Hyperoxia causes angiopoietin 2–mediated acute lung injury and necrotic cell death

Abstract

The angiogenic growth factor angiopoietin 2 (Ang2) destabilizes blood vessels, enhances vascular leak and induces vascular regression and endothelial cell apoptosis. We considered that Ang2 might be important in hyperoxic acute lung injury (ALI). Here we have characterized the responses in lungs induced by hyperoxia in wild-type and Ang2-/- mice or those given either recombinant Ang2 or short interfering RNA (siRNA) targeted to Ang2. During hyperoxia Ang2 expression is induced in lung epithelial cells, while hyperoxia-induced oxidant injury, cell death, inflammation, permeability alterations and mortality are ameliorated in Ang2-/- and siRNA-treated mice. Hyperoxia induces and activates the extrinsic and mitochondrial cell death pathways and activates initiator and effector caspases through Ang2-dependent pathways in vivo. Ang2 increases inflammation and cell death during hyperoxia in vivo and stimulates epithelial necrosis in hyperoxia in vitro. Ang2 in plasma and alveolar edema fluid is increased in adults with ALI and pulmonary edema. Tracheal Ang2 is also increased in neonates that develop bronchopulmonary dysplasia. Ang2 is thus a mediator of epithelial necrosis with an important role in hyperoxic ALI and pulmonary edema.

Angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone

“…2 While the role of angiopoietin 2 (Ang2) in regulating angiogenesis and vascular integrity has been well recognized, 7,8 recent reports have implicated an important role in inflammation. [9][10][11][12] Ang2 expression is increased dramatically at the sites of endothelial activation and is induced by various cytokines. 13 The release of Ang2 resulted in rapid destabilization of the endothelium and triggered an inflammatory response.…”

“…[13][14][15] A recent study has highlighted Ang2 as having a critical role in animal models of hyperoxia-induced lung injury and inflammation. 12 Ang2 caused increased inflammation and cell death in the lung on exposure to hyperoxia. 12 In addition, it was reported that tracheal aspirate (TA) concentrations of Ang2 were increased in a small number of babies with respiratory distress syndrome who went on to have adverse outcome (BPD/death).…”

“…12 Ang2 caused increased inflammation and cell death in the lung on exposure to hyperoxia. 12 In addition, it was reported that tracheal aspirate (TA) concentrations of Ang2 were increased in a small number of babies with respiratory distress syndrome who went on to have adverse outcome (BPD/death). 12 Hence, we hypothesized that Ang2 has an important role in the pathogenesis of BPD.…”

“…12 In addition, it was reported that tracheal aspirate (TA) concentrations of Ang2 were increased in a small number of babies with respiratory distress syndrome who went on to have adverse outcome (BPD/death). 12 Hence, we hypothesized that Ang2 has an important role in the pathogenesis of BPD. Our objective in the present study was to measure Ang2 in TA samples and its association with the development of BPD or death, in a large cohort of VPIs.…”

Association of polymorphisms in the mannose-binding lectin gene and pulmonary morbidity in preterm infants

“…Pro-and antiapoptotic mechanisms are known to play an important role in BPD as shown by experimental and clinical studies. [39][40][41] A deficiency in MBL may thus lead to a disturbed balance of the indicated pathways contributing to severe alterations in alveolo-and vasculogenesis as well as fibrotic changes. 42 Furthermore, the complexity of BPD pathogenesis suggests a potential role for different humoral lectins in pulmonary defense mechanisms and modulation of infectious complications as well as local inflammatory processes.…”