Mizokami Daisuke, Araki Koji, Tanaka Nobuaki, Suzuki Hiroshi, Tomifuji Masayuki, Yamashita Taku, Ueda Yasuji, Shimada Hideaki, Matsushita Kazuyuki, Shiotani Akihiro
Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
DNAVEC Corporation, Tsukuba, Ibaraki, Japan.
PLoS One. 2015 Jan 8;10(1):e0116279. doi: 10.1371/journal.pone.0116279. eCollection 2015.
Acquired tracheal stenosis remains a challenging problem for otolaryngologists. The objective of this study was to determine whether the Sendai virus (SeV)-mediated c-myc suppressor, a far upstream element (FUSE)-binding protein (FBP)-interacting repressor (FIR), modulates wound healing of the airway mucosa, and whether it prevents tracheal stenosis in an animal model of induced mucosal injury. A fusion gene-deleted, non-transmissible SeV vector encoding FIR (FIR-SeV/ΔF) was prepared. Rats with scraped airway mucosae were administered FIR-SeV/ΔF through the tracheostoma. The pathological changes in the airway mucosa and in the tracheal lumen were assessed five days after scraping. Untreated animals showed hyperplasia of the airway epithelium and a thickened submucosal layer with extensive fibrosis, angiogenesis, and collagen deposition causing lumen stenosis. By contrast, the administration of FIR-SeV/ΔF decreased the degree of tracheal stenosis (P < 0.05) and improved the survival rate (P < 0.05). Immunohistochemical staining showed that c-Myc expression was downregulated in the tracheal basal cells of the FIR-SeV/ΔF-treated animals, suggesting that c-myc was suppressed by FIR-SeV/ΔF in the regenerating airway epithelium of the injured tracheal mucosa. The airway-targeted gene therapy of the c-myc suppressor FIR, using a recombinant SeV vector, prevented tracheal stenosis in a rat model of airway mucosal injury.
获得性气管狭窄对于耳鼻喉科医生而言仍是一个具有挑战性的问题。本研究的目的是确定仙台病毒（SeV）介导的c-myc抑制因子，一种远上游元件（FUSE）结合蛋白（FBP）相互作用抑制因子（FIR），是否能调节气道黏膜的伤口愈合，以及它是否能在诱导性黏膜损伤的动物模型中预防气管狭窄。制备了一种编码FIR的融合基因缺失、不可传播的SeV载体（FIR-SeV/ΔF）。对气道黏膜刮伤的大鼠通过气管造口给予FIR-SeV/ΔF。刮伤五天后评估气道黏膜和气管腔的病理变化。未治疗的动物表现出气道上皮增生以及黏膜下层增厚，伴有广泛的纤维化、血管生成和胶原沉积，导致管腔狭窄。相比之下，给予FIR-SeV/ΔF可降低气管狭窄程度（P < 0.05）并提高存活率（P < 0.05）。免疫组织化学染色显示，在接受FIR-SeV/ΔF治疗的动物的气管基底细胞中，c-Myc表达下调，这表明在受损气管黏膜再生的气道上皮中，c-myc被FIR-SeV/ΔF抑制。使用重组SeV载体对c-myc抑制因子FIR进行气道靶向基因治疗，可预防气道黏膜损伤大鼠模型中的气管狭窄。
