基于“HPA轴”途径探索直接灸“足三里”改善CTX大鼠骨髓抑制的生物学机制

The bone marrow suppression caused by tumor chemotherapy is easy to reduce the immunity of the body and is not conducive to the treatment and rehabilitation of the tumor. In recent years, it has been found that moxibustion has a definite effect on improving bone marrow suppression after chemotherapy. The current research is mainly focused on the influence of moxibustion on the proliferation, differentiation and migration of bone marrow cells. Studies have confirmed that HPA axis plays an important regulatory role in the proliferation of bone marrow stem / progenitor cells. However, the mechanism of moxibustion can activate bone marrow stem / progenitor cells by activating HPA axis is not clear..Therefore, this study proposed the scientific hypothesis that "activating the HPA axis is one of the key mechanisms of moxibustion to improve the bone marrow suppression after chemotherapy". The rat bone marrow suppression model was established by using CTX. With glucocorticoid as an entry point, the hormone downstream of the HPA axis. After the HPA axis was blocked by CRH receptor specific blocker (CP-154526), the changes of HPA axis related hormones and bone marrow stem / progenitor cells in bone marrow suppression rats were observed by direct moxibustion at "Zusanli(ST 36)" point. To explore the biological mechanism of moxibustion to improve the bone marrow suppression after chemotherapy, and to open up a new idea for the study of the mechanism of moxibustion on improving the mechanism of bone marrow suppression after chemotherapy.

肿瘤化疗后引起的骨髓抑制容易降低机体的免疫力，不利于肿瘤的治疗与康复。近几年研究发现艾灸在改善化疗后的骨髓抑制方面有确切的疗效，而当前研究主要集中在艾灸对骨髓细胞的增殖、分化及迁徙等方面的影响。研究已证实HPA轴对骨髓干/祖细胞的增殖具有重要的调控作用，但艾灸能否通过激活HPA轴引起骨髓干/祖细胞增殖的机制研究尚不清楚。.因此，本研究提出“激活HPA轴是艾灸改善化疗后骨髓抑制的关键机制之一”的科学假说。拟采用CTX建立大鼠骨髓抑制模型，以HPA轴下游糖皮质激素为切入点，用CRH受体的特异性阻滞剂(CP-154526)阻滞HPA轴后，通过直接灸“足三里”穴观察骨髓抑制模型大鼠HPA轴相关激素与骨髓干/祖细胞的变化，探讨艾灸改善化疗后骨髓抑制的生物学机制，为艾灸改善化疗后骨髓抑制的机制研究开辟新思路。

近几年研究发现应激状态下的下丘脑-垂体-肾上腺轴(HPA)与促进造血干/祖细胞的增殖、改善骨髓抑制有着密切的联系。因此，项目立项时提出“激活HPA轴是艾灸改善化疗后骨髓抑制的关键机制之一”的科学假说。拟通过直接灸“足三里”穴观察骨髓抑制模型大鼠HPA轴相关激素与骨髓干/祖细胞的变化，探讨艾灸改善化疗后骨髓抑制的生物学机制。.本项目改良了CTX建立骨髓抑制模型的剂量及方法（即在造模第5天模型成立后，采用隔天注射减半剂量），对维持模型的稳定性至关重要，为实验的下一步实施奠定了基础。实验明确了艾炷灸可促进骨髓造血细胞从G2期向M期的转化，促进造血干细胞LSK、HSC的增殖。HPA轴方面，环磷酰胺使骨髓抑制模型的HPA轴负反馈调剂机制受损，超生理水平量的糖皮质激素并未对骨髓细胞的增殖起到积极作用。但经过艾炷灸后，GR的含量增加，恢复了HPA轴的负反馈调节机制，促使骨髓造血机制趋于正常化。说明艾炷灸通过恢复HPA轴的生理功能，增加糖皮质激素受体调控骨髓造血细胞的增殖。随着研究的深入，我们在基因测序中发现艾灸主要通过调控细胞因子和细胞因子受体间相互作用、造血细胞系等通路来实现对骨髓造血细胞的调控。意外的是，我们在实验中发现艾炷灸可以改善CTX骨髓抑制模型的腹泻情况，可以恢复模型鼠机体的固有免疫，诱导巨噬细胞增强对机体损伤组织的清除功能，其主要发挥作用的通路可能与造血细胞系、调节炎症性肠病、及Th1和Th2细胞分化等相关通路有关。.本项目的研究结果为今后艾炷灸治疗骨髓抑制提供实验依据，从基因层面上提出了新的研究方向，为艾炷灸防治骨髓抑制的推广提供理论支持。同时证实了艾灸可以减轻CTX对腹腔的毒副作用，为临床上艾灸治疗化疗后的腹泻提供基础研究。