PI3K-AKT Signaling via Nrf2 Protects against Hyperoxia-Induced Acute Lung Injury, but Promotes Inflammation Post-Injury Independent of Nrf2 in Mice

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.

Melatonin protects against arsenic trioxide-induced liver injury by the upregulation of Nrf2 expression through the activation of PI3K/AKT pathway

“…These results suggested that melatonin exhibited antioxidant effects by activating Nrf2 signaling pathway. Previous research has demonstrated that the PI3K/AKT pathway plays a critical role in modulating Nrf2/HO-1 protein expression as an upstream signaling molecule [22]. In this study, we found melatonin upregulated the phosphorylation of PI3K and AKT.…”

Simvastatin preparations promote PDGF‐BB secretion to repair LPS‐induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway

“…It is important to identify the upstream regulatory molecules associated with IQGAP1. According to some studies, the PI3K/Akt pathway is not only a crucial regulatory molecule for various cellular functions, but also important in transduction signalling underlying endothelial barrier function during sepsis . In the present study, we found that SV/SV‐NPs activated the PI3K/Akt pathway and promoted Akt phosphorylation, which was inhibited by LPS.…”

“…According to some studies, the PI3K/Akt pathway is not only a crucial regulatory molecule for various cellular functions, but also important in transduction signalling underlying endothelial barrier function during sepsis. [50][51][52][53] In the present study, we found that SV/SV-NPs activated the PI3K/Akt pathway and promoted Akt phosphorylation, which was inhibited by LPS. We then used the PI3K inhibitor LY294002 to determine whether the PI3K/Akt pathway had a mediating function in SV/SV-NPs-induced barrier protection.…”

High Nrf2 expression in alveolar type I pneumocytes is associated with low recurrences in primary spontaneous pneumothorax

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