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.

• Authors: Narsa M Reddy, Haranatha R Potteti, Suryanarayana Vegiraju, Hsin-Jou Chen, Chandra Mohan Tamatam, Sekhar P Reddy
• Journal: PloS one (PLoS One) Vol. 10 Issue 6 Pg. e0129676 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26075390 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Chromones
• Morpholines
• NF-E2-Related Factor 2
• Phosphoinositide-3 Kinase Inhibitors
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Proto-Oncogene Proteins c-akt

Topics

• Acute Lung Injury (etiology, metabolism, pathology)
• Alveolar Epithelial Cells (metabolism)
• Animals
• Cell Line
• Chromones (pharmacology)
• Disease Models, Animal
• Gene Knockdown Techniques
• Hyperoxia (complications)
• Macrophages, Alveolar (metabolism)
• Mice
• Mice, Knockout
• Morpholines (pharmacology)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Neutrophil Infiltration
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)