Effect of the oral leukotriene B4 receptor antagonist LTB019 on inflammatory sputum markers in patients with chronic obstructive pulmonary disease.

This study aimed to evaluate the effect of a LTB4 receptor antagonist on inflammatory markers in induced sputum, in particular sputum neutrophilia, in ex-smokers with moderate stable chronic obstructive pulmonary disease (COPD). The trial followed a double-blind, randomized, cross-over design including two treatment periods (4 weeks) separated by a 4-week washout period. Sputum inductions and lung function measurements were carried out at the beginning of each period, and after 2 and 4 weeks. Twenty-four patients were included (18/6 m/f; mean (+/-S.D.) age 64+/-5 years; FEV 1 57+/-10% predicted); the per-protocol population comprised 17 patients. No significant differences occurred between LTB019 and placebo regarding the percentage of sputum neutrophils (treatment means, 68.0% vs. 69.3%), total cell count (in units of 10(6)/mL, log e of treatment means: 1.56 vs. 1.27), or the levels of MPO, IL-8, and TNF-alpha. There were also no differences in FEV 1, FVC, or the use of rescue medication. We therefore conclude that a 4-week treatment with LTB019 had no effect on sputum neutrophil numbers and related cytokine levels in these patients, despite the plasma concentrations achieved being similar to those shown to prevent the ex vivo LTB4-induced upregulation of CD11b/18 on neutrophils. The present data suggest that LTB4 antagonism by LTB019 is not a promising therapeutic approach for attenuating chronic airway neutrophilia, at least in patients with moderate COPD.

Interleukin-2 inhalation therapy temporarily induces asthma-like airway inflammation.

BACKGROUND: Inhaled interleukin-2 (IL-2) is an effective and safe treatment in metastasing renal cell carcinoma (mRCC) but known to potentially elicit respiratory symptoms. OBJECTIVES: The present study analyses the effects of IL-2 using a panel of measures including markers of airway inflammation. METHODS: Ten patients with mRCC (7m/3f; mean age, 63 yrs) were measured at baseline, 6-10 days after start of therapy (n = 5, inhaled IL-2 only; n = 5, inhaled IL-2 plus 1/11th of daily dose subcutaneously), and 16-29 days later under continuous combined (inhaled plus subcutaneous) therapy, including additional subcutaneous IFN-alpha in 8 patients. RESULTS: After start of therapy median FEV1 declined from 108 to 85 to 90 % predicted and the provocative concentration of methacholine eliciting a 20 % fall in FEV1 (PC20 FEV1) from 16 to 8 to 3 mg/mL, while the level of exhaled nitric oxide (FENO) rose from 27 to 79 to 60 ppb and the percentage of sputum eosinophils from 2 to 18 to 37 % (p<0.01, each), accompanied by cough and dyspnoea (p<0.05). One patient who stopped therapy, was back to baseline values when measured 2 months later. Cytokine production by blood or sputum T lymphocytes was not markedly altered by IL-2 inhalation. CONCLUSIONS: IL-2 inhalation therapy in patients with metastasing renal cell carcinoma is capable of temporarily inducing symptomatic, functional and inflammatory alterations similar to those of bronchial asthma.

Reproducibility of forced inspiratory and expiratory volumes after bronchodilation in patients with COPD or asthma.

The aim of the present study was to assess the reproducibility of changes in forced inspiratory volumes after bronchodilator inhalation. Thirteen patients with chronic obstructive pulmonary disease (COPD) (FEV1, 32-75%pred) and 10 patients with asthma (FEV1, 43-75%pred) inhaled either 200 microg fenoterol or 200 microg oxitropium bromide or placebo, each of them on three occasions, on nine different days in a randomised, cross-over, double-blind fashion. Forced expiratory (FEV1) and inspiratory (FIV1) volumes were measured before and 30 min after inhalation. In patients with COPD, the increase in FEV1 (coefficient of variation) was 221 ml (43%) after fenoterol and 235 ml (33%) after oxitropium; changes in FIV1 were 301 ml (45%) and 360 ml (29%). In patients with asthma, FEV1 improved by 618 ml (26%) and 482 ml (25%), FIV1 by 553 ml (41%) and 475 ml (23%). In less severe COPD or asthma, the reduction in dyspnoea was associated with the improvements in both FIV1 and FEV1, but in severe COPD with the improvement in FIV1 only. The data demonstrate that, at least in terms of relative changes, the reproducibility of bronchodilator responses in terms of FIV1 is similar to that of FEV1 and they underline the assertion of FIV1 being a sensible parameter particularly in severe COPD.

The relationship between airway hyper-responsiveness, markers of inflammation and lung function depends on the duration of the asthmatic disease.

BACKGROUND: The combination of airway hyper-responsiveness, eosinophilic airway inflammation, and lung function impairment is considered as a hallmark of bronchial asthma. Since airway function might change with time in chronic asthma, the association between parameters which are characteristic of asthma could be different in subjects with different durations of the disease. OBJECTIVE: We assessed whether in patients with asthma the relationship between airway hyperresponsiveness, non-invasive markers of airway inflammation, and baseline lung function depended on the duration of the disease. METHODS: Sixty-six non-smoking patients with mild to moderate allergic asthma without corticosteroids were assigned to two groups, according to a duration of the disease (time interval since doctor's diagnosis) of either < or = 16 years (median 8 years; mean FEV1, 92.6% pred.; n = 34) or > 16 year (median 25 years; mean FEV1, 87.9% pred.; n = 32). RESULTS: Groups did not differ statistically in PC20FEV1 of methacholine, sputum composition, levels of exhaled nitric oxide (NO), lung function parameters, or history of treatment. There were significant correlations between PC20FEV1, eosinophils and NO in patients with a duration of the disease < or = 16 year, but no relation to lung function. In contrast, patients with a duration > 16 year showed a correlation between PC20FEV1 of methacholine and lung function but not eosinophils or NO. In both groups, eosinophils and NO were associated with each other. These results were corroborated by the statistical procedure of factor analysis that revealed 'inflammation' and 'lung function' as major entities and found 'responsiveness' to be associated with only one of them in each group. CONCLUSION: Our data demonstrate that with a shorter duration of the asthmatic disease airway hyper-responsiveness is associated with airway inflammation, whereas with a longer duration it is associated with impaired lung function, suggesting that in chronic asthma ongoing alterations become the primary determinant of functional characteristics.

A short protocol for methacholine provocation testing adapted to the Rosenthal-Chai dosimeter technique.

BACKGROUND: The purpose of this study was to develop a rapid and safe methacholine provocation protocol equivalent to the standard dosimeter technique. METHODS: The rapid protocol comprised a short and a long subprotocol. The challenge was started with one of these subprotocols according to the subject's answers to a questionnaire and baseline lung function. If FEV1 dropped by 10% during the short subprotocol, the test was continued with the long subprotocol. The concentrations of methacholine and numbers of inhalations were chosen to match the concentrations of the standard method as closely as possible. To verify the protocol, we compared both methods in 38 subjects with asthma and 10 control subjects. RESULTS: The provocative concentrations of methacholine (PC20FEV1) obtained with the standard method and the rapid method were within one doubling concentration in 38 of 40 subjects. None of the subjects who were normoreactive according to the standard method (PC20FEV1 > 8 mg/mL) responded in the rapid protocol. The standard method required, on average (+/-SD), 34+/-11 min; the rapid method required 15+/-3 min. CONCLUSIONS: The rapid provocation protocol is equivalent to the standard method, without loss in precision and safety, but with considerable saving in time. Therefore, it appears to be particularly suited for studies that require comparability with provocative concentrations obtained with the Rosenthal-Chai dosimeter method.

Mitochondrial myopathy: tissue-specific expression of a defect in ubiquinol-cytochrome c reductase.

We have expanded our studies on a patient with a mitochondrial myopathy caused by a defect at the level of complex III of the respiratory chain. Using activity measurements, electron microscopy, protein synthesis in the presence of emetine, and antibody binding, we have demonstrated that the defect is not expressed in cultured skin fibroblasts from this patient. Electron microscopy of peripheral blood leukocytes and activity measurements in transformed lymphoid cells indicated that the defect was not expressed in these cells either. These results imply that there are either isoforms of complex III components which show differential tissue expression or that independent segregation and assortment of defective mitochondria has occurred during development.