title: 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.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Narsa M
authors.initials: NM
authors.lastname: Reddy
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Haranatha R
authors.initials: HR
authors.lastname: Potteti
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Suryanarayana
authors.initials: S
authors.lastname: Vegiraju
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Hsin-Jou
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Chandra Mohan
authors.initials: CM
authors.lastname: Tamatam
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D018496:Hyperoxia / Q000150:complications*; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002867:Chromones; D009025:Morpholines; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one