EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-α-induced pulmonary fibrosis
EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-α-induced pulmonary fibrosis
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DOI：
10.1152/ajplung.00020.2008
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发表时间：
2008-06-01
影响因子：
4.9
通讯作者：
Korfhagen, Thomas R.
中科院分区：
文献类型：
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作者：
Hardie, William D.;Davidson, Cynthia;Korfhagen, Thomas R.
转化生长因子-α (TGF-α) 是 EGF 受体 (EGFR) 的配体。 EGFR 激活与人类肺部疾病和肺纤维化动物模型中的纤维增殖过程相关。我们确定了 EGFR 酪氨酸激酶抑制剂吉非替尼（易瑞沙）和厄洛替尼（特罗凯）对 TGF-α 诱导的肺纤维化发生和进展的影响。使用多西环素调节肺特异性 TGF-α 表达的转基因小鼠模型，我们确定了吉非替尼和厄洛替尼治疗对肺组织学变化、肺总胶原、肺力学、肺动脉高压以及与 ECM 合成和血管重塑相关的基因表达的影响。肺中 TGF-α 的诱导导致 8 周内进行性肺纤维化。每日服用吉非替尼或厄洛替尼可防止纤维化的发展，减少肺总胶原蛋白的积累，防止体重减轻，并防止肺力学的变化。诱导 TGF-α 后 4 周用吉非替尼治疗小鼠可防止总胶原水平进一步增加并部分逆转以及肺力学和肺动脉高压的变化。与 ECM 合成相关的基因表达的增加以及与血管重塑相关的基因的减少也被阻止或部分逆转。吉非替尼或厄洛替尼的给药不会引起间质纤维化或灌洗细胞计数增加。小分子 EGFR 酪氨酸激酶抑制剂的施用可防止 EGFR 激活直接诱导的肺纤维化进一步增加并部分逆转，而不会诱导炎症细胞流入或额外的肺损伤。
Transforming growth factor-alpha (TGF-alpha) is a ligand for the EGF receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. We determined the effects of EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) on the development and progression of TGF-alpha-induced pulmonary fibrosis. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-alpha expression, we determined effects of treatment with gefitinib and erlotinib on changes in lung histology, total lung collagen, pulmonary mechanics, pulmonary hypertension, and expression of genes associated with synthesis of ECM and vascular remodeling. Induction in the lung of TGF-alpha caused progressive pulmonary fibrosis over an 8-wk period. Daily administration of gefitinib or erlotinib prevented development of fibrosis, reduced accumulation of total lung collagen, prevented weight loss, and prevented changes in pulmonary mechanics. Treatment of mice with gefitinib 4 wk after the induction of TGF-alpha prevented further increases in and partially reversed total collagen levels and changes in pulmonary mechanics and pulmonary hypertension. Increases in expression of genes associated with synthesis of ECM as well as decreases of genes associated with vascular remodeling were also prevented or partially reversed. Administration of gefitinib or erlotinib did not cause interstitial fibrosis or increases in lavage cell counts. Administration of small molecule EGFR tyrosine kinase inhibitors prevented further increases in and partially reversed pulmonary fibrosis induced directly by EGFR activation without inducing inflammatory cell influx or additional lung injury.