Jet and ultrasonic nebulization of single chain urokinase plasminogen activator (scu-PA)

Recent studies have indicated that the deposition of intra-alveolar fibrin may play a central role in the pathogenesis of acute respiratory distress syndrome (ARDS). Our aim was to study whether the indigenous fibrinolytic agent (urokinase) normally present in the alveoli can be administered locally by nebulization in a recombinant zymogen form as single chain urokinase plasminogen activator (scu-PA). We aimed to characterize the particle size distribution, drug output, and enzymatic activity of scu-PA after nebulization with a Ventstream jet nebulizer (Medic-Aid, Bognor Regis, UK) and a Syst'AM DP-100 ultrasonic nebulizer (Pulmolink, Kent, UK). The particle size distribution was measured with a laser diffraction method and the drug output was determined by collection on filters. The amount of protein on the filters was determined with the Lowry method, and the enzymatic activity after nebulization was measured with a microtiter fibrin plate assay. The mass median diameter (MMD) of the scu-PA aerosol generated with the ultrasonic nebulizer was 3.69 (3.53-3.83) microm and with the jet nebulizer 2.96 (2.91-3.03) microm (p < 0.001). The drug output from the two nebulizers did not differ between nebulizers (p = 0.054). Fibrinolytically active scu-PA was generated with both nebulizers, but in contrast to jet nebulization, ultrasonic nebulization caused partial inactivation of scu-PA (p < 0.001). In conclusion, nebulization of scu-PA with the jet nebulizer is superior to ultrasonic nebulization in terms of particle size distribution and preservation of fibrinolytic activity.