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Inhibition of 5-lipoxygenase alleviates graft-versus-host disease
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2017-11-06 , DOI: 10.1084/jem.20170261
Barbara Maximino Rezende 1 , Rayssa Maciel Athayde 1 , William Antônio Gonçalves 1 , Carolina Braga Resende 1 , Priscila Teles de Tolêdo Bernardes 1 , Denise Alves Perez 1 , Lísia Esper 2 , Alesandra Côrte Reis 1 , Milene Alvarenga Rachid 3 , Marina Gomes Miranda e Castor 4 , Thiago Mattar Cunha 5 , Fabiana Simão Machado 2 , Mauro Martins Teixeira 2 , Vanessa Pinho 1
Affiliation  

Leukotriene B4 (LTB4), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this study, we evaluated the participation of the 5-LO/LTB4 axis in graft-versus-host disease (GVHD) pathogenesis by transplanting 5-LO–deficient leukocytes and investigated the effect of pharmacologic 5-LO inhibition by zileuton and LTB4 inhibition by CP-105,696. Mice that received allogeneic transplant showed an increase in nuclear 5-LO expression in splenocytes, indicating enzyme activation after GVHD. Mice receiving 5-LO–deficient cell transplant or zileuton treatment had prolonged survival, reduced GVHD clinical scores, reduced intestinal and liver injury, and decreased levels of serum and hepatic LTB4. These results were associated with inhibition of leukocyte recruitment and decreased production of cytokines and chemokines. Treatment with CP-105,696 achieved similar effects. The chimerism or the beneficial graft-versus-leukemia response remained unaffected. Our data provide evidence that the 5-LO/LTB4 axis orchestrates GVHD development and suggest it could be a target for the development of novel therapeutic strategies for GVHD treatment.



中文翻译:

抑制5-脂氧合酶可减轻移植物抗宿主病

白三烯B 4(LTB 4)是由5-脂氧合酶(5-LO)产生的促炎介质,它与许多炎性疾病的发展有关。在这项研究中,我们评估了5-LO / LTB 4轴在移植物抗宿主病(GVHD)发病机理中的作用,方法是移植有5-LO缺陷的白细胞,并研究了齐留通和LTB对5-LO抑制的药理作用4由CP-105,696抑制。接受同种异体移植的小鼠显示脾细胞中核5-LO表达增加,表明GVHD后酶被激活。接受5-LO不足细胞移植或齐留通治疗的小鼠可延长生存期,降低GVHD临床评分,减少肠和肝损伤,并降低血清和肝LTB 4的水平。这些结果与抑制白细胞募集和减少细胞因子和趋化因子的产生有关。CP-105,696的处理也达到了类似的效果。嵌合或有益的移植物抗白血病反应仍然不受影响。我们的数据提供了证据,表明5-LO / LTB 4 轴协调GVHD的发展,并暗示它可能是针对GVHD治疗的新型治疗策略发展的目标。

更新日期:2017-11-06
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