Angiopoietin-1 Treatment Reduces Inflammation but Does Not Prevent Ventilator-Induced Lung Injury

Abstract

BackgroundLoss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation.MethodsMice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with either an inspiratory pressure of 10 cmH2O (‘low’ tidal volume ∼7.5 ml/kg; LVT) or 18 cmH2O (‘high’ tidal volume ∼15 ml/kg; HVT). At initiation of HVT-ventilation, recombinant human Ang-1 was intravenously administered (1 or 4 µg per animal). Non-ventilated mice served as controls.ResultsHVT-ventilation influenced the Ang-Tie2 system in lungs of healthy mice since Ang-1, Ang-2 and Tie2 mRNA were decreased. Treatment with Ang-1 increased Akt-phosphorylation indicating Tie2 signaling. Ang-1 treatment reduced infiltration of granulocytes and expression of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-1β caused by HVT-ventilation. Importantly, Ang-1 treatment did not prevent vascular leakage and impaired gas exchange in HVT-ventilated mice despite inhibition of inflammation, vascular endothelial growth factor (VEGF) and Ang-2 expression.ConclusionsAng-1 treatment downregulates pulmonary inflammation, VEGF and Ang-2 expression but does not protect against vascular leakage and impaired gas exchange induced by HVT-ventilation.

Ventilator-Induced Lung Injury: Mechanisms and Future Therapeutic Interventions

“…Moreover, we observed that HV T -ventilation caused increased expression of VEGF (figure 4g) which is in agreement with a prior report (Nin et al, 2008). Our findings strongly suggest that changes in the Ang-Tie2 system, together with elevated VEGF expression, are involved in the development of VILI (Hegeman et al, 2010). Fig.…”

“…However, even in our relatively mild model of VILI, mechanical ventilation with either low (LV T ) or high tidal volumes (HV T ) caused increased cytokine, chemokine and adhesion molecule expression compared to non-ventilated control (NVC) animals, which was accompanied by marked granulocyte infiltration (Hegeman et al, 2011b). BALf neutrophil numbers and inflammatory mediator levels were even higher when comparing lungs of HV T -ventilated mice to lungs of LV T -ventilated mice (Hegeman et al, 2011b). Since lower PaO 2 /FiO 2 ratios were only observed after HV T -ventilation, it seems plausible that ventilator-induced lung inflammation ultimately impairs gas exchange.…”

“…In this way, we were able to prevent shock, metabolic acidosis and substantial damage to lung architecture commonly associated with high tidal volumes and/or inspiratory pressures (Wolthuis et al, 2009b). However, even in our relatively mild model of VILI, mechanical ventilation with either low (LV T ) or high tidal volumes (HV T ) caused increased cytokine, chemokine and adhesion molecule expression compared to non-ventilated control (NVC) animals, which was accompanied by marked granulocyte infiltration (Hegeman et al, 2011b). BALf neutrophil numbers and inflammatory mediator levels were even higher when comparing lungs of HV T -ventilated mice to lungs of LV T -ventilated mice (Hegeman et al, 2011b).…”

“…Most experimental models of VILI, however, applied excessively high tidal volumes and/or inspiratory pressures compared to those applied in the clinical setting (Copland et al, 2004;Haitsma et al, 2003;Wilson et al, 2003). In an attempt to better reflect the human situation, we used clinically more relevant ventilator settings in our animal studies (Hegeman et al, 2010). In this way, we were able to prevent shock, metabolic acidosis and substantial damage to lung architecture commonly associated with high tidal volumes and/or inspiratory pressures (Wolthuis et al, 2009b).…”

“…It may well be that a disturbed balance between Ang-1 and VEGF plays an indispensable role in VILI as well. Therefore, we examined whether 5 hours of either LV T or HV Tventilation would influence the Ang-Tie2 system and VEGF expression in lungs of healthy mice (Hegeman et al, 2010). Particularly in lungs of HV T -ventilated mice, marked changes in the Ang-Tie2 system were observed.…”