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肿瘤坏死因子α诱导小鼠迷走神经肺传入神经超敏反应

Hypersensitivity of Vagal Pulmonary Afferents Induced by Tumor Necrosis Factor Alpha in Mice.

作者信息

Lin Ruei-Lung, Gu Qihai, Lee Lu-Yuan

机构信息

Department of Physiology, University of Kentucky, Lexington, KY, United States.

Department of Biomedical Sciences, Mercer University, Macon, GA, United States.

出版信息

Front Physiol. 2017 Jun 14;8:411. doi: 10.3389/fphys.2017.00411. eCollection 2017.

Abstract

Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFα also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFα caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFα on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFα (10 μg/ml, 0.03 ml) and vehicle (Veh; phosphate buffered saline (PBS), 0.03 ml) were administered by intra-tracheal instillation in each mouse of treated (TNF) and control (Veh) groups, respectively, the peak activity of pulmonary C-fibers in response to an intravenous bolus injection of a low dose of capsaicin (Cap; 0.5 μg/kg) was significantly elevated in TNF group (6.5 ± 1.3 impulses/s, = 12) 24-48 h later, compared to that in Veh group (2.2 ± 0.5 impulses/s, = 11; < 0.05). Interestingly, the same low dose of Cap injection also evoked a distinct burst of discharge (2.4 ± 0.7 impulses/s) in 75% of the silent rapidly adapting receptors (RARs), a subtype of RARs exhibiting no phasic activity, in TNF group, but did not stimulate any of the silent RARs in Veh group. To further determine if this sensitizing effect involves a direct action of TNFα on these sensory nerves, the change in intracellular Ca concentration in response to Cap challenge was measured in isolated mouse vagal pulmonary sensory neurons. The Cap-evoked Ca influx was markedly enhanced in the neurons incubated with TNFα (50 ng/ml) for ~24 h, and this sensitizing effect was attenuated in the neurons isolated from the TNF-receptor double homozygous mutant mice. In conclusion, the TNFα pretreatment enhanced the Cap sensitivity in both pulmonary C-fibers and silent RARs, and the action was mediated through TNF receptors. These sensitizing effects of TNFα may contribute, at least in part, to the pathogenesis of airway hyperresponsiveness induced by this cytokine.

摘要

肿瘤坏死因子α(TNFα)是一种促炎细胞因子,在过敏性哮喘的发病机制中起重要作用。吸入TNFα也会在健康人体受试者中诱发气道高反应性,其潜在机制尚未完全明确。最近一项研究报道,TNFα可引起小鼠气道炎症和肺化学反射反应持续升高,提示迷走神经肺C纤维敏感性增加可能与之有关。为了探究这种可能性,本研究旨在探讨TNFα预处理对麻醉小鼠迷走神经肺传入神经敏感性的影响。分别对处理组(TNF)和对照组(Veh)的每只小鼠经气管内滴注TNFα(10μg/ml,0.03ml)和载体(Veh;磷酸盐缓冲盐水(PBS),0.03ml)后,24 - 48小时后,TNF组静脉注射低剂量辣椒素(Cap;0.5μg/kg)后肺C纤维的峰值活性显著升高(6.5±1.3冲动/秒,n = 12),而Veh组为(2.2±0.5冲动/秒,n = 11;P < 0.05)。有趣的是,相同低剂量的Cap注射在TNF组中还诱发了75%的静息快速适应性感受器(RARs)出现明显的放电爆发(2.4±0.7冲动/秒),RARs的这一亚型无相位活动,而Veh组中未刺激任何静息RARs。为进一步确定这种致敏作用是否涉及TNFα对这些感觉神经的直接作用,在分离的小鼠迷走神经肺感觉神经元中测量了对Cap刺激的细胞内钙浓度变化。用TNFα(50ng/ml)孵育约24小时的神经元中,Cap诱发的钙内流明显增强,并且这种致敏作用在从TNF受体双纯合突变小鼠分离的神经元中减弱。总之,TNFα预处理增强了肺C纤维和静息RARs对Cap的敏感性,且该作用通过TNF受体介导。TNFα的这些致敏作用可能至少部分促成了由该细胞因子诱导的气道高反应性的发病机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c81/5470033/2e18d512fb43/fphys-08-00411-g0001.jpg

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