Abstract
Lung epithelial and endothelial cell death accompanied by inflammation contributes to hyperoxia-induced acute lung injury (ALI). Impaired resolution of ALI can promote and/or perpetuate lung pathogenesis, including fibrosis. Previously, we have shown that the transcription factor Nrf2 induces cytoprotective gene expression and confers protection against hyperoxic lung injury, and that Nrf2-mediated signaling is also crucial for the restoration of lung homeostasis post-injury. Although we have reported that PI3K/AKT signaling is required for Nrf2 activation in lung epithelial cells, significance of the PI3K/AKT-Nrf2 crosstalk during hyperoxic lung injury and repair remains unclear. Thus, we evaluated this aspect using Nrf2 knockout (Nrf2 –/–) and wild-type (Nrf2 +/+) mouse models. Here, we show that pharmacologic inhibition of PI3K/AKT signaling increased lung inflammation and alveolar permeability in Nrf2 +/+ mice, accompanied by decreased expression of Nrf2-target genes such as Nqo1 and Hmox1. PI3K/AKT inhibition dampened hyperoxia-stimulated Nqo1 and Hmox1 expression in lung epithelial cells and alveolar macrophages. Contrasting with its protective effects, PI3K/AKT inhibition suppressed lung inflammation in Nrf2 +/+ mice during post-injury. In Nrf2 –/– mice exposed to room-air, PI3K/AKT inhibition caused lung injury and inflammation, but it did not exaggerate hyperoxia-induced ALI. During post-injury, PI3K/AKT inhibition did not augment, but rather attenuated, lung inflammation in Nrf2 –/– mice. These results suggest that PI3K/AKT-Nrf2 signaling is required to dampen hyperoxia-induced lung injury and inflammation. Paradoxically, the PI3K/AKT pathway promotes lung inflammation, independent of Nrf2, during post-injury.
Highlights
Lung alveolar epithelial and endothelial cell death accompanied by inflammation is a major hallmark of acute lung injury (ALI) caused by oxidant and pro-fibrotic agents
To define the role of phosphatidylinositol 3’-kinase (PI3K)/AKT signaling in the regulation of hyperoxia-induced ALI in vivo, the wild-type (Nrf2+/+) mice were treated with vehicle or PI3K/AKT inhibitor, LY294002, during hyperoxia exposure
The increase in the number of total cells was mainly attributed to the increased accumulation of neutrophils and macrophages (Fig 1C). These results suggest that PI3K/AKT signaling is required for mitigating hyperoxiainduced lung injury and inflammation
Summary
Lung alveolar epithelial and endothelial cell death accompanied by inflammation is a major hallmark of acute lung injury (ALI) caused by oxidant and pro-fibrotic agents. The phosphatidylinositol 3’-kinase (PI3K)/AKT signaling pathway regulates cell survival during oxidative stress [10,11,12,13] and confers protection against oxidant-induced lung injury in rodents [13]. We have shown that the PI3K/AKT pathway regulates Nrf activation by hyperoxia in lung epithelial cells [11, 14, 15]. Genetic ablation of PI3K-γ enhanced neutrophil sequestration in experimental sepsis [18], and PI3K/AKT inhibitor LY294002 suppressed inflammatory responses in experimental asthma [19]. These results suggest the PI3K/AKT pathway regulates lung injury and inflammation in a contextual manner
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