Abstract
BackgroundVentilator–induced lung injury (VILI) is characterized by vascular leakage and inflammatory responses eventually leading to pulmonary dysfunction. Vascular endothelial growth factor (VEGF) has been proposed to be involved in the pathogenesis of VILI. This study examines the inhibitory effect of dexamethasone on VEGF expression, inflammation and alveolar–capillary barrier dysfunction in an established murine model of VILI.MethodsHealthy male C57Bl/6 mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with an inspiratory pressure of 10 cmH2O (“lower” tidal volumes of ∼7.5 ml/kg; LVT) or 18 cmH2O (“higher” tidal volumes of ∼15 ml/kg; HVT). Dexamethasone was intravenously administered at the initiation of HVT–ventilation. Non–ventilated mice served as controls. Study endpoints included VEGF and inflammatory mediator expression in lung tissue, neutrophil and protein levels in bronchoalveolar lavage fluid, PaO2 to FiO2 ratios and lung wet to dry ratios.ResultsParticularly HVT–ventilation led to alveolar–capillary barrier dysfunction as reflected by reduced PaO2 to FiO2 ratios, elevated alveolar protein levels and increased lung wet to dry ratios. Moreover, VILI was associated with enhanced VEGF production, inflammatory mediator expression and neutrophil infiltration. Dexamethasone treatment inhibited VEGF and pro–inflammatory response in lungs of HVT–ventilated mice, without improving alveolar–capillary permeability, gas exchange and pulmonary edema formation.ConclusionsDexamethasone treatment completely abolishes ventilator–induced VEGF expression and inflammation. However, dexamethasone does not protect against alveolar–capillary barrier dysfunction in an established murine model of VILI.
Highlights
Mechanical ventilation (MV) has the potential to cause progressive damage to pulmonary tissue, a phenomenon often referred to as ventilator–induced lung injury (VILI) [1,2]
PaO2 to FiO2 ratios were lower whereas bronchoalveolar lavage fluid (BALF) protein levels and BALF neutrophil counts were higher in HVT–ventilated mice, but not in LVT–ventilated mice
Since enhanced Vascular endothelial growth factor (VEGF) expression and pro–inflammation may initiate alveolar–capillary barrier dysfunction, we evaluated whether dexamethasone administration at the initiation of HVT– ventilation would protect against alveolar–capillary barrier dysfunction
Summary
Mechanical ventilation (MV) has the potential to cause progressive damage to pulmonary tissue, a phenomenon often referred to as ventilator–induced lung injury (VILI) [1,2]. Vascular endothelial growth factor (VEGF) is recognized to be involved in the regulation of vascular permeability [6] and enhanced expression has been associated with vascular leakage in various experimental models of lung injury, including VILI [7,8,9]. MV provokes a pro–inflammatory state of the lung, characterized by infiltration of neutrophils and release of inflammatory mediators [10,11,12]. Activated neutrophils can cause oxidative stress and protease activity in the alveoli, subsequently inducing severe disruption of pulmonary epithelial–endothelial barriers and leading to impaired gas exchange [13]. Ventilator–induced lung injury (VILI) is characterized by vascular leakage and inflammatory responses eventually leading to pulmonary dysfunction. Vascular endothelial growth factor (VEGF) has been proposed to be involved in the pathogenesis of VILI. This study examines the inhibitory effect of dexamethasone on VEGF expression, inflammation and alveolar–capillary barrier dysfunction in an established murine model of VILI
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