Alterations of the pulmonary surfactant system in sepsis

Pulmonary surfactant is a phospholipid-protein material secreted from type II pneumocytes that coats the inner surface of the lung. The functions of surfactant include reducing surface tension thereby stabilizing the lung, as well as participating in innate host defense. Alterations of the pulmonary surfactant system have been observed in patients with the acute respiratory distress syndrome (ARDS) and contribute to the associated lung dysfunction. Despite extensive research efforts the mortality of ARDS remains unacceptably high, ranging from 30--70%. Sepsis is the most common cause of ARDS and is associated with the highest mortality compared to other predisposing conditions. The major goal of the research presented in this thesis was to determine if changes in the endogenous surfactant system occur in sepsis, and investigate possible mechanisms responsible for these changes. To achieve this goal, an animal model that mimicked the pathophysiology of sepsis in humans was developed. This model involved the cecal ligation and perforation (CLP) procedure, to induce peritonitis and subsequently systemic sepsis. Mechanical ventilation, the main supportive therapy for patients with respiratory failure was also investigated as a factor contributing to the pathogenesis of sepsis-induced ARDS, as this intervention has been shown to have harmful effects on the lung.;An important and novel finding from these series of experiments was that alterations in the surfactant system occurred early in the development of sepsis before significant lung dysfunction was present. Experiments utilizing transgenic animals showed that surfactant protein (SP)-A had no role in the development of sepsis-induced lung injury, both with respect to the surfactant changes observed, and the development of pulmonary inflammation. In addition, although exogenous surfactant administration did not mitigate the lung injury associated with spontaneously breathing septic animals, it did protect against the mechanical ventilation-induced lung dysfunction observed in this model.;Therefore, we have shown that alterations of the alveolar surfactant system occur relatively early after a systemic insult, prior to the development of lung injury. Although these surfactant changes did not contribute to the development of sepsis or the associated lung dysfunction in this model, they did predispose the host to a subsequent insult, thereby resulting in severe lung dysfunction.