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Inhibition of 5-lipoxygenase Alleviates Graft-Versus-Host Disease

Inhibition of 5-lipoxygenase Alleviates Graft-Versus-Host Disease

Barbara Maximino Rezende, Rayssa Maciel Athayde, William Antônio Gonçalves, Carolina Braga Resende, Priscila Teles de Tolêdo Bernardes, Denise Alves Perez, Lísia Esper, Alesandra Côrte Reis, Milene Alvarenga Rachid, etc.

J Exp Med. 2017 Nov 6;214(11):3399-3415.

PMID: 28947611

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP158081993	CP-105,696		158081-99-3	Price

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