鞘内注射白三烯 B4 通过刺激致敏大鼠 HPA 轴的 BLT1 受体减轻抗原诱导的哮喘反应。
Intracerebroventricular injection of leukotriene B4 attenuates antigen-induced asthmatic response via BLT1 receptor stimulating HPA-axis in sensitized rats.
机构信息
Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical Science College of Zhejiang University, Hangzhou, China.
出版信息
Respir Res. 2010 Apr 20;11(1):39. doi: 10.1186/1465-9921-11-39.
BACKGROUND
Basic and clinical studies suggest that hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine-immune pathway that functionally regulates the chronic inflammatory disease including asthma. Our previous studies showed corresponding changes of cytokines and leukotriene B4 (LTB4) between brain and lung tissues in antigen-challenged asthmatic rats. Here, we investigated how the increased LTB4 level in brain interacts with HPA axis in regulating antigen-induced asthmatic response in sensitized rats.
METHODS
Ovalbumin-sensitized rats were challenged by inhalation of antigen. Rats received vehicle, LTB4 or U75302 (a selective LTB4 BLT1 receptor inhibitor) was given via intracerebroventricular injection (i.c.v) 30 min before challenge. Lung resistance (RL) and dynamic lung compliance (Cdyn) were measured before and after antigen challenge. Inflammatory response in lung tissue was assessed 24 h after challenge. Expression of CRH mRNA and protein in hypothalamus were evaluated by RT-PCR and Western Blot, and plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were measured using the ELISA kits.
RESULTS
Antigen challenge decreased pulmonary function and induced airway inflammation, evoked HPA axis response in sensitized rats. Administration of LTB4 via i.c.v markedly attenuated airway contraction and inflammation. Meanwhile, LTB4 via i.c.v markedly increased CORT and ACTH level in plasma before antigen challenge, and followed by further increases in CORT and ACTH levels in plasma after antigen challenge in sensitized rats. Expression of CRH mRNA and protein in hypothalamus were also significantly increased by LTB4 via i.c.v in sensitized rats after antigen challenge. These effect were completely blocked by pre-treatment with BLT1 receptor antagonist U75302 (10 ng), but not by BLT2 antagonist LY255283.
CONCLUSIONS
LTB4 administered via i.c.v down-regulates the airway contraction response and inflammation through activation of the HPA axis via its BLT1 receptor. This study expands our concept of the regulatory role of intracranial inflammatory mediators in inflammatory diseases including asthma. The favourable effects of LTB4 on the HPA axis may help to explain the phenomenon of self-relief after an asthmatic attack.
背景
基础和临床研究表明，下丘脑-垂体-肾上腺（HPA）轴是一种神经内分泌免疫途径，可调节包括哮喘在内的慢性炎症性疾病。我们之前的研究表明，在抗原攻击的哮喘大鼠中，大脑和肺组织之间的细胞因子和白三烯 B4（LTB4）会发生相应变化。在这里，我们研究了大脑中增加的 LTB4 水平如何与 HPA 轴相互作用，从而调节致敏大鼠中抗原诱导的哮喘反应。
方法
卵清蛋白致敏大鼠通过吸入抗原进行攻击。在攻击前 30 分钟，大鼠通过脑室内注射（i.c.v）接受载体、LTB4 或 U75302（一种选择性 LTB4 BLT1 受体抑制剂）。在抗原攻击前后测量肺阻力（RL）和动态肺顺应性（Cdyn）。在攻击后 24 小时评估肺组织中的炎症反应。通过 RT-PCR 和 Western Blot 评估下丘脑 CRH mRNA 和蛋白的表达，使用 ELISA 试剂盒测量血浆中促肾上腺皮质激素（ACTH）和皮质酮（CORT）的水平。
结果
抗原攻击降低了肺功能并诱导了气道炎症，引发了致敏大鼠的 HPA 轴反应。通过 i.c.v 给予 LTB4 可明显减轻气道收缩和炎症。同时，LTB4 通过 i.c.v 显著增加了致敏大鼠抗原攻击前的血浆皮质醇和 ACTH 水平，随后在致敏大鼠抗原攻击后进一步增加了血浆皮质醇和 ACTH 水平。LTB4 通过 i.c.v 还显著增加了致敏大鼠抗原攻击后下丘脑 CRH mRNA 和蛋白的表达。这些作用完全被 BLT1 受体拮抗剂 U75302（10 ng）预处理阻断，但不是由 BLT2 拮抗剂 LY255283 阻断。
结论
通过 i.c.v 给予 LTB4 通过其 BLT1 受体激活 HPA 轴，下调气道收缩反应和炎症。本研究扩展了我们对包括哮喘在内的炎症性疾病中颅内炎症介质调节作用的认识。LTB4 对 HPA 轴的有利影响可能有助于解释哮喘发作后自我缓解的现象。
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