Inhibition of 5-lipoxygenase alleviates graft-versus-host disease.

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.

• Authors: 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, Marina Gomes Miranda E Castor, Thiago Mattar Cunha, Fabiana Simão Machado, Mauro Martins Teixeira, Vanessa Pinho
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 214 Issue 11 Pg. 3399-3415 (Nov 06 2017) ISSN: 1540-9538 [Electronic] United States
• PMID: 28947611 (Publication Type: Journal Article)
• Copyright: © 2017 Rezende et al.

Chemical References

• Benzopyrans
• Carboxylic Acids
• Chemokines
• Cytokines
• Leukotriene Antagonists
• Lipoxygenase Inhibitors
• Leukotriene B4
• Arachidonate 5-Lipoxygenase
• zileuton
• Hydroxyurea
• CP 105696

Topics

• Animals
• Arachidonate 5-Lipoxygenase (genetics, metabolism)
• Benzopyrans (pharmacology)
• Carboxylic Acids (pharmacology)
• Cell Transplantation (adverse effects, methods)
• Chemokines (metabolism)
• Cytokines (metabolism)
• Graft vs Host Disease (drug therapy, etiology, metabolism)
• Hydroxyurea (analogs & derivatives, pharmacology)
• Leukocytes (cytology, enzymology, metabolism)
• Leukotriene Antagonists (pharmacology)
• Leukotriene B4 (antagonists & inhibitors, metabolism)
• Lipoxygenase Inhibitors (pharmacology)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Microscopy, Confocal
• Transplantation, Homologous