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Prolonged Activation of P2X7R Leads to Alveolar Epithelial Type I Cell Death by Suppressing Wnt/beta‐catenin Pathway
Author(s) -
GUO YUJIE,
MISHRA AMARJIT,
WENG TINGTING,
WANG YANG,
GOU DEMING,
LIU LIN
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.618.5
Subject(s) - wnt signaling pathway , microbiology and biotechnology , programmed cell death , gsk 3 , catenin , beta catenin , lrp5 , signal transduction , gsk3b , biology , chemistry , cancer research , biochemistry , apoptosis
Hyperoxic acute lung injury (ALI) is characterized by pulmonary endothelial and epithelial injury. This work is aimed to understand the mechanisms of cell death of alveolar epithelial type I cells (AEC I) during ALI. We have previously shown that purinergic P2X7 receptor (P2X7R) is specifically expressed in AEC I. We hypothesized that the activation of P2X7R causes AEC I cell death through the suppression of the Wnt/beta‐catenin pathway and thus contribute to the development of ALI. To test this hypothesis, an immortal AECI cell line E10 and a primary alveolar epithelial type I‐like cell were used as models. The prolonged activation of P2X7R by 2′‐3′‐O‐(4‐benzoylbenzoyl)‐ATP (BzATP) caused cell death in both types of cells. Beta‐catenin was released from the plasma membrane and degraded by the increased activity of glycogen synthase kinase‐3beta in the BzATP‐treated cells. The downstream genes of Wnt/beta‐catenin pathway were also significantly suppressed. The activation of Wnt/beta‐catenin pathway by the inhibition of glycogen synthase kinase‐3beta or the addition of Wnt3a completely blocked the P2X7R‐medaited cell death. These data support an important role of P2X7R and Wnt/beta‐catenin pathway in the pathogenesis of ALI. Strategies to interfere with the activities of P2X7R or Wnt/beta‐catenin signaling may therefore represent potential therapeutic method to limit the damage of ALI.