Department of Anesthesia and General Intensive Care, Medical University of Vienna, Vienna, Austria.
Department of Cardiovascular Research, Medical University of Vienna, Vienna, Austria.
J Thorac Cardiovasc Surg. 2015 Apr;149(4):1194-202. doi: 10.1016/j.jtcvs.2014.11.088. Epub 2014 Dec 4.
Azithromycin has become a standard of care in therapy of bronchiolitis obliterans following lung transplantation. Matrix metalloprotease-9 broncho-alveolar lavage levels increase in airway neutrophilia and bronchiolitis obliterans. Interleukin-17 may play a role in lung allograft rejection, and interleukin-12 is downregulated in bronchiolitis obliterans. Whether these mechanisms can be targeted by azithromycin remains unclear.
Bronchiolitis obliterans was induced by transplantation of Fischer F344 rat left lungs to Wistar Kyoto rats. Allografts with azithromycin therapy from day 1 to 28 or 56 and mono- or combination therapy with the broad-spectrum matrix metalloprotease inhibitor tanomastat from day 1 to 56 were compared to control allografts and isografts. Graft histology was assessed, and tissue cytokine expression studied using Western blotting and immunofluorescence.
The chronic airway rejection score in the azithromycin group did not change between 4 and 8 weeks after transplantation, whereas it significantly worsened in control allografts (P = .041). Azithromycin+tanomastat prevented complete allograft fibrosis, which occurred in 40% of control allografts. Azithromycin reduced interleukin-17 expression (P = .049) and the number of IL-17(+)/CD8(+) lymphocytes at 4 weeks, and active matrix metalloprotease-9 at 8 weeks (P = .017), and increased interleukin-12 expression (P = .025) at 8 weeks following transplantation versus control allografts.
The expression of interleukin-17 and matrix metalloprotease-9 in bronchiolitis obliterans may be attenuated by azithromycin, and the decrease in interleukin-12 expression was prevented by azithromycin. Combination of azithromycin with a matrix metalloprotease inhibitor is worth studying further because it prevented complete allograft fibrosis in this study.
阿奇霉素已成为肺移植后闭塞性细支气管炎治疗的标准疗法。基质金属蛋白酶-9 支气管肺泡灌洗液水平在气道中性粒细胞增多和闭塞性细支气管炎中增加。白细胞介素-17 可能在肺同种异体移植排斥中发挥作用，而白细胞介素-12 在闭塞性细支气管炎中下调。阿奇霉素是否可以靶向这些机制尚不清楚。
通过将 Fischer F344 大鼠左肺移植到 Wistar Kyoto 大鼠中来诱导闭塞性细支气管炎。从第 1 天到第 28 天或第 56 天给予阿奇霉素治疗的同种异体移植物，以及从第 1 天到第 56 天给予广谱基质金属蛋白酶抑制剂 tanomastat 的单一或联合治疗，与对照同种异体移植物和同基因移植物进行比较。评估移植物组织学，并使用 Western 印迹和免疫荧光研究组织细胞因子表达。
在移植后 4 至 8 周，阿奇霉素组的慢性气道排斥评分没有变化，而对照同种异体移植物的评分则明显恶化（P =.041）。阿奇霉素+tanomastat 可预防对照同种异体移植物中发生的 40%完全移植物纤维化。阿奇霉素可降低白细胞介素-17 表达（P =.049）和第 4 周的 IL-17（+）/CD8（+）淋巴细胞数量，以及第 8 周的活性基质金属蛋白酶-9（P =.017），并增加白细胞介素-12 表达（P =.025）与对照同种异体移植物相比，移植后 8 周。
阿奇霉素可减弱闭塞性细支气管炎中白细胞介素-17 和基质金属蛋白酶-9 的表达，并防止白细胞介素-12 表达下降。在这项研究中，阿奇霉素与基质金属蛋白酶抑制剂的联合应用可进一步研究，因为它可防止完全同种异体移植物纤维化。
