In a variety of diseases, inflammation causes microvascular leakage and activates thrombin. Evidence suggests that thrombin increases cytosolic calcium and stimulates human airway smooth muscle (ASM) cell proliferation. The receptor subtypes, however, that mediate the effects of thrombin on ASM cell growth or calcium mobilization remain unknown. In this study, we postulate that thrombin, which activates specific protease-activated receptors (PARs), also stimulates contraction of isolated human bronchial rings. With the use of intact human bronchial rings, α-thrombin (1–20 U/ml) increased bronchial tone to 19 ± 3% of basal tone ( P = 0.008; n = 5 experiments) and represents 20 ± 8% of the maximum carbachol response. The EC50 for thrombin-induced force generation was 12.2 U/ml (95% confidence interval 9.9–15.3 U/ml) and was not altered in bronchial rings that had the epithelium removed. In parallel experiments, a specific thrombin receptor-activating peptide (TRAP-14; 0.1–100 μmol/l) increased isometric tension to levels (14 ± 2%; P = 0.0005; n = 5 experiments) comparable to those rings stimulated with thrombin. To characterize the receptors that mediate thrombin effects on human ASM, the expression of PARs in cultured human ASM cells was analyzed by RT-PCR analysis with specific primers for PARs. In these cells, PAR1 (thrombin receptor), PAR2, and PAR3 were expressed at comparable levels. In other experiments using immunocytochemical staining with specific antibodies to PAR1 and PAR2, we showed that ASM in bronchial rings and cultured ASM cells express PAR1 and PAR2 proteins. Taken together, these studies suggest that α-thrombin, in a receptor-specific and dose-dependent manner, induces contraction of bronchial rings in vitro. In addition, cultured human ASM cells express mRNA of PAR1, PAR2, and PAR3 and express PAR1 and PAR2 protein. Further studies are needed to determine whether α-thrombin plays a role in stimulating bronchoconstriction in inflammatory airway diseases such as asthma and bronchiolitis obliterans.

Our study shows that BALF contains inhibitory components for non-viral gene transfer. We could not detect a specific inhibitory component, but inhibition was most likely due to the change in the surface charge of the gene vectors. Interestingly, there is evidence for complement activation when the route of pulmonary gene vector administration is chosen. Consequently, shielding of gene vectors to circumvent interaction with the ASL environment should be a focus for pulmonary administration in the future.

Service management has been a hot topic in the research community for the last couple of years. However, due to the complexity of this research area, no commonly accepted definition of the terms service, service management, and the associated management tasks has evolved yet. This paper contributes to the ongoing process of defining these terms by proposing a top-down oriented and systematic methodology that is used to analyze and identify the necessary actors and the corresponding inter-and intra-organizational relationships. Then, a generic service model is introduced that defines commonly needed servicerelated terms, concepts and structuring rules in a general and unambiguous way. Since most of the work that is being presented here is still in flux, the service model is finally used to identify and structure open research questions.

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