Smoking is a risk factor for developing chronic obstructive pulmonary disease (COPD), but there are no good indicators for early identification of subjects who will develop symptomatic COPD. The aim of this study was to investigate inflammatory mechanisms related to changes in lung function and emphysematous changes on high resolution computed tomography (HRCT) in 'healthy' smokers. Subjects were 60-year-old men from a population study. Bronchoscopy was performed in 30 smokers and 18 who had never smoked. Blood tests, lung function measurements and HRCT were carried out in 58 and 34 subjects, respectively. In comparison with never-smokers, smokers had higher levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and lysozyme in blood, higher levels of MPO, interleukin-8 (IL-8) and HNL in bronchial lavage (BL), and of IL-8, HNL and interleukin-lbeta (IL-1beta) in bronchoalveolar lavage (BAL). Smokers also had lower levels of Clara cell protein 16 (CC-16) in blood. HNL in BL and BAL showed strong correlations to other inflammatory markers (MPO, IL-8, IL-1beta). The variations in MPO in BL were explained by variations in HNL (R2 =0.69), while these variations in BAL were explained by variations in HNL and IL-1beta (R2 = 0.76). DL(CO) was the lung function variable most closely related to MPO and IL-8 in BL and BAL and to IL-1beta in BAL. In a multiple regression analysis, MPO, IL-1beta, IL-8 and CC-16 in BL and MPO in BAL contributed to the explanation of variations in DL(CO) to 41% and 22%. respectively, independent of smoking habits. In smokers with emphysematous lesions on HRCT, HNL in BAL correlated to emphysema score (r(s) = 0.71). We conclude that 'healthy' smoking men with a near normal FEV1 show signs of inflammation in the lower airways that are related to a decrease in DL(CO) and to emphysematous lesions on HRCT. This inflammation seems to be the result of both monocyte/macrophage and neutrophil activation.
Background-Formoterol and salmeterol are new long acting P2 adrenoceptor agonists. The maximum relaxant effect, potency and functional antagonism against carbachol induced contraction for salmeterol, formoterol and salbutamol have been compared in the guinea pig isolated trachea. In addition, the possibility of inducing a non-fl adrenoceptor mediated relaxation by salmeterol was studied. Methods-Concentration response experiments were conducted with isolated tracheal preparations (n = 4-6 in all experiments), precontracted by carbachol to cause either 40% (60 nmol/l), 80% (0.3,umol/l) 75% (5%) v 71% (12%) of precontraction). In the non-cumulative experiments, formoterol displayed more relaxant effect than salmeterol (remaining active tension: 51% (6%) v 65% (6%) of precontraction). Finally, formoterol significandy relaxed salmeterol relaxed airways (relaxant effect: 22% (8%) of precontraction) whereas there was no significant response to salmeterol in formoterol relaxed airways (relaxant effect: 5% (12%) of precontraction). Conclusions-In the guinea pig isolated trachea, formoterol and salbutamol produce more relaxant effect than salineterol, suggesting that salmeterol is a partial #2 agonist. Very high concentrations of salmeterol may induce non-fl adrenoceptor mediated relaxation. Formoterol is more potent than both salbutamol and salmeterol. There is no pronounced difference in the magnitude of antagonism against carbachol induced contractions between salmeterol, formoterol, and salbutamol. (Thorax 1993;48:547-553) In acute severe asthma there is a high level of airway smooth muscle contraction.' 2 Clinical trials of fl2 adrenoceptor agonists are, however, often performed in subjects with mild to moderate asthma3-5 and in vitro studies often examine the relaxant effect of /32 agonists on airway smooth muscle at a single moderate level of precontraction.6-l0The /2 agonists salmeterol and formoterol produce bronchodilation of long duration in human subjects3-5 11-13 as well as in guinea pig isolated airways.67 1O1F17 It is not known whether the rank order of the maximum relaxant effect and potency of salmeterol and formoterol differ at various levels of airway smooth muscle contraction and are different from salbutamol.
To better understand the mechanism of ozone-induced airway hyperresponsiveness we determined the time course of the ozone effect in dogs. To do this we assessed airway responsiveness before ozone exposure and then at 1 h, 1 day, and 1 wk after ozone exposure. To assess responsiveness we anesthetized the dogs and obtained dose-response curves of increasing concentrations of acetylcholine or histamine aerosols delivered to the airways vs. pulmonary resistance. Ozone exposures were carried out with the dogs awake and at rest in an exposure chamber for 2 h breathing either through the nose and mouth at a level of 2.2 ppm or through a tracheostomy at a level of 1.0 ppm. For both acetylcholine and histamine and for both routes of ozone delivery airway responsiveness increased most markedly at 1 h after ozone, increased to a lesser degree 1 day later, and returned to control levels by 1 wk. The results are similar to our previous studies in humans that showed that ozone-induced hyperresponsiveness occurs shortly after exposure and is rapidly reversible and suggest that the ozone effect is linked to an acute inflammatory response in the airways.
We determined whether neutrophil recruitment induced by the T-lymphocyte cytokine, interleukin-17 (IL-17) is modulated by tachykinins in airways in vivo. Cell recruitment into airways was induced by either human (h) IL-17 (1 microgram) or rat (r) IL-1beta (2. 5 ng), instilled intratracheally in rats (n = 5 to 7). Six hours after instillation, hIL-17 (3.1 +/- 1.2 x 10(6) cells/ml) and rIL-1beta (4.1 +/- 0.5 x 10(6) cells/ml), respectively, induced a significant and selective increase in neutrophil count in bronchoalveolar lavage fluid (BAL) when compared with vehicle (0.6 +/- 0.2 x 10(6) cells/ml). For hIL-17, this effect was dose-dependent. Inhalation of peptidase inhibitors (phosphoramidon plus captopril) potentiated the effect of both hIL-17 and rIL-1beta. Inhalation of a neutral endopeptidase inhibitor (phosphoramidon) alone also increased the neutrophil count for hIL-17, whereas an angiotensin-converting enzyme inhibitor (captopril) alone did not. A selective neurokinin (NK)-1 receptor antagonist (SR 140333) reduced the neutrophil count, both with and without phosphoramidon pretreatment. In conclusion, IL-17 selectively recruits neutrophils into rat airways in vivo and this effect is modulated by endogenous tachykinins acting via NK-1 receptors.
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