Risks of Treating Idiopathic Pulmonary Fibrosis with a TAM Receptor Kinase Inhibitor
Risks of Treating Idiopathic Pulmonary Fibrosis with a TAM Receptor Kinase Inhibitor
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使用 TAM 受体激酶抑制剂治疗特发性肺纤维化的风险
DOI：
10.1164/rccm.201805-0871le
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发表时间：
2018
影响因子：
24.7
通讯作者：
Gabazza Esteban C.
中科院分区：
文献类型：
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作者：
D’Alessandro-Gabazza Corina N.;Kobayashi Tetsu;Gabazza Esteban C.
我们怀着极大的兴趣阅读了埃斯皮多拉和他的同事们关于抑制(Tyro3，Ax1，Mer)受体激酶对特发性肺纤维化患者的潜在有益影响的优雅工作(1，2)。这是朝着开发治疗这种毁灭性疾病的新药迈出的第一步。然而，我们有一些担忧。需要解决的一个关键问题是肺泡上皮细胞是否表达受体。从埃斯皮多拉及其同事的文章(1)图1D中描述的免疫组织化学研究结果来看，似乎除了成纤维细胞外，肺上皮细胞也表达AXL蛋白的活性形式。肺泡上皮细胞的慢性损伤和凋亡被认为在肺间质纤维化的发病机制中起重要作用，而受体激酶激活Akt通路是防止细胞凋亡的关键[3，4]。在此基础上，如果肺泡上皮细胞表达受体，用受体激酶抑制剂治疗可能意味着加速肺上皮细胞凋亡的风险，从而导致疾病进展。先前的一项研究表明，受体配体蛋白S在博莱霉素诱导的肺纤维化中具有保护作用，这进一步支持了受体失活可能的不良后果(5)。在IPF中使用激酶抑制剂的另一个主要担忧是损害巨噬细胞介导的凋亡细胞吞噬或泡腾作用，而生长停滞特异性6/蛋白S/轴在其中发挥核心作用(6)。不幸的是，目前还没有关于使用激酶抑制剂治疗的人源化小鼠和/或使用博莱霉素治疗的生长停滞特异性6基因缺陷小鼠是否存在细胞凋亡或炎症增加的描述。这些信息将有助于预测潜在的不良反应，如果受体抑制剂在未来用于治疗特发性肺纤维化。
We read with great interest the elegant work of Espindola and colleagues on the potential beneficial effect of inhibiting TAM (Tyro3, Axl, Mer) receptor kinases in patients with idiopathic pulmonary fibrosis (IPF)(1, 2). This is the first step toward the development of a novel drug for the treatment of this devastating disease. However, we have some concerns. A critical question that needs to be addressed is whether alveolar epithelial cells express TAM receptors. From the results of the immunohistochemistry study described in Figure 1D in the article by Espindola and colleagues (1), it appears that besides fibroblasts, lung epithelial cells also express the active form of Axl protein. Chronic injury and apoptosis of alveolar epithelial cells are believed to play important roles in the pathogenesis of IPF, and it is well recognized that activation of the Akt pathway by the TAM receptor kinases is essential to prevent cell apoptosis (3, 4). On this basis, if alveolar epithelial cells express TAM receptors in IPF, therapy with the receptor kinase inhibitor may imply a risk of accelerating lung epithelial apoptosis that consequently leads to disease progression. A previous study showing that the TAM receptor ligand protein S is protective in bleomycin-induced pulmonary fibrosis further supports the possible adverse consequences of TAM receptor inactivation (5). Another major concern about using a TAM kinase inhibitor in IPF is the risk of impairing macrophage-mediated phagocytosis of apoptotic cells, or efferocytosis, in which the growth arrest–specific 6/protein S/TAM axis plays a central role (6). Unfortunately, there was no description of whether there was augmentation of apoptosis or increased inflammation in humanized mice treated with the kinase inhibitor and/or in the growth arrest–specific 6–deficient mice treated with bleomycin. This information would help predict potential adverse effects if TAM receptor inhibitors are to be useful in treating IPF in the future.■