β-catenin in the fibroproliferative response to acute lung injury
β-catenin in the fibroproliferative response to acute lung injury
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DOI：
10.1165/rcmb.2005-0277oc
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发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Voelkel, NF
中科院分区：
文献类型：
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作者：
Douglas, IS;del Valle, FD;Voelkel, NF
急性肺损伤后肺泡上皮/毛细血管膜损伤的解决需要协调和有效的组织修复，以重建功能性肺泡上皮/毛细血管膜屏障。我们假设，在小鼠模型中，在深度氧化应激肺损伤后的恢复和重塑阶段，肺泡芽个体发育中重要的信号通路被激活。为了测试这一点，我们的特点表达的非经典P-连环蛋白途径蛋白E-钙粘蛋白，整合素连接激酶-1，P-连环蛋白在小鼠暴露于丁基羟基甲苯（BHT，ionol）和伴随的亚致死（75%O-2）高氧后进行常氧恢复。小鼠发生早期急性肺损伤，随后发生炎症、胶原沉积、间质细胞增殖和肺结构变形。BHT和高氧6 d后E-cadherin表达减少，伴随着随后常氧恢复期间β-连环蛋白表达增强和核定位以及整合素连接激酶-1表达增加。这导致共转录调节因子TCF-1和-3和cyclin D1的表达增加。与溶剂处理的对照小鼠相比，在相同时间点，用BHT醌甲基化物和高氧处理8 h后以及正常氧恢复48 h后，体外小鼠肺上皮-12细胞的增殖增加了2.7倍。接受泛半胱天冬酶抑制剂z-ASP治疗的BHT/高氧暴露小鼠尽管存在TUNEL阳性细胞，但急性肺损伤增加，存活率降低，表明肺细胞坏死增强。在BHT/高氧后，z-ASP-共处理的肺中β-连环蛋白表达降低。非经典钙粘蛋白-β-连环蛋白轴与BHT/高氧暴露后的纤维增生修复相关，并可调节上皮增殖和肺基质重塑以及肺损伤后的修复。
Resolution of alveolar epithelial/capillary membrane damage after acute lung injury requires coordinated and effective tissue repair to reestablish a functional alveolar epithelial/capillary membrane barrier. We hypothesized that signaling pathways important in lung alveolar bud ontogeny are activated in the recovery and remodeling phases after profound oxidant stress lung injury in a murine model. To test this, we characterized the expression of noncanonical P-catenin pathway proteins E-cadherin, integrin-linked kinase-1, and P-catenin in mice undergoing normoxic recovery after exposure to butylated hydroxytoluene (BHT, ionol) and concomitant sublethal (75% O-2) hyperoxia. Mice developed early acute lung injury with subsequent inflammation, Collagen deposition, interstitial cellular proliferation, and lung architectural distortion. Reduced E-cadherin expression after 6 d of BHT and hyperoxia was accompanied by enhanced expression and nuclear localization of beta-catenin and increased integrin-linked kinase-1 expression during subsequent normoxic recovery. This resulted in increased expression of the cotranscriptional regulators TCF-1 and -3 and cyclin D1. Proliferation of murine lung epithelial-12 cells in vitro after 8 h of treatment with BHT quinone-methide and hyperoxia and 48 h of normoxic recovery was enhanced 2.7-fold compared with vehicle-treated control mice at the same time point. BHT/hyperoxia-exposed mice treated with the pan-caspase inhibitor z-ASP had increased acute lung injury and reduced survival despite the presence of TUNEL-positive cells, suggesting enhanced lung cell necrosis. beta-Catenin expression was reduced in z-ASP-co-treated lungs after BHT/hyperoxia. The noncanonical cadherin-beta-catenin axis is associated with fibroproliferative repair after BHT/hyperoxia exposure and may regulate epithelial proliferation and lung matrix remodeling and repair in response to lung injury.