grantor:
University of TorontoVentilator-induced lung injury is recognized as a source of significant morbidity and mortality in intensive care units. Until recently, studies examining the pathophysiology of this disorder focused almost exclusively on the physiological effects and structural sequelae of different ventilatory strategies. These studies demonstrated that ventilation at either extreme of lung volume is injurious, and can produce injury comparable to that observed with the acute respiratory distress syndrome. In this thesis we explored the hypothesis that there is an active cellular and molecular mediated component involved in the pathogenesis of ventilator-induced lung injury. Using an isolated rat lung model to assess the effect of ventilation on the lung independent of confounding hemodynamic or systemic effects, we demonstrated that ventilation with strategies that produced high end-inspiratory or low end-expiratory lung volume increased inflammatory cytokine production by the lung. The time course of production of TNFÃ at the protein and steady state mRNA levels was found to be dependent on both time and the particular ventilator strategy used. Increased TNFÃ appeared to precede signs of histologic injury, and was associated with evidence of surfactant dysfunction. In situ hybridization for TNFÃ and IL-6 revealed that injurious ventilation produced an increase in expression of these inflammatory cytokines by the vast airway and alveolar epithelium. In contrast, epithelial expression of these cytokines in lungs subjected to non-injurious ventilation was significantly less, and comparable to that seen in lungs freshly harvested. As the epithelium of the lung is exposed directly to the mechanical stresses of ventilation, further studies were performed 'in vitro' to assess whether cell stretch was responsible, in part, for inducing the changes in alveolar epithelial cytokine expression we observed. We conclude that mechanical ventilation can have a significant effect on the inflammatory response of the lung and that this may be important in the initiation and propagation of lung injury, as well as potentially the development of a persistent systemic inflammatory response. We speculate that the use of interventions that target the inflammatory sequelae of ventilation combined with manipulation of ventilatory parameters may reduce the morbidity and mortality of patients with acute respiratory failure.Ph.D
