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首页> 外文期刊>Clinical and experimental allergy : >Lidocaine-derivative JMF2-1 prevents ovalbumin-induced airway inflammation by regulating the function and survival of T cells.
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Lidocaine-derivative JMF2-1 prevents ovalbumin-induced airway inflammation by regulating the function and survival of T cells.

机译：利多卡因衍生物JMF2-1通过调节T细胞的功能和存活来预防卵白蛋白引起的气道炎症。

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BACKGROUND: Inhalation of the local anaesthetic lidocaine has been suggested to be beneficial for asthmatics, but airway anaesthesia is unpleasant and may exacerbate bronchoconstriction. Our previous study showed that inhalation of the lidocaine analogue JMF2-1 can elicit the anti-inflammatory properties of lidocaine without anaesthesia. This prompted further research on the mechanism of action and putative therapeutic application of JMF2-1. OBJECTIVE: We tested the hypothesis that JMF2-1 would prevent allergen-induced lung inflammation and airway hyperresponsiveness (AHR) by modulating T cell function in vivo and in vitro. Methods Local and systemic changes in leucocyte levels, cytokine production and lung mechanics were examined in a murine model of lung inflammation. JMF2-1 (0.05-2%) or saline was aerosolized twice a day during the ovalbumin (OVA)-provocation period (19-21 days post-sensitization). Analyses were performed 24 h after the final challenge. Primary cultured lymph node cells were used to assess the effects of JMF2-1 (100-600 mum) at the cellular level. RESULTS: OVA challenge resulted in lung recruitment of CD4(+) T cells and eosinophils, increased generation of inflammatory cytokines and AHR to inhaled methacholine within 24 h. These changes were prevented by JMF2-1 nebulization, and occurred in parallel with an increase in the number of apoptotic cells in the lung. JMF2-1 treatment did not alter levels of CD4(+) or CD8(+) T cells in the thymus or lymph nodes of naive mice, although it inhibited OVA-induced IL-13 production and the lymphocyte proliferative response in vitro. It also induced apoptosis of OVA-activated lymphocytes in a mechanism sensitive to z-VAD, indicating that JMF2-1 mediates caspase-dependent apoptosis. CONCLUSION: Inhalation of JMF2-1 prevents the cardinal features of asthma by reducing T(H) 2 cytokine generation and lung eosinophilic inflammatory infiltrates via local inhibition of T cell function and survival. JMF2-1 may represent a novel therapeutic alternative for asthma control with distinct advantages over local anaesthetics.
机译：背景：已建议吸入局部麻醉剂利多卡因对哮喘患者有益，但气道麻醉令人不快，可能加剧支气管狭窄。我们先前的研究表明，吸入利多卡因类似物JMF2-1可以在不麻醉的情况下引起利多卡因的抗炎特性。这促使人们进一步研究JMF2-1的作用机理和可能的治疗应用。目的：我们检验了JMF2-1通过调节体内和体外T细胞功能来预防变应原诱发的肺部炎症和气道高反应性（AHR）的假设。方法在小鼠肺炎症模型中检查白细胞水平，细胞因子产生和肺力学的局部和全身变化。在卵清蛋白（OVA）激发期间（致敏后19-21天），每天两次喷雾JMF2-1（0.05-2％）或盐水。最后一次攻击后24小时进行分析。原代培养的淋巴结细胞用于评估JMF2-1（100-600微米）在细胞水平上的作用。结果：OVA刺激导致CD4（+）T细胞和嗜酸性粒细胞在肺部募集，在24小时内吸入乙酰甲胆碱的炎症细胞因子和AHR生成增加。这些变化被JMF2-1雾化阻止，并且与肺中凋亡细胞数量的增加同时发生。 JMF2-1处理并没有改变幼稚小鼠胸腺或淋巴结中CD4（+）或CD8（+）T细胞的水平，尽管它抑制了OVA诱导的IL-13产生和体外淋巴细胞增殖反应。它还以对z-VAD敏感的机制诱导OVA激活的淋巴细胞凋亡，表明JMF2-1介导caspase依赖性凋亡。结论：吸入JMF2-1可通过减少T（H）2细胞因子的产生和局部抑制T细胞功能和存活来抑制肺嗜酸性粒细胞浸润，从而预防哮喘的主要特征。 JMF2-1可能代表了一种新型的哮喘控制替代疗法，具有优于局部麻醉药的独特优势。

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