TRPA1; a potential therapeutic target in idiopathic pulmonary fibrosis

特发性肺纤维化（IPF）是一种预后不良的常见疾病。所有诊断为IPF的患者中有一半将在3-4年内死亡。肺中发生瘢痕形成过程，最终用致密的瘢痕组织取代正常健康的肺组织，这阻止氧气进入血液和与呼吸相关的正常肺扩张。结果，患者出现持续咳嗽，变得极度呼吸困难，最后因肺衰竭而死亡。IPF的病因不明。只有两种治疗方法可用，但这些都不是很有效，并产生频繁和不愉快的副作用。大量证据表明，称为肌成纤维细胞的细胞参与了IPF肺瘢痕组织的生成。这些细胞在正常的伤口愈合中很重要，并为包括肺在内的健康器官提供结构，但在疾病中它们表现异常。正是肌成纤维细胞产生填充肺部的致密组织。此外，它们移动到异常位置并繁殖，导致肌成纤维细胞和瘢痕组织的密集聚集，扭曲正常的肺结构。所有的细胞都含有一种叫做离子通道的蛋白质，它可以将钙离子传导到细胞内。我们已经在人肺肌成纤维细胞中鉴定出一种称为TRPA 1的离子通道，并认为这是肌成纤维细胞产生瘢痕组织的关键信号分子。我们将在本提案中测试这一假设，如果我们是正确的，我们预计阻断TRPA 1将减缓或停止IPF的进展。阻断TRPA 1的药物已经在其他疾病中进行了研究，到目前为止，患者的耐受性良好。因此，我们预计我们的研究结果将为在IPF患者临床试验中评估TRPA 1阻滞剂提供有力的依据。

Idiopathic pulmonary fibrosis (IPF) is a common disease with a bleak prognosis. Half of all patients diagnosed with IPF will die within 3-4 years. A scarring process occurs in the lungs, eventually replacing normal healthy lung tissue with dense scar tissue, which prevents oxygen passing into the blood and the normal lung expansion associated with breathing. As a result patients develop persistent cough, become extremely breathless, and finally die as a result of lung failure. The cause of IPF is unknown. Only two treatments are available, but these are not very effective, and produce frequent and unpleasant side effects. Considerable evidence implicates cells known as myofibroblasts in the generation of lung scar tissue in IPF. These cells are important in normal wound healing and provide structure to healthy organs including lungs, but in disease they behave abnormally. It is myofibroblasts that produce the dense tissue that fills the lungs. In addition they move to abnormal locations and multiply, leading to dense collections of myofibroblasts and scar tissue that distort normal lung structure. All cells contain proteins called ion channels that conduct ions such as calcium into the cell. We have identified an ion channel called TRPA1 in human lung myofibroblasts, and believe that this is a key signalling molecule through which myofibroblasts generate scar tissue. We will test this hypothesis in this proposal, and if we are correct, we expect that blocking TRPA1 will slow or halt the progress of IPF. Drugs that block TRPA1 are already being studied in other diseases, and to-date, have been well tolerated by patients. We therefore expect that the results from our study will provide a strong rationale for the assessment of TRPA1 blockers in clinical trials for patients with IPF.