Breaking a novel feedback loop to inhibit fibrosis

摘要 在美国，肺纤维化等纤维化疾病与高达45%的死亡相关。 在这些疾病中，称为纤维化病变的不适当的疤痕组织在内部器官中形成。没有FDA- 目前，已经批准了逆转纤维化的治疗方法，并且关于驱动纤维化的机制仍有许多尚待了解。在 在小鼠和人肺的纤维化病变中，唾液酸酶的水平增加， 从细胞外糖蛋白和其他糖缀合物的末端除去唾液酸。唾液酸酶 似乎至少部分通过增加产生的促纤维化细胞因子TGF-β1的水平来增强纤维化 免疫系统的细胞。相反，TGF-β1导致肺上皮细胞、肺成纤维细胞和一些 免疫系统细胞上调唾液酸酶。我们的假设是纤维化部分是由一种失控的 其中唾液酸酶增强纤维化和纤维化增强唾液酸酶的正反馈环。为支持这一 假设，我们发现两种不同的唾液酸酶抑制剂的注射减少小鼠肺纤维化 博莱霉素模型为了深入了解似乎是一种基本的机制， 系统肺上皮细胞和成纤维细胞，以及有助于驱动纤维化的机制，我们提出， 三个具体目标。由于鉴定在纤维化中上调的关键唾液酸酶将鉴定潜在的 我们的第一个目标是测试一种叫做NEU 3的唾液酸酶是抑制纤维化的主要靶点的假设。 促进纤维化的唾液酸酶。我们的第二个目标是确定哪些免疫系统细胞对 唾液酸酶并阐明免疫系统细胞借以感测上调的唾液酸酶的受体，和 从而识别潜在目标以阻断反馈回路。我们的第三个目标是确定唾液酸酶是如何引起 TGF-β1的上调，因此基本上在朝向目的的唾液酸酶传感途径上反向工作。 2工作。总之，这项工作将有助于阐明一种调节先天免疫系统的新机制 和纤维化，并可能导致纤维化疾病的新疗法。

Abstract Fibrosing diseases such as pulmonary fibrosis are associated with up to 45% of the deaths in the US. In these diseases, inappropriate scar tissue called fibrotic lesions forms in internal organs. There are no FDA- approved therapies that reverse fibrosis, and much remains to be known about mechanisms driving fibrosis. In fibrotic lesions in mouse and human lungs, there is an increase in the levels of sialidases, enzymes that remove sialic acids from the distal tips of extracellular glycoproteins and other glycoconjugates. Sialidases appear to potentiate fibrosis at least in part by increasing levels of the pro-fibrotic cytokine TGF-β1 produced by some immune system cells. Conversely, TGF-β1 causes lung epithelial cells, lung fibroblasts, and some immune system cells to upregulate sialidases. Our hypothesis is that fibrosis is driven in part by a runaway positive feedback loop where sialidase potentiates fibrosis and fibrosis potentiates sialidase. In support of this hypothesis, we found that injections of two different sialidase inhibitors reduce pulmonary fibrosis in the mouse bleomycin model. To gain insight into what appears to be a fundamental mechanism linking the immune system to lung epithelial cells and fibroblasts, as well as a mechanism that helps drive fibrosis, we propose three specific aims. Since identifying the key sialidase(s) that is/are upregulated in fibrosis will identify potential targets to inhibit fibrosis, our first aim is to test the hypothesis that a sialidase called NEU3 is the major sialidase that potentiates fibrosis. Our second aim is to determine which immune system cells respond to sialidases and elucidate the receptor(s) whereby immune system cells sense the upregulated sialidases, and thus identify potential targets to block the feedback loop. Our third aim is to determine how sialidases cause an upregulation of TGF-β1, thus essentially working backwards on the sialidase sensing pathway toward the Aim 2 work. Together, this work will help to elucidate a novel mechanism that regulates the innate immune system and fibrosis, and may lead to new therapies for fibrosing diseases.