Ventilator-induced lung injury : pathogenesis & therapeutic interventions

Although mechanical ventilation is a life-saving procedure at the intensive care unit, it may exacerbate or even induce damage to the lung itself (ventilator-induced lung injury, VILI). Mechanical ventilation destabilizes alveolar-capillary barriers thereby leading to protein-rich edema formation and impaired gas exchange. It has been thought that cell death and loss of cell integrity are important in the ventilator-induced disruption of alveolar-capillary barriers. We observed that necrosis, and not apoptosis, is the major executive mechanism of cell death in our model of VILI. Moreover, we showed that mechanical ventilation causes significant changes in the angiopoeitin-Tie2 system which is involved in the maintenance of endothelial cell integrity. These data imply that the angiopoietin-Tie2 system and necrotic cell death may be crucial in the development of VILI. An intriguing clinical observation is that most ventilated critically-ill patients do not succumb to acute lung failure but to multiple organ failure (MOF). In this respect, we showed that mechanical ventilation increased the pro-inflammatory state of the lung but also of organs distal to the lung, like liver and kidney. These data indicate that alveolar stretch due to mechanical ventilation may play a significant role in the pathogenesis of MOF. The main focus was to evaluate whether different therapeutic interventions protect against various aspects of VILI like inflammation, protein-rich edema formation and impaired gas exchange. It has been recognized that granulocytes and inflammatory mediators play an essential role in the pathogenesis of VILI. Consequently, anti-inflammatory agents like dexamethasone have been used to attenuate or prevent detrimental effects induced by mechanical ventilation. Although dexamethasone effectively inhibits ventilator-induced lung inflammation, systemic administration may cause severe side effects like increased blood glucose levels. Drug delivery systems aimed at preventing these unwanted systemic side effects could therefore be of therapeutic importance. We showed that liposome-encapsulated dexamethasone was capable of inhibiting important parameters of ventilator-induced lung inflammation. Since lung inflammation may precede injury, we investigated if the anti-inflammatory action of dexamethasone could diminish protein-rich edema formation and impaired gas exchange. These more ‘crude’ parameters of VILI however were not affected by dexamethasone treatment. Furthermore, we examined if treatment with angiopoietin (Ang)-1 (Tie2 receptor agonist) protects against the detrimental effects of mechanical ventilation. We observed that Ang-1 inhibited granulocyte infiltration and inflammatory mediator expression induced by mechanical ventilation. Nonetheless, Ang-1 did not prevent protein-rich edema formation and impaired gas exchange induced by mechanical ventilation. Taken together, we propose that prevention of lung inflammation does not preclude a loss of pulmonary function in our experimental model of VILI. In this respect, we would like to propose that anti-inflammatory agents should not be used to combat the mechanosensitive aspects of VILI. However, anti-inflammatory therapy may well be considered when inflammation is the primary inducer of lung injury, like in non-ventilated patients diagnosed with inflammatory lung diseases. Finally, the findings in this thesis suggest that future therapeutic interventions in the ventilated, critically-ill patient should aim at attacking the ventilator-induced impairment of alveolar-capillary barrier function for instance with inhibitors of necrosi