Department of Biology, Texas A&M University, College Station, TX 77843-3474, USA.
Int J Mol Sci. 2022 Dec 23;24(1):239. doi: 10.3390/ijms24010239.
Fibrosing diseases are a major medical problem, and are associated with more deaths per year than cancer in the US. Sialidases are enzymes that remove the sugar sialic acid from glycoconjugates. In this review, we describe efforts to inhibit fibrosis by inhibiting sialidases, and describe the following rationale for considering sialidases to be a potential target to inhibit fibrosis. First, sialidases are upregulated in fibrotic lesions in humans and in a mouse model of pulmonary fibrosis. Second, the extracellular sialidase NEU3 appears to be both necessary and sufficient for pulmonary fibrosis in mice. Third, there exist at least three mechanistic ways in which NEU3 potentiates fibrosis, with two of them being positive feedback loops where a profibrotic cytokine upregulates NEU3, and the upregulated NEU3 then upregulates the profibrotic cytokine. Fourth, a variety of NEU3 inhibitors block pulmonary fibrosis in a mouse model. Finally, the high sialidase levels in a fibrotic lesion cause an easily observed desialylation of serum proteins, and in a mouse model, sialidase inhibitors that stop fibrosis reverse the serum protein desialylation. This then indicates that serum protein sialylation is a potential surrogate biomarker for the effect of sialidase inhibitors, which would facilitate clinical trials to test the exciting possibility that sialidase inhibitors could be used as therapeutics for fibrosis.
纤维性疾病是一个主要的医学问题，每年在美国造成的死亡人数超过癌症。唾液酸酶是一种从糖缀合物中去除糖唾液酸的酶。在这篇综述中，我们描述了通过抑制唾液酸酶来抑制纤维化的努力，并描述了将唾液酸酶视为抑制纤维化的潜在靶点的以下基本原理。首先，唾液酸酶在人类纤维化病变和肺纤维化的小鼠模型中上调。其次，细胞外唾液酸酶 NEU3 似乎对小鼠肺纤维化既是必需的也是充分的。第三，至少有三种机制可以使 NEU3 增强纤维化，其中两种是正反馈回路，其中一种促纤维化细胞因子上调 NEU3，而上调的 NEU3 则上调促纤维化细胞因子。第四，多种 NEU3 抑制剂可阻断小鼠模型中的肺纤维化。最后，纤维化病变中高唾液酸酶水平导致血清蛋白明显脱唾液酸化，在小鼠模型中，阻止纤维化的唾液酸酶抑制剂可逆转血清蛋白脱唾液酸化。这表明血清蛋白唾液酸化是唾液酸酶抑制剂作用的潜在替代生物标志物，这将有助于临床试验，以检验令人兴奋的可能性，即唾液酸酶抑制剂可用作纤维化的治疗药物。
