Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes: Implications for treatment of fibrotic diseases
Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes: Implications for treatment of fibrotic diseases
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DOI：
10.1124/jpet.106.113407
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Thannickal, Victor J.
中科院分区：
文献类型：
--
作者：
Vittal, Ragini;Zhang, Hengmin;Thannickal, Victor J.
哺乳动物的组织损伤会引发炎症和修复反应，在某些情况下会导致纤维化。纤维化的特征是活化的肌成纤维细胞持续存在、无效的上皮再形成以及受损组织内不同程度的炎症。蛋白激酶抑制剂（PKI）甲磺酸伊马替尼已被提议作为潜在的抗纤维化治疗剂。在这项研究中，检查了甲磺酸伊马替尼在体外和体内调节纤维形成反应的功效。在体外成纤维细胞培养模型中，伊马替尼抑制血小板源性生长因子受体激活和成纤维细胞增殖，但不抑制稳定分化的肌成纤维细胞表型。此外，伊马替尼抑制肺上皮细胞增殖和存活，但不诱导上皮间质转化。伊马替尼不会改变任一细胞类型中的转化生长因子-β/SMAD3 信号传导。在肺纤维化的小鼠模型中，博来霉素诱导的肺上皮损伤会引起早期炎症反应，并在肺损伤的后期修复阶段出现更多的延迟纤维化。在损伤后修复阶段施用甲磺酸伊马替尼（10 mg/kg/天，通过腹腔注射或口服灌胃）未能显着改变通过组织病理学、胶原含量和受伤肺内肌成纤维细胞积累评估的纤维形成反应。这些研究表明，PKI 抑制成纤维细胞增殖的能力可能不足以在组织损伤修复的后期发挥显着的抗纤维化作用。调节分化（肌）成纤维细胞的活性和命运而不干扰上皮细胞再生能力的药物可能对治疗未解决的进行性纤维化疾病更有效。
Tissue injury in mammals triggers both inflammatory and repair responses that, in some contexts, results in fibrosis. Fibrosis is characterized by the persistence of activated myofibroblasts, ineffective re-epithelialization, and variable degrees of inflammation within injured tissues. The protein kinase inhibitor (PKI), imatinib mesylate, has been proposed as a potential antifibrotic therapeutic agent. In this study, the efficacy of imatinib mesylate to modulate fibrogenic responses, both in vitro and in vivo, was examined. In an in vitro fibroblast culture model, imatinib inhibits platelet-derived growth factor receptor activation and fibroblast proliferation but not the stably differentiated myofibroblast phenotype. Furthermore, imatinib inhibits lung epithelial cell proliferation and survival but not the induction of epithelial-mesenchymal transition. Imatinib does not alter transforming growth factor-beta/SMAD3 signaling in either cell type. In a murine model of lung fibrosis, bleomycin-induced injury to the pulmonary epithelium provokes an early inflammatory response with more delayed fibrosis during the late reparative phase of lung injury. Imatinib mesylate (10 mg/kg/day by i.p. injection or oral gavage), administered during the postinjury repair phase, failed to significantly alter fibrogenic responses assessed by histopathology, collagen content, and the accumulation of myofibroblasts within the injured lung. These studies indicate that the capacity of a PKI to inhibit fibroblast proliferation may be insufficient to mediate significant antifibrotic effects in late stages of tissue injury repair. Pharmacologic agents that modulate the activities and fate of differentiated (myo) fibroblasts, without interfering with the regenerative capacity of epithelial cells, are likely to be more effective for treatment of nonresolving, progressive fibrotic disorders.