The role of the endothelin system in experimental acute lung injury : With special reference to the formation of extra-vascular lung water

Abstract: Acute lung injury is a major clinical challenge in the intensive care unit. Sepsis is the most frequent underlying cause of this pulmonary syndrome, which contains inflammation- induced diffuse alveolar damage and early stage high permeability edema. In spite of extensive research few therapies have reached the clinical arena, a fact that calls for additional interventional strategies. The role of the endothelin system in pulmonary disease has been established, and recently it has also been implicated in the pathogenesis of acute lung injury. The 21-amino acid endothelin-1(ET-1), has in addition to its vasoconstrictive properties also mitogenic and permeability increasing effects. Consequently, endothelin receptor antagonism might be a potential therapeutic strategy in acute lung injury. The major aim of this thesis was to investigate the role of the endothelin system in the pathophysiology of endotoxin-induced acute lung injury, with special attention to edema formation. Moreover, we wanted to evaluate two different indicator dilution methods for assessment of the extra-vascular lung water in relation to the well established gravimetrical method. Endotoxin induced a severe deterioration in pulmonary function and gas-exchange along with increased extra-vascular lung water, pulmonary capillary pressure and pulmonary venous vascular resistance. The molecular double indicator dilution method for measurement extra-vascular lung water was unable to detect any change in this parameter despite a two-fold increase measured by gravimetry. The thermal single indicator method systematically overestimated extra-vascular lung water and was influenced by regional changes in ventilation and perfusion. This method relies on an empirically derived relationship between the intrathoracic blood volume and the global end diastolic volume. By simultaneous measurements of these parameters we found their relationship to be altered during endotoxemic conditions. However, the method was able to detect relative changes in extravascular lung water over time during endotoxemia. The dual (ETA/ETB) endothelin receptor antagonist tezosentan abolished the endotoxininduced increase in extra-vascular lung water, pulmonary capillary pressure and pulmonary venous resistance and improved gas-exchange. Furthermore, in vivo challenges with ET-1 and the ETB receptor agonist sarafotoxin increased pulmonary capillary pressure and pulmonary venous vascular resistance. Congruent results were obtained in vitro by the same agents. These findings point towards the importance of the ETB receptor in endotoxin-induced pulmonary hypertension. We conclude that during endotoxemia the endothelin system is involved in development of venous pulmonary hypertension and edema formation which may be prevented by dual ET receptor antagonism. When we tried to estimate pulmonary edema with either molecular double indicators or a single thermal indicator we found inaccuracies, which raise the question of their use in the clinical situation. Our results together with growing evidence that show the potential of ET receptor antagonists to reduce inflammation, permeability and possibly pulmonary fibrosis, suggest that we might have come to a point where clinical studies could be of interest.