1 Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medical Science, University of Fukui, Fukui, Japan; and.
2 Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Am J Respir Cell Mol Biol. 2018 Oct;59(4):448-457. doi: 10.1165/rcmb.2017-0325OC.
In this study, we found Cystatin SN (CST1), a type 2 cystatin subfamily member, to be highly expressed in nasal polyps from patients with intractable chronic rhinosinusitis (CRS) with nasal polyps, using a whole-transcript analysis with next-generation sequencing. Eosinophilic CRS (ECRS) involves nasal polyps that are refractory and recur immediately after endoscopic sinus surgery. We hypothesized that CST1 may contribute to the pathogenesis of ECRS. We examined the expression of CST1 in nasal polyps from patients with ECRS by assessing mRNA expression levels using real-time PCR and immunohistochemistry. CST1 showed significantly greater expression in the epithelial cells of nasal polyps from patients with ECRS than in those from patients who did not have ECRS (non-ECRS). In particular, CST1 showed very strong expression in patients with severe ECRS. The expression of CST1 may be correlated with the recurrent and refractory nature of ECRS. We examined the function of CST1 using nasal epithelial cells and nasal fibroblasts. Stimulation by a combination of IL-4 plus double-stranded RNA plus CST1 significantly elevated mRNA expression levels and protein levels of TSLP in nasal epithelial cells. Stimulation by TSLP or IL-33 significantly elevated mRNA expression levels of CST1 in nasal epithelial cells. Stimulation of CST1 significantly elevated mRNA expression levels of CCL11 and POSTN in nasal fibroblasts. CST1 could amplify eosinophilic infiltration and T-helper cell type 2 inflammation by interacting with epithelial-derived cytokines and fibroblasts on nasal polyps. CST1 may be involved in the pathogenesis of ECRS, and may contribute to the severity and recurrence of CRS with nasal polyps after endoscopic sinus surgery.
在这项研究中，我们通过下一代测序的全转录分析发现，胱抑素 SN（CST1）在难治性慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）患者的鼻息肉中高度表达。嗜酸性 CRS（ECRS）涉及到鼻息肉，其在鼻内镜鼻窦手术后立即出现难治性和复发。我们假设 CST1 可能有助于 ECRS 的发病机制。我们通过实时 PCR 和免疫组织化学评估 CST1 在 ECRS 患者鼻息肉中的表达，以检查 CST1 的表达。CST1 在 ECRS 患者鼻息肉的上皮细胞中的表达明显高于没有 ECRS（非 ECRS）的患者。特别是，在严重 ECRS 患者中 CST1 表达非常强烈。CST1 的表达可能与 ECRS 的复发性和难治性有关。我们使用鼻上皮细胞和鼻成纤维细胞检查 CST1 的功能。IL-4 加双链 RNA 加 CST1 的联合刺激显著提高了鼻上皮细胞中 TSLP 的 mRNA 表达水平和蛋白水平。TSLP 或 IL-33 的刺激显著提高了鼻上皮细胞中 CST1 的 mRNA 表达水平。CST1 的刺激显著提高了鼻成纤维细胞中 CCL11 和 POSTN 的 mRNA 表达水平。CST1 可以通过与鼻息肉上皮细胞衍生的细胞因子和成纤维细胞相互作用，放大嗜酸性粒细胞浸润和辅助性 T 细胞 2 型炎症。CST1 可能参与 ECRS 的发病机制，并可能导致内镜鼻窦手术后伴鼻息肉的 CRS 的严重程度和复发。
