RESUMO
Pulmonary thrombosis is a significant cause of patient mortality; however, there are no effective in vitro models of thrombi formation in human lung microvessels that could also assess therapeutics and toxicology of antithrombotic drugs. Here, we show that a microfluidic lung alveolus-on-a-chip lined by human primary alveolar epithelium interfaced with endothelium and cultured under flowing whole blood can be used to perform quantitative analysis of organ-level contributions to inflammation-induced thrombosis. This microfluidic chip recapitulates in vivo responses, including platelet-endothelial dynamics and revealed that lipopolysaccharide (LPS) endotoxin indirectly stimulates intravascular thrombosis by activating the alveolar epithelium, rather than acting directly on endothelium. This model is also used to analyze inhibition of endothelial activation and thrombosis due to a protease activated receptor-1 (PAR-1) antagonist, demonstrating its ability to dissect complex responses and identify antithrombotic therapeutics. Thus, this methodology offers a new approach to study human pathophysiology of pulmonary thrombosis and advance drug development.
Assuntos
Barreira Alveolocapilar/efeitos dos fármacos , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Fibrinolíticos/farmacologia , Dispositivos Lab-On-A-Chip , Técnicas Analíticas Microfluídicas/instrumentação , Microvasos/efeitos dos fármacos , Alvéolos Pulmonares/irrigação sanguínea , Trombose/tratamento farmacológico , Barreira Alveolocapilar/metabolismo , Barreira Alveolocapilar/patologia , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Medicina Baseada em Evidências/métodos , Humanos , Microvasos/metabolismo , Microvasos/patologia , Segurança do Paciente , Medição de Risco , Transdução de Sinais/efeitos dos fármacos , Trombose/metabolismo , Trombose/patologia , Pesquisa Translacional Biomédica/métodosRESUMO
Changes in the delivery of health care and changes in population characteristics and health care requirements mandate changing requirements in nursing education. This is necessary to meet patient and family needs and to deliver quality health care. This paper describes the background to nursing education in the Nordic countries and gives an account of an initiative in Norway to prepare advanced practice nurses for clinical practice in this dynamic environment.