Vittal Ragini, Zhang Hengmin, Han Meilan K, Moore Bethany B, Horowitz Jeffrey C, Thannickal Victor J
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
J Pharmacol Exp Ther. 2007 Apr;321(1):35-44. doi: 10.1124/jpet.106.113407. Epub 2007 Jan 11.
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.
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、上皮再形成无效以及损伤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一种潜在的抗纤维化治疗药物。在本研究中，检测了甲磺酸伊马替尼在体外和体内调节纤维化反应的功效。在体外成纤维细胞培养模型中，伊马替尼抑制血小板衍生生长因子受体激活和成纤维细胞增殖，但不影响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，但不影响上皮-间质转化的诱导。伊马替尼在两种细胞类型中均不改变转化生长因子-β/SMAD3信号传导。在肺纤维化小鼠模型中，博莱霉素诱导的肺上皮损伤在肺损伤的后期修复阶段引发早期炎症反应，并伴有更延迟的纤维化。在损伤后修复阶段给予甲磺酸伊马替尼（通过腹腔注射或灌胃给予10mg/kg/天），未能通过组织病理学、胶原蛋白含量以及损伤肺内肌成纤维细胞的积累来显著改变纤维化反应。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介导显著的抗纤维化作用。调节分化的（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无法消退的进行性纤维化疾病更有效。
