Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul, Korea.
J Allergy Clin Immunol. 2016 Jan;137(1):87-98.e7. doi: 10.1016/j.jaci.2015.07.026. Epub 2015 Sep 2.
Nasal polyps (NPs) imply a refractory clinical course in patients with chronic rhinosinusitis (CRS). Previously, we showed that hypoxia-inducible factor (HIF) 1 could mediate nasal polypogenesis through epithelial-to-mesenchymal transition (EMT). Sirtuin 1 (SIRT1), a histone deacetylase, reportedly suppresses the transcriptional activity of HIF-1. Thus we hypothesized that SIRT1 attenuates nasal polyposis by inhibiting HIF-1-induced EMT.
We sought to determine the role of SIRT1 in patients with nasal polyposis.
The effects of SIRT1 on nasal polypogenesis were investigated in previously developed murine models. Immunohistochemistry, immunoblotting, and immunoprecipitation were done to evaluate SIRT1, EMT, and hypoxic markers in human nasal epithelial cells or sinonasal tissues from the mice and the patients with CRS with or without NPs.
SIRT1 transgenic mice had significantly fewer mucosal lesions with epithelial disruption and fewer NPs than wild-type (WT) mice. In addition, resveratrol (a SIRT1 activator) treatment suppressed nasal polypogenesis in WT mice; however, sirtinol (a SIRT1 inhibitor) administration increased the polyp burden in SIRT1 transgenic mice. In sinonasal specimens from patients with CRS, SIRT1 was downregulated in the mucosa from patients with polyps compared with levels seen in patients without polyps. SIRT1 overexpression or activation reversed hypoxia-induced EMT in human nasal epithelial cells. The intranasal transfection of a small hairpin SIRT1 lentiviral vector induced more nasal polypoid lesions in SIRT1 transgenic mice. Finally, mucosal extracts from patients with CRS without NPs increased SIRT1 expression in nasal epithelial cells, whereas those from patients with CRS with NPs did not.
SIRT1 suppressed NP formation, possibly because of inhibition of HIF-1-induced EMT. Thus nasal epithelium SIRT1 might be a therapeutic target for NPs.
鼻息肉（NPs）提示慢性鼻-鼻窦炎（CRS）患者的临床病程具有难治性。先前我们已经表明，缺氧诱导因子（HIF）1 可通过上皮间质转化（EMT）来介导鼻息肉的发生。组蛋白去乙酰化酶 Sirtuin 1（SIRT1）据报道可抑制 HIF-1 的转录活性。因此，我们假设 SIRT1 通过抑制 HIF-1 诱导的 EMT 来减轻鼻息肉。
我们旨在确定 SIRT1 在鼻息肉患者中的作用。
我们在先前开发的小鼠模型中研究了 SIRT1 对鼻息肉形成的影响。我们通过免疫组织化学、免疫印迹和免疫沉淀来评估人鼻上皮细胞或来自患有 CRS 伴或不伴 NPs 的小鼠和患者的 SIRT1、EMT 和缺氧标志物。
SIRT1 转基因小鼠的黏膜损伤伴上皮破坏和息肉数量明显少于野生型（WT）小鼠。此外，白藜芦醇（SIRT1 激活剂）治疗抑制 WT 小鼠的鼻息肉形成；然而，Sirtinol（SIRT1 抑制剂）给药增加了 SIRT1 转基因小鼠的息肉负担。在 CRS 患者的鼻鼻窦标本中，与无息肉患者相比，息肉患者的黏膜中 SIRT1 下调。SIRT1 过表达或激活逆转了人鼻上皮细胞中的缺氧诱导的 EMT。SIRT1 短发夹 RNA 慢病毒载体的鼻腔转染在 SIRT1 转基因小鼠中诱导了更多的鼻息肉样病变。最后，无息肉的 CRS 患者的黏膜提取物增加了鼻上皮细胞中的 SIRT1 表达，而有息肉的 CRS 患者的黏膜提取物则没有。
SIRT1 抑制 NP 形成，可能是因为抑制了 HIF-1 诱导的 EMT。因此，鼻上皮 SIRT1 可能是 NP 的治疗靶点。
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