title: Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death.
abstract: Acute lung injury (ALI) is characterized by pulmonary endothelial and epithelial cell damage, and loss of the alveolar-capillary barrier. We have previously shown that P2X7 receptor (P2X7R), a cell death receptor, is specifically expressed in alveolar epithelial type I cells (AEC I). In this study, we hypothesized that P2X7R-mediated purinergic signaling and its interaction with Wnt/β-catenin signaling contributes to AEC I death. We examined the effect of P2X7R agonist 2'-3'-O-(4-benzoylbenzoyl)-ATP (BzATP) and Wnt agonist Wnt3a on AEC I death in vitro and in vivo. We also assessed the therapeutic potential of Wnt3a in a clinically relevant ALI model of intratracheal lipopolysaccharide (LPS) exposure in ventilated mice. We found that the activation of P2X7R by BzATP caused the death of AEC I by suppressing Wnt/β-catenin signaling through stimulating glycogen synthase kinase-3β (GSK-3β) and proteasome. On the other hand, the activation of Wnt/β-catenin signaling by Wnt3a, GSK-3β inhibitor, or proteasome inhibitor blocked the P2X7R-mediated cell death. More importantly, Wnt3a attenuated the AEC I damage caused by intratracheal instillation of BzATP in rats or LPS in ventilated mice. Our results suggest that Wnt3a overrides the effect of P2X7R on the Wnt/β-catenin signaling to prevent the AEC I death and restrict the severity of ALI.
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Lundberg-Kienlen Lung Biology and Toxicology Laboratorym, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Y
authors.identifier: 0000000203079266
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Lundberg-Kienlen Lung Biology and Toxicology Laboratorym, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Lundberg-Kienlen Lung Biology and Toxicology Laboratorym, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: T
authors.initials: T
authors.lastname: Weng
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Lundberg-Kienlen Lung Biology and Toxicology Laboratorym, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Chintagari
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Lundberg-Kienlen Lung Biology and Toxicology Laboratorym, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Lundberg-Kienlen Lung Biology and Toxicology Laboratorym, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Lundberg-Kienlen Lung Biology and Toxicology Laboratorym, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: C
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Physiological Sciences, Center for Veterinary Health Sciences, Lundberg-Kienlen Lung Biology and Toxicology Laboratorym, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: L
authors.initials: L
authors.lastname: Liu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D010975:Platelet Aggregation Inhibitors; D058486:Receptors, Purinergic P2X7; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate