Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Toxicol Sci. 2010 Jun;115(2):547-56. doi: 10.1093/toxsci/kfq071. Epub 2010 Mar 3.
Exposure to nickel sulfate (NiSO(4)) leads to impaired olfaction and anosmia through an unknown mechanism. We tested the hypothesis that ATP is released following NiSO4-induced injury and that ATP promotes regenerative cell proliferation in the olfactory epithelium (OE). Male Swiss Webster mice were intranasally instilled with NiSO(4) or saline followed by ATP, purinergic receptor antagonists, or saline. We assessed the olfactory epithelium for NiSO(4)-induced changes using histology and immunohistochemistry 1-7 days postinstillation and compared results to olfactory bulb ablation-induced toxicity. Intranasal instillation of NiSO(4) produced a dose- and time-dependent reduction in the thickness of turbinate OE. These reductions were due to sustentacular cell loss, measured by terminal dUTP nick-end labeling (TUNEL) staining at 1-day postinstillation and caspase-3-dependent apoptosis of olfactory sensory neurons at 3 days postinstillation. A significant increase in cell proliferation was observed at 5 and 7 days postinstillation of NiSO(4) evidenced by BrdU incorporation. Treatment with purinergic receptor antagonists significantly reduced NiSO(4)-induced cell proliferation and posttreatment with ATP significantly increased cell proliferation. Furthermore, posttreatment with ATP had no effect on sustentacular cell viability but significantly reduced caspase-3-dependent neuronal apoptosis. In a bulbectomy-induced model of apoptosis, exogenous ATP produced a significant increase in cell proliferation that was not affected by purinergic receptor antagonists, suggesting that ATP is not released during bulbectomy-induced apoptosis. ATP is released following NiSO(4)-induced apoptosis and has neuroproliferative and neuroprotective functions. These data provide therapeutic strategies to alleviate or cure the loss of olfactory function associated with exposure to nickel compounds.
接触硫酸镍（NiSO4）会导致嗅觉和味觉丧失，但其具体机制尚不清楚。我们通过实验验证了以下假说，即 NiSO4 诱导损伤后会释放 ATP，而 ATP 则可以促进嗅上皮（OE）中的再生细胞增殖。雄性瑞士韦伯斯特小鼠经鼻腔内滴注 NiSO4 或生理盐水后，分别给予 ATP、嘌呤能受体拮抗剂或生理盐水。我们在鼻腔内滴注 NiSO4 后 1-7 天通过组织学和免疫组织化学评估嗅上皮的变化，并将结果与嗅球消融诱导的毒性进行比较。鼻腔内滴注 NiSO4 会导致鼻甲 OE 的厚度呈剂量和时间依赖性减少。这种减少是由于支持细胞的丧失引起的，通过在滴注后 1 天进行末端 dUTP 缺口末端标记（TUNEL）染色和在滴注后 3 天进行 caspase-3 依赖性嗅感觉神经元凋亡来测量。在 NiSO4 滴注后 5 和 7 天观察到细胞增殖显著增加，这是通过 BrdU 掺入证明的。嘌呤能受体拮抗剂的治疗显著减少了 NiSO4 诱导的细胞增殖，而 ATP 的后续治疗显著增加了细胞增殖。此外，ATP 的后续治疗对支持细胞的存活没有影响，但显著减少了 caspase-3 依赖性神经元凋亡。在嗅球切除术诱导的凋亡模型中，外源性 ATP 显著增加了细胞增殖，而嘌呤能受体拮抗剂对其没有影响，这表明在嗅球切除术诱导的凋亡过程中没有释放 ATP。ATP 是在 NiSO4 诱导的凋亡后释放的，具有神经增殖和神经保护功能。这些数据为减轻或治疗与接触镍化合物相关的嗅觉功能丧失提供了治疗策略。
