Utrecht University (logo) (logo)
Universitair Medisch Centrum Utrecht (logo)
You are here: Home > Education > PhD > PhD theses > 2010 > Hegeman

Jessica Hegeman

Thursday 4 November 2010

Ventilator-induced lung injury: pathogenesis and therapeutic interventions

Promotor: Prof.dr C.J. Heijnen and prof.dr A.J. van Vught
Defence: 4 November 2010

Mechanical ventilation has the potential to induce or aggravate damage to lung tissue, so-called ventilator-induced lung injury (VILI). Recently, it has been recognized that VILI may not only occur after “injurious” ventilation strategies with high tidal volumes but also after “protective” ventilation strategies with low tidal volumes which are meant to preserve alveolar integrity. Apart from improving current ventilation strategies, additional therapies to prevent detrimental ventilator-induced effects on the lung are urgently needed. In this thesis, we first describe possible mechanisms that may underlie the pathogenesis of VILI. The main focus of this thesis is to evaluate if and how different therapeutic interventions protect against various aspects of VILI like inflammation, alveolar-capillary permeability and impaired gas exchange. In our experiments, we mechanically ventilated mice for 5 hours.

The most important conclusions of this thesis are:
- Mechanical ventilation with high pressures does not only provoke endothelial activation and pro-inflammation in the lung but also induces a pro-inflammatory environment in organs distal to the lung. Moreover, mechanical ventilation with high pressures impairs functioning of peripheral lymphocytes (peripheral immune suppression).
- Fcγ-receptor targeted IgG-dexamethasone-liposomes are pharmacologically more effective than dexamethasone-liposomes in particular with respect to inhibition of granulocyte infiltration induced by mechanical ventilation. Especially IgG-dexamethasone-liposomes downregulate important parameters of ventilator-induced lung inflammation as efficiently as free dexamethasone.
- Treatment with either dexamethasone or angiopoietin-1 did not prevent the development of the more crude parameters of VILI (i.e. alveolar-capillary permeability, pulmonary edema, impaired gas exchange) despite inhibition of lung inflammation and vascular endothelial growth factor (VEGF) expression. Thus, prevention of inflammation does not preclude loss of pulmonary function implying that lung inflammation and injury are two independent components of VILI.
- Lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats is associated with activation of both caspase-dependent and caspase-independent pathways of cell death, with a crucial role for p53 and calpains respectively. In contrast, mechanical ventilation primarily activates caspase-independent pathways of cell death.