Background

Obliterative bronchiolitis (OB) is the major complication limiting the long-term survival of allografts after lung transplantation. In this study, we investigated the effect of tacrolimus (FK506) combined with GM6001，a matrix metalloproteinase (MMP) inhibitor， on the formation of OB using a mouse heterotopic tracheal transplantation model.

Methods

Syngeneic tracheal grafts were transplanted heterotopically from BALB/c mice to BALB/c mice. Allografts from C57BL/6 mice were transplanted to BALB/c mice. Isograft group, allograft group, allograft+FK506 group, allograft +GM6001 group and allograft+FK506 + GM6001 group was given respectively intraperitoneal injection of saline, saline, FK506, GM6001 and FK506 + GM6001 once a day. At 28 day after transplantation, OB incidence was determined by hematoxylin-eosin staining and the expressions of MMPs and cytokines were assessed using enzyme linked immunosorbent assay, immunohistochemical assays and western blot assay.

Results

The tracheal occlusion rates of isograft group, allograft group, allograft+FK506 group, allograft+GM6001 group and allograft+FK506 + GM6001 group were 0, 74.1 ± 9.79%, 34.4 ± 6.04%, 40.3 ± 8.77% and 26.5 ± 5.73% respectively. There were significant differences between the latter two groups (P < .001). The serum MMP-8 and MMP-9 levels of allograft group were significantly higher than those of isograft group (P < .05) and had no significant decrease when treated by FK506. The serum MMP-8 and MMP-9 levels of allograft+FK506 + GM6001 group were significantly lower than those of allograft+FK506 group (P < .05). MMP-8 and MMP-9 protein expression in the grafts of allograft+FK506 + GM6001 group were lower than those of allograft+FK506 group verified by immunohistochemical staining and western blotting.

Conclusion

FK506 combined with GM6001 could alleviate tracheal obliteration in mouse heterotopic tracheal transplantation model, due to its inhibitory effect on MMPs.

中文翻译：

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FK506与GM6001组合可防止异位气管移植小鼠模型中的气管闭塞。

背景

闭塞性细支气管炎（OB）是限制肺移植后同种异体移植物长期生存的主要并发症。在本研究中，我们使用小鼠异位气管移植模型研究了他克莫司（FK506）与基质金属蛋白酶（MMP）抑制剂GM6001联合对OB形成的影响。

方法

同质气管移植物从BALB / c小鼠异位移植到BALB / c小鼠。将来自C57BL / 6小鼠的同种异体移植到BALB / c小鼠中。同种异体移植组，同种异体移植组，同种异体移植物+ FK506组，同种异体移植物+ GM6001组和同种异体移植物+ FK506 + GM6001组分别每天一次腹膜内注射盐水，生理盐水，FK506，GM6001和FK506 + GM6001。移植后第28天，通过苏木精-曙红染色确定OB发生率，并使用酶联免疫吸附测定，免疫组织化学测定和western blot测定来评估MMP和细胞因子的表达。

结果

同种异体移植组，同种异体移植组，同种异体移植+ FK506组，同种异体移植+ GM6001组和同种异体移植+ FK506 + GM6001组的气管阻塞率分别为0、74.1±9.79％，34.4±6.04％，40.3±8.77％和26.5±5.73％ 。后两组之间存在显着差异（P  <.001）。同种异体移植组的血清MMP-8和MMP-9水平显着高于同种异体移植组（P  <0.05），经FK506治疗后无明显降低。同种异体移植+ FK506 + GM6001组的血清MMP-8和MMP-9水平明显低于同种异体移植+ FK506组（P <.05）。免疫组织化学染色和Western blotting证实，同种异体移植+ FK506 + GM6001组移植物中的MMP-8和MMP-9蛋白表达低于同种异体移植+ FK506组。

结论

FK506与GM6001联合使用可减轻小鼠异位气管移植模型中的气管闭塞，因为它具有抑制MMP的作用。