Ventilation and virus induced inflammation

Summary

This thesis expands current knowledge on ventilator induced lung injury and provides insights on the immunological effects of mechanical ventilation during viral respiratory infections. The experimental studies in the first part of this thesis improve our understanding of how mechanical ventilation induces lung injury in healthy lungs. It is shown that mechanical ventilation causes pulmonary endothelial activation and inflammation as well as inflammation in organs distal to the lungs. In addition we demonstrate that lung protective ventilation (aimed at limiting peak pressures and tidal volumes with sufficient PEEP), attenuates but not completely abolishes pulmonary inflammation. We investigated the effects of 2 drugs (dexamethasone and angiopoietin-1) in the treatment and/or prevention of ventilator induced lung injury (VILI). Neither drug had a beneficial effect on ventilator induced vascular leakage and lung dysfunction despite a clear down regulation of neutrophil infiltration and protein expression of pro-inflammatory mediators. Interestingly, none of the pharmacological interventions studied by others have been successful in either treating or preventing VILI. To date, only lung protective mechanical ventilation has proven to be effective in preventing VILI. In the second section part of this thesis, we focus on ‘virus induced inflammation’ and its possible interaction with ventilator induced inflammation. First, factors associated with turning an essentially trivial community acquired RSV infection into a life-threatening disease are reviewed. In addition, we show that mechanical ventilation during experimental RSV infection enhances pulmonary inflammation, reflected by increased influx of cells and pro-inflammatory cytokines in the bronchoalveolar space. Gene expression analysis demonstrates that this enhanced inflammation is attributable to the ventilator induced distinct molecular stress response additive to, but not aggravating, the innate immune response seen in RSV. Furthermore, we show that the use of low tidal volumes (6 ml/kg), as compared to high tidal volumes (12 ml/kg), partially prevents ventilation-induced cellular and cytokine influx into the bronchoalveolar space during experimental RSV LRTI. Previous clinical studies showed increased levels of inflammatory mediators in airways of RSV infected ventilated children. In these studies cytokine analysis was performed on samples collected while patients were already ventilated. We demonstrate that the need for mechanical ventilation in RSV-infected infants is not associated with enhanced virus-induced pulmonary inflammation at baseline. Using pre- and post-intubation observations we show that endotracheal intubation and subsequent mechanical ventilation induces additional inflammation expressed by increased levels of cytokine concentrations in nasopharyngeal aspirates after 24 hours. This is in concordance with results from our experimental studies. Finally, using a human genetic study as well as an experimental model we demonstrate that opioid receptor signaling has a potential beneficial role in the outcome of respiratory viral disease. We show that opioid receptor signaling is required to control RSV replication and thereby to control disease severity. As opioids are frequently used for sedative and analgesic purposes during mechanical ventilation for severe viral infection in infancy, opioid receptors might offer powerful novel pharmacologic targets to ameliorate virus-induced airway inflammation.

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