Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death
Date
2014-06-12Author
Guo, Y.
Mishra, A.
Weng, T.
Chintagari, N. R.
Wang, Y.
Zhao, C.
Huang, C.
Liu, L.
Metadata
Show full item recordAbstract
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/B-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/B-catenin signaling through stimulating glycogen synthase kinase-3B (GSK-3B) and proteasome. On the other hand, the activation of Wnt/B-catenin signaling by Wnt3a, GSK-3B 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/B-catenin signaling to prevent the AEC I death and restrict the severity of ALI.
Citation
Guo, Y., Mishra, A., Weng, T., Chintagari, N. R., Wang, Y., Zhao, C., ... Liu, L. (2014). Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death. Cell Death and Disease, 5(6). https://doi.org/10.1038/cddis.2014.254