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.

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。