Divisions of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Am J Pathol. 2010 Feb;176(2):679-86. doi: 10.2353/ajpath.2010.090123. Epub 2009 Dec 30.
Transforming growth factor-alpha (TGFalpha) is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. EGFR signaling activates several intracellular signaling pathways including phosphatidylinositol 3'-kinase (PI3K). We previously showed that induction of lung-specific TGFalpha expression in transgenic mice caused progressive pulmonary fibrosis over a 4-week period. The increase in levels of phosphorylated Akt, detected after 1 day of doxycycline-induced TGFalpha expression, was blocked by treatment with the PI3K inhibitor, PX-866. Daily administration of PX-866 during TGFalpha induction prevented increases in lung collagen and airway resistance as well as decreases in lung compliance. Treatment of mice with oral PX-866 4 weeks after the induction of TGFalpha prevented additional weight loss and further increases in total collagen, and attenuated changes in pulmonary mechanics. These data show that PI3K is activated in TGFalpha/EGFR-mediated pulmonary fibrosis and support further studies to determine the role of PI3K activation in human lung fibrotic disease, which could be amenable to targeted therapy.
转化生长因子-α（TGFα）是表皮生长因子受体（EGFR）的配体。EGFR 的激活与人类肺部疾病和肺纤维化动物模型中的纤维增生过程有关。EGFR 信号转导激活了几种细胞内信号通路，包括磷脂酰肌醇 3-激酶（PI3K）。我们之前的研究表明，在转基因小鼠中诱导肺特异性 TGFα 表达会导致在 4 周内发生进行性肺纤维化。在诱导 TGFα表达后 1 天检测到磷酸化 Akt 的增加被 PI3K 抑制剂 PX-866 阻断。在 TGFα诱导期间每天给予 PX-866 可防止肺胶原和气道阻力增加以及肺顺应性降低。在诱导 TGFα 4 周后，用口服 PX-866 治疗可防止体重进一步减轻和总胶原进一步增加，并减轻肺力学的变化。这些数据表明，PI3K 在 TGFα/EGFR 介导的肺纤维化中被激活，并支持进一步研究以确定 PI3K 激活在人类肺纤维化疾病中的作用，这可能适合靶向治疗。
