Therapeutic targeting of IL-4- and IL-13-responsive cells in pulmonary fibrosis
Therapeutic targeting of IL-4- and IL-13-responsive cells in pulmonary fibrosis
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DOI：
10.1385/ir:30:3:339
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发表时间：
2004-01-01
影响因子：
4.4
通讯作者：
Hogaboam, CM
中科院分区：
文献类型：
--
作者：
Jakubzick, C;Kunkel, SL;Hogaboam, CM
特发性间质性肺炎（IIP）的严重形式，如普通型间质性肺炎（UIP），可能不受现代类固醇和免疫抑制治疗方案的影响，因此强调需要新的有效疗法。了解可能影响免疫和结构细胞活化的细胞因子网络，从而影响这些致命性纤维化疾病的进展，一直是我们研究的重点。在这方面，我们已经研究了白细胞介素（IL）-4和IL-13及其各自的受体亚单位在这一过程中的作用。临床手术肺活检（SLB）的检查表明，IIP的特征在于结合IL-4和IL-13的受体亚单位的异常、升高的表达。具体而言，IL-4 R α和IL-13 R α 2（高亲和力IL-13受体亚基）在IIP患者的SLB和成纤维细胞中的丰度高于正常患者，后者未表现出肺纤维化的证据。这些临床发现促使我们研究靶向对IL-4和IL-13高度应答的肺细胞类型是否是IIP中可行的治疗选择。使用由人IL-13和来自假单胞菌的外毒素的截短形式（缩写为IL 13-PE）组成的嵌合蛋白，我们观察到IL 13-PE选择性地靶向从IIP SLB生长的人肺成纤维细胞，而它对从正常患者的活检生长的成纤维细胞具有最小的影响。在以异常气道或间质性纤维化反应为特征的鼠模型中，鼻内施用IL 13-PE通过靶向表达IL-4 Ra和IL-13 Ra 2的肺细胞（包括单核细胞、巨噬细胞和肺成纤维细胞）显著减弱纤维化反应。总之，这些数据表明，IL-4和IL-13是肺纤维化的启动和维持所必需的，并强调了进一步研究在临床肺纤维化期间防止两种细胞因子作用的抗纤维化治疗的重要性。
Severe forms of idiopathic interstitial pneumonia (IIP), such as usual interstitial pneumonia (UIP), can be impervious to modern steroid and immunosuppressive treatment regimens, thereby emphasizing the need for novel effective therapies. Understanding the cytokine networks that may affect immune and structural cell activation and, hence, the progression of these fatal fibrotic diseases, has been a focus in our research. In this regard, we have examined the role of interleukin (IL)-4 and IL-13 and their respective receptor subunits in this process. Examination of clinical surgical lung biopsies (SLBs) showed that IIP is characterized by the abnormal, heightened expression of the receptor subunits that bind IL-4 and IL-13. Specifically, IL-4Ralpha and IL-13Ralpha2 (the high-affinity IL-13 receptor subunit) was present in greater abundance in SLBs and fibroblasts from IIP patients compared with normal patients, who exhibited no evidence of pulmonary fibrosis. These clinical findings prompted us to investigate whether the targeting Of Pulmonary cell types that were highly responsive to IL-4 and IL-13 was a viable therapeutic option in IIP. Using a chimeric protein comprised of human IL-13 and a truncated version of an exotoxin from Pseudomonas (abbreviated IL13-PE), we observed that IL13-PE selectively targeted human pulmonary fibroblasts grown from IIP SLBs, whereas it had a minimal effect on fibroblasts grown from biopsies from normal patients. In murine models characterized by abnormal airway or interstitial fibrotic responses, the intranasal administration of IL13-PE significantly attenuated the fibrotic response through the targeting of IL-4Ralpha- and IL-13Ralpha2-expressing pulmonary cells, including monocytes, macrophages, and pulmonary fibroblasts. Together, these data demonstrate that IL-4 and IL-13 are required for the initiation and maintenance of pulmonary fibrosis, and highlight the importance of further investigation of anti-fibrotic therapeutics that prevent the action of both cytokines during clinical pulmonary fibrosis.