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COPD: cells and genes

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1R. Carter, 2R. Mumford, 2K. Treonze, 1R. Stockley. 1University Hospital Birmingham, Birmingham, UK, 2MSD, Rahway, USA

Initial descriptions of the association between α-1-antitrypsin deficiency (AATD) and lower zone pulmonary emphysema1 were closely followed by the confirmation that neutrophil elastase (NE) could induce emphysema in animal models.2 Mathematical and in vitro models have demonstrated an exponential relationship between released enzyme activity and distance from the neutrophil3 4 and since the neutrophil NE concentration at release is substantially higher than the physiological concentration of AAT an area of obligate proteolytic damage will occur, which is substantially larger in patients with AATD. This process of quantum proteolysis is a simple concept that explains the increased susceptibility of subjects with AATD to emphysema, but, since it occurs in the neutrophil microenvironment, it has been difficult to demonstrate in vivo. The aim of this study was to explore the relationship of a specific (preinhibition) NE cleavage product of fibrinogen (Aα360) to AAT and the presence of airflow obstruction in deficient subjects.

Methods Plasma Aα360 was measured in a group of 68 subjects with a wide range of plasma AAT levels. Subsequently, postbronchodilator spirometry was related to plasma Aα360 concentrations in a further 72 patients (49 male and 23 female) with PiZ AATD in the stable state. Correlations were determined using non-parametric statistical tests.

Results Aα360 showed an exponential relationship to plasma AAT concentration that increased at levels <11 μm (the putative protective threshold), as shown in fig 1, consistent with theoretical modelling and in vitro experiments. The mean forced expiratory volume in 1 s (FEV1) and FEV­:vital capacity (VC) were 50.7% predicted and 37.26%, respectively, and 61 patients had an FEV1:VC <70%. There was no relationship between Aα360 and age, height, gender …

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