Damage to Olfactory Progenitor Cells Is Involved in Cigarette Smoke-Induced Olfactory Dysfunction in Mice
Damage to Olfactory Progenitor Cells Is Involved in Cigarette Smoke-Induced Olfactory Dysfunction in Mice
复制标题
DOI：
10.1016/j.ajpath.2015.11.009
复制
发表时间：
2016-03-01
影响因子：
6
通讯作者：
Yamasoba, Tatsuya
中科院分区：
文献类型：
--
作者：
Ueha, Rumi;Ueha, Satoshi;Yamasoba, Tatsuya
暴露在香烟烟雾中是嗅觉功能障碍的主要原因。然而，香烟烟雾干扰高度再生的嗅觉神经系统的潜在机制尚不清楚。为了研究香烟烟雾是否通过破坏嗅上皮（OE）的细胞增殖和细胞存活来诱导嗅觉功能障碍，我们建立了一个吸烟小鼠模型，该模型涉及鼻内给药香烟烟雾溶液（CSS）。免疫组织学分析和行为学测试表明，连续24天使用CSS可减少OE中嗅觉标记蛋白阳性的成熟嗅觉受体神经元（orn）的数量，并诱导嗅觉功能障碍。这些变化与OE基底层SOX2(+) ORN祖细胞和Ki-67（+）增殖细胞数量减少，caspase-3（+）凋亡细胞数量增加，炎症细胞因子IL-1 β和IL-6 mRNA表达增加相一致。值得注意的是，在停止使用CSS处理后，增殖的ORN祖细胞群体恢复，导致随后成熟的ORN数量和嗅觉恢复。这些结果表明，SOX2(+) ORN祖细胞是CSS诱导OE损伤的靶点，通过破坏ORN祖细胞群和增加ORN死亡，CSS暴露最终会破坏上皮的再生能力，导致成熟ORN数量减少和嗅觉功能障碍。
Exposure to cigarette smoke is a major cause of olfactory dysfunction. However, the underlying mechanisms by which cigarette smoke interferes with the highly regenerative olfactory nerve system remain unclear. To investigate whether cigarette smoke induces olfactory dysfunction by disrupting cell proliferation and cell survival in the olfactory epithelium (OE), we developed a mouse model of smoking that involved intranasal administration of a cigarette smoke solution (CSS). Immunohistologicat analyses and behavioral testing showed that CSS administration during a period of 24 days reduced the number of olfactory marker protein positive mature olfactory receptor neurons (ORNs) in the OE and induced olfactory dysfunction. These changes coincided with a reduction in the number of SOX2(+) ORN progenitors and Ki-67(+) proliferating cells in the basal layer of the OE, an increase in the number of caspase-3(+) apoptotic cells, and an increase in the expression of mRNA for the inflammatory cytokines IL-1 beta and IL-6. Notably, the proliferating ORN progenitor population recovered after cessation of treatment with CSS, resulting in the subsequent restoration of mature ORN numbers and olfaction. These results suggest that SOX2(+) ORN progenitors are targets of CSS-induced impairment of the OE, and that by damaging the ORN progenitor population and increasing ORN death, CSS exposure eventually overwhelms the regenerative capacity of the epithelium, resulting in reduced numbers of mature ORNs and olfactory dysfunction.