Abstract
BackgroundMechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). Ly6C+high monocytes are involved in the pathogenesis of VILI. In this study, we investigated whether pulmonary infiltrated Ly6C+high monocytes produce vascular endothelial growth factor (VEGF) and contribute to VILI.MethodsA clinically relevant two-hit mouse model of VILI, with intravenous lipopolysaccharide (LPS, 20 ng/mouse) immediately before high tidal volume (HTV, 20 mL/kg) ventilation (LPS+HTV), was established. Blood gas and respiratory mechanics were measured to ensure the development of VILI. Flow cytometry and histopathological analyses revealed pulmonary infiltration of leukocytes subsets. Clodronate liposomes were intravenously injected to deplete pulmonary monocytes. In vitro endothelial cell permeability assay with sorted Ly6C+high monocytes condition media assessed the role of Ly6C+high monocytes in vascular permeability.ResultsLPS+HTV significantly increased total proteins, TNF-α, IL-6, vascular endothelial growth factor (VEGF) and mononuclear cells in the bronchoalveolar lavage fluid (BALF). Pulmonary Ly6C+high monocytes (SSClowCD11b+F4/80+Ly6C+high), but not Ly6C+low monocytes (SSClowCD11b+F4/80+Ly6C+low), were significantly elevated starting at 4 hr. Clodronate liposomes were able to significantly reduce pulmonary Ly6C+high monocytes, and VEGF and total protein in BALF, and restore PaO2/FiO2. There was a strong correlation between pulmonary Ly6C+high monocytes and BALF VEGF (R2 = 0.8791, p<0.001). Moreover, sorted Ly6C+high monocytes were able to produce VEGF, resulting in an increased permeability of endothelial cell monolayer in an in vitro endothelial cell permeability assay.ConclusionVEGF produced by pulmonary infiltrated Ly6C+high monocytes regulates vasculature permeability in a two-hit model of HTV-induced lung injury. Ly6C+high monocytes play an important role in the pathogenesis of VILI.
Highlights
Mechanical ventilation is an important life-saving procedure, but often causes lung injury due to regional over-distension of pulmonary alveoli, with larger tidal volumes, and leads to ventilator-induced lung injury (VILI) [1, 2]
We investigated whether pulmonary infiltrated Ly6C+high monocytes produce vascular endothelial growth factor (VEGF) and contribute to VILI
VEGF produced by pulmonary infiltrated Ly6C+high monocytes regulates vasculature permeability in a two-hit model of HTV-induced lung injury
Summary
Mechanical ventilation is an important life-saving procedure, but often causes lung injury due to regional over-distension of pulmonary alveoli, with larger tidal volumes, and leads to ventilator-induced lung injury (VILI) [1, 2]. VILI is characterized by increased recruitment of leukocytes that mediate acute inflammatory responses by releasing inflammatory chemokines, cytokines, and mediators. These molecules increase the pulmonary-vasculature permeability and leakage, resulting in protein-rich pulmonary edema that impairs gas exchange [3, 4]. Lung marginated monocytes are responsible for TNF-mediated microvascular endothelial cell activation and vascular injury in a subclinical low dose LPS-induced early endotoxemia [9]. Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, it may cause pulmonary vascular inflammation and leakage, leading to ventilatorinduced lung injury (VILI). We investigated whether pulmonary infiltrated Ly6C+high monocytes produce vascular endothelial growth factor (VEGF) and contribute to VILI.
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