUND: Various vasoactive substances are released during cardiopulmonary bypass. They may deteriorate pulmonary circulation after the Fontan operation. Effects of plasma endothelin-1 (ET-1), a vasoconstricting peptide, on the Fontan circulation have not been investigated. METHODS: Eleven patients (aged 11.1+/-7.5 years) who underwent the modified Fontan operation (group F) and seven patients (aged 9.9+/-6.0 years) who underwent the biventricular repair (group C) were studied. Plasma samples were obtained for measuring ET-1 on the first postoperative day (Early I), on returning to floor care from the intensive care unit (Early II), and during postoperative cardiac catheterization (Late). RESULTS: Plasma concentrations of ET-1 increased in group F (Early I, 4.37+/-1.78 pg/ml; Early II, 4.07+/-1.90 pg/ml) as compared with the basal value of 1.0+/-0.5 pg/ml. The central venous pressure, which reflects the pulmonary circulatory state, soon after the Fontan operation correlated significantly with the increased ET-1 concentration (y=1.809 x+6.484; r=0.809; p=0.0026). Although the Late ET-1 concentrations in group F were significantly decreased, the central venous pressure and the ET-1 concentrations demonstrated a significant correlation (y=3.074 x +5.427; r=0.740; p=0.0227). CONCLUSIONS: The increased humoral vasoactive substances such as ET-1, which induces pulmonary vasoconstriction following the Fontan operation, may have important implications for the Fontan circulation.     

Induced sputum cell profiles in lung transplant recipients with or without chronic rejection: correlation with lung function

BACKGROUND: Sputum induction is a non-invasive procedure for measuring inflammatory processes of the lower respiratory tract. The aim of this study was to establish sputum cell counts and differentials in patients after lung transplantation (LTx), with or without chronic transplant rejection. METHODS: Sputum induction was performed in 41 LTx patients (25 single LTx (sLTx), 16 double LTx (dLTx) and 15 healthy non-smoking volunteers. Sputum was processed according to standard protocols. Total cell count was calculated as mean (SE) cells x 10(6)/ml sputum and cell differential (%) was evaluated after staining. Cellular profiles were correlated with lung function. RESULTS: Total sputum cell counts were increased in sLTx (9 (1.9) cells x 10(6)/ml, p=0.01) and dLTx patients (7.2 (1.5) x 10(6)/ml, p=0.01) compared with healthy controls (2.6 (0.6) x 10(6)/ml). There was also a marked sputum neutrophilia in both patient groups (59 (6)% and 62 (6)%, respectively, p<0.001 v controls). Moreover, in both sLTx and dLTx patients with chronic transplant rejection there was an increased number of sputum neutrophils compared with patients with normal graft function (p<0.05 both comparisons), and neutrophils were inversely correlated with lung function (forced expiratory volume in one second (FEV(1)) % predicted): sLTx, r=-0.61, p=0.001; dLTx, r=-0.75, p=0.001, respectively). Sputum lymphocytes and eosinophils were similar in both groups. No relevant side effects occurred during sputum induction. CONCLUSIONS: Sputum induction is a safe and non-invasive tool for monitoring lower respiratory tract inflammation in LTx patients. Both sLTx and dLTx patients with chronic rejection had increased sputum neutrophils compared with patients with normal transplant function. These data support findings of other authors highlighting a possible role for neutrophils in the pathogenesis of chronic transplant rejection.     

Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD

BACKGROUND: Patients with more frequent exacerbations of chronic obstructive pulmonary disease (COPD) may have increased bronchial inflammation. Airway inflammation was measured in patients who had been thoroughly investigated with full pulmonary function testing, thoracic HRCT scanning, and sputum microbiology to examine further the relationship between exacerbation frequency and bronchial inflammation. METHODS: Airway inflammation (spontaneous sputum sol phase myeloperoxidase (MPO), elastase, leukotriene (LT)B(4), interleukin (IL)-8, secretory leukoprotenase inhibitor (SLPI), protein leakage) and serum levels of C reactive protein (CRP) were compared in 40 patients with stable, smoking related COPD, divided into those with frequent (> or =3/year) or infrequent (< or =2/year) exacerbations according to the number of primary care consultations during the preceding year. The comparisons were repeated after excluding eight otherwise clinically indistinguishable patients who had tubular bronchiectasis on the HRCT scan. RESULTS: Patients with frequent (n=12) and infrequent (n=28) exacerbations were indistinguishable in terms of their clinical, pulmonary function, and sputum characteristics, CRP concentrations, and all of their bronchial inflammatory parameters (p>0.05). The patients without evidence of tubular bronchiectasis (n=32) were equally well matched but the sputum concentrations of SLPI were significantly lower in the frequent exacerbators (n=8) in this subset analysis (p<0.05). CONCLUSIONS: There are several clinical features that directly influence bronchial inflammation in COPD. When these were carefully controlled for, patients with more frequent reported exacerbations had lower sputum concentrations of SLPI. This important antiproteinase is also known to possess antibacterial and antiviral activity. Further studies are required into the nature of recurrent exacerbations and, in particular, the regulation and role of SLPI in affected individuals.     

Renal and hemodialysis clearances of endogenous natriuretic peptide. A clinical and experimental study

The purpose of the present study was to assess the plasma levels of atrial natriuretic peptide (ANP) in chronically uremic patients not submitted to dialysis and to determine the predialysis plasma concentration of ANP, the effect of ultrafiltration on plasma levels of ANP (hemodialysis, (HD), and the HD clearance of ANP in a population of adult patients treated with maintenance HD. The mean plasma ANP concentration (pg/ml) in HD was 370.2 +/- 35.5 pg/ml (mean +/- SEM) before HD and decreased to 165.3 +/- 15.2 after HD (p less than 0.01). Both values were significantly higher than in controls (28 +/- 2; n = 39). The changes in plasma ANP levels correlated inversely with those in plasma protein concentration (r = -0.53; p less than 0.03; y = 48.6 +/- 0.8 x). ANP clearance across the cuprophan membrane averaged 13 +/- 6.4 ml/mn. Resting plasma ANP values in the 16 uremic patients ranged between 16 and 277 pg/ml (124 +/- 11 pg/ml). These levels were significantly higher than those observed in controls (p less than 0.01). In these patients there was a highly significant correlation between serum creatinine and plasma ANP concentrations (p less than 0.01; r = 0.75; y = 0.2x + 3). Furthermore we report the results of the determination of the renal clearance of ANP in normal dogs. In all dogs a fall in plasma ANP concentration was recorded between the aorta (28.6 +/- 4.5 pg/ml) and the renal vein (14.2 +/- 2.7 pg/ml). The renal extraction ratio averaged 51.3 +/- 3.7%. Mean ANP renal clearance was 38.2 +/- 5.2 ml/mn.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neutrophil apoptosis, proinflammatory mediators and cell counts in bronchiectasis

BACKGROUND: Lower airway secretions from patients with bronchiectasis show inflammatory cell infiltration and increased proinflammatory mediators. The aim of this study was to investigate the effects of antibiotic treatment for exacerbations on neutrophil apoptosis and necrosis. METHODS: Sputum was induced from 15 subjects with idiopathic bronchiectasis at the beginning of an acute exacerbation and after intravenous antibiotic treatment. Neutrophil apoptosis and necrosis were assessed using flow cytometry and morphology and the supernatant was analysed for concentrations of inflammatory mediators. RESULTS: Neutrophil numbers (x10(6) cells/g sputum) in sputum were significantly greater on day 0 than on day 14 (median difference (95% confidence interval (CI)) 5.14 (1.27 to 8.46), p = 0.02). Controls had a significantly higher percentage of sputum macrophages than patients with bronchiectasis (day 0, 1.35 (95% CI 0.48 to 2.89), p = 0.004; day 14, 1.09 (95% CI 0.26 to 2.86), p = 0.02). The concentrations of tumour necrosis factor alpha (pg/ml), interleukin 8 (ng/ml), and neutrophil elastase (ng/ml) in sputum supernatant were significantly reduced on day 14 compared with day 0 (median difference -94 (95% CI -158 to -27), p = 0.005; -106 (95% CI -189 to -50), p = 0.0006; and -73 451 (95% CI -135 495 to -12 303), p = 0.02 respectively). Patients with bronchiectasis had a significantly lower percentage of cells which were neither apoptotic nor necrotic than healthy controls (both days, -38.8 (95% CI -49.6 to -8.5), p = 0.002; -45.0 (95% CI -58.0 to -34.1), p = 0.0003, respectively), and on day 14 they had a significantly higher percentage of secondary necrotic cells than healthy controls (40 (95% CI 11.6 to 57.5), p = 0.004). CONCLUSIONS: This study shows that antibiotic treatment affects concentrations of proinflammatory mediators and cell death and clearance may be altered in bronchiectasis.     

Comparison of spontaneous and induced sputum for investigation of airway inflammation in chronic obstructive pulmonary disease

BACKGROUND: Although sputum induction is used as a technique to investigate lower airway inflammation in asthmatic subjects, advantages over spontaneous sputum in patients with chronic obstructive pulmonary disease (COPD) have not been investigated. METHODS: Samples of spontaneous sputum and sputum induced with 3% hypertonic saline for 14 minutes were collected from 27 patients with chronic obstructive pulmonary disease (COPD) who usually produced spontaneous sputum. Spirometric indices and oxygen saturation (Sao2) were measured at seven minute intervals. The spontaneous, seven and 14 minute sputum samples were analysed for total and differential cell counts, cell viability, and interleukin 8 levels. RESULTS: Analysis of the sputum revealed that median cell viability was higher in the seven minute (62.8%; p = 0.004) and 14 minute (65%; p = 0.001) induced sputum samples than in spontaneous sputum (41.2%). There was no significant difference in total and differential cell counts or in interleukin 8 levels between spontaneous and induced sputum. During the sputum induction procedure the mean (SD) fall in forced expiratory volume in one second (FEV1) was 0.098 (0.111) 1 (p < 0.001) and in forced vital capacity (FVC) was 0.247 (0.233) 1 (p < 0.001). There was a small but significant fall in Sao2 during sputum induction (p = 0.03). CONCLUSIONS: Induced sputum contains a higher proportion of viable cells than spontaneous sputum. There are no significant differences between the sputum samples obtained at seven minutes and at 14 minutes of hypertonic saline nebulisation. Sputum induction is safe and well tolerated in patients with COPD.