Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process.

Patients with COPD can be assigned a clinical phenotype reflecting the prevalent mechanism of airflow limitation. The standardized identification of the predominant phenotype may permit to clinically characterize COPD beyond its unifying spirometric definition.

AimsThis study aimed at evaluating changes in airway patency, lung volumes and perception of breathing discomfort intensity following salbutamol administration via the Diskus dry-powder inhaler (DPI) or a pressurized metered-dose inhaler with the Volumatic valved holding chamber (pMDI + Volumatic) in asthmatic patients with methacholine-induced bronchoconstriction. MethodsOn six different study days, 18 patients inhaled methacholine until forced expiratory volume in 1 s (FEV 1 ) decreased by approximately 35% of baseline. Following placebo, 200 and 400 m g of salbutamol through the pMDI + Volumatic or the Diskus, changes in FEV 1 , volume-adjusted mean forced expiratory flow from 25 to 75% of the forced vital capacity (isoFEF 25 -75 ), lung volumes and breathing discomfort intensity, assessed by visual analogue scale (VAS) score, were repeatedly measured over a 60-min observation period. ResultsInduced bronchoconstriction was accompanied by obvious reductions in lung volumes and increases in VAS score. After salbutamol administration, FEV 1 and VAS score changes were similar in all experimental conditions. However, following 400 m g salbutamol via pMDI + Volumatic, isoFEF 25 -75 values increased up to 4.48 l s -1 (95% confidence interval 4.06, 4.90), a significantly ( P < 0.01) higher value than those attained in all other experimental conditions. Independently of the salbutamol dose, lung volumes rose to significantly ( P < 0.01) higher levels in pMDI + Volumatic than in Diskus trials. The low salbutamol dose via the pMDI + Volumatic and the high dose via the DPI increased isoFEF 25 -75 and lung volumes to similar extents. ConclusionsSalbutamol via the pMDI + Volumatic provides greater isoFEF 25 -75 and lung volume increases in asthmatic patients with induced bronchoconstriction; salbutamol-induced changes in VAS scores poorly reflect those in small airway patency. The lack of differences in FEV 1 increases observed after 200 and 400 m g salbutamol may reflect attainment of the flat portion of the dose-response curve using either device. Responses to salbutamol inhaled via different devices in asthmatic patientsBr J Clin Pharmacol 58 :5 513

AimsTo evaluate the speed of onset of bronchodilation following salbutamol administered via a metered-dose inhaler with a spacer (pMDI + Volumatic) and a dry-powder inhaler (Diskus), as well as the relative potencies of these devices in asthmatic patients with methacholine-induced bronchoconstriction. MethodsEighteen patients inhaled methacholine (MCh) until FEV 1 decreased by 35% of control. Following administration of placebo, 200 µ g salbutamol or 400 µ g salbutamol through the pMDI + Volumatic or the Diskus, we calculated the time elapsed from drug administration and the appearance of a 90% increase in post-MCh forced vital capacity (FVC), FEV 1 and volume-adjusted mid-expiratory flow (recovery times). The salbutamol doses to be delivered by the two inhalation devices to achieve similar recovery times and the relative potencies of the devices were calculated by using the 2-by-2 Finney parallel regression method. ResultsFor all functional variables, recovery times were significantly ( P < 0.01) shorter in pMDI + Volumatic than Diskus trials. The salbutamol doses to be delivered by the Diskus to achieve recovery times for FVC, FEV 1 and volume-adjusted mid-expiratory flow similar to those obtained with 200 µ g salbutamol administered via the pMDI + Volumatic were 558 (95% CI 537, 579) µ g, 395 (95% CI 388, 404) µ g and 404 (95% CI 393, 415) µ g, respectively, and corresponded to relative potencies of 2.79 (95% CI 2.68, 2.90), 1.98 (95% CI 1.94, 2.02), and 2.02 (95% CI 1.96, 2.07). ConclusionsAdministration of salbutamol via the pMDI + Volumatic provides faster reversal of induced bronchoconstriction than via the Diskus. The salbutamol dose targeting the lungs with the pMDI + Volumatic is approximately twice that with the Diskus.

No abstract