Tsai Yih-Jeng, Hao Sheng-Po, Chen Chih-Li, Lin Brian J, Wu Wen-Bin
Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; Department of Chemistry, Graduate Institute of Applied Science and Engineering, College of Science and Engineering, Fu-Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Basic Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
PLoS One. 2015 May 13;10(5):e0126853. doi: 10.1371/journal.pone.0126853. eCollection 2015.
Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the sinonasal mucosa either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP accounts for the majority of CRS cases and is characterized by fibrosis and neutrophilic inflammation. However, the pathogenesis of CRS, especially CRSsNP, remains unclear. Immunohistochemistry of CRSsNP specimens in the present study showed that the submucosa, perivascular areas, and the mucous glands were abundant in fibroblasts. Therefore, we investigated the effects bradykinin (BK), an autacoid known to participate in inflammation, on human CRSsNP nasal mucosa-derived fibroblasts (NMDFs). BK increased CXCL1 and -8 secretion and mRNA expression with EC50 ranging from 0.15~0.35 μM. Moreover, BK enhanced cell proliferation and upregulated the expressions of proinflammatory molecules, including cell adhesion molecules (CAMs) and cyclooxygenase (COX)-1 and -2. These functionally caused an increase in monocyte adhesion to fibroblast monolayer. Using pharmacological intervention and BKR siRNA knockdown, we demonstrated that the BK-induced CXCL chemokine release, cell proliferation and COX and CAM expressions were mainly through the B2 receptor (B2R). Accordingly, the B2R was preferentially expressed in the NMDFs than B1R. The B2R was highly expressed in the CRSsNP than the control specimens, while the B1R and kininogen (KNG)/BK expression slightly increased in the CRSsNP mucosa. Collectively, we report here for the first time that fibroblasts, KNG/BK, and BKRs are overexpressed in CRSsNP mucosa and BK upregulates chemokine expression, proliferation, and proinflammatory molecule expression in NMDFs via B2R activation, which lead to a functional increase in monocyte-fibroblast interaction. Our findings reveal a critical role of fibroblast, KNG/BK, and BKRs in the development of CRSsNP.
慢性鼻-鼻窦炎（CRS）是一种鼻窦黏膜的慢性炎症性疾病，可伴有息肉形成（CRSwNP）或不伴有息肉（CRSsNP）。CRSsNP占CRS病例的大多数，其特征为纤维化和中性粒细胞炎症。然而，CRS的发病机制，尤其是CRSsNP的发病机制仍不清楚。本研究中对CRSsNP标本进行的免疫组织化学显示，黏膜下层、血管周围区域和黏液腺中存在大量成纤维细胞。因此，我们研究了缓激肽（BK），一种已知参与炎症反应的自分泌物质，对人CRSsNP鼻黏膜来源的成纤维细胞（NMDFs）的影响。BK增加了CXCL1和-8的分泌及mRNA表达，其半数有效浓度（EC50）范围为0.15~0.35 μM。此外，BK增强了细胞增殖，并上调了促炎分子的表达，包括细胞黏附分子（CAMs）以及环氧化酶（COX）-1和-2。这些功能性变化导致单核细胞与成纤维细胞单层的黏附增加。通过药理学干预和BKR小干扰RNA（siRNA）敲低，我们证明BK诱导的CXCL趋化因子释放、细胞增殖以及COX和CAM表达主要是通过B2受体（B2R）介导的。相应地，B2R在NMDFs中的表达比B1受体（B1R）更具优势。B2R在CRSsNP中的表达高于对照标本，而B1R和激肽原（KNG）/BK在CRSsNP黏膜中的表达略有增加。总体而言，我们首次在此报告，成纤维细胞、KNG/BK和BKRs在CRSsNP黏膜中过表达，并且BK通过激活B2R上调NMDFs中的趋化因子表达、增殖和促炎分子表达，这导致单核细胞与成纤维细胞相互作用的功能性增强。我们的研究结果揭示了成纤维细胞、KNG/BK和BKRs在CRSsNP发病过程中的关键作用。
