Inhibition of 5-lipoxygenase alleviates graft-versus-host disease
| Autor: | Mauro M. Teixeira, Denise A. Perez, Carolina Braga de Resende, Marina G. M. Castor, William Antonio Gonçalves, Priscila T. T. Bernardes, Milene Alvarenga Rachid, Thiago M. Cunha, Fabiana S. Machado, Lisia Esper, Rayssa Maciel Athayde, Alesandra C. Reis, Bárbara M. Rezende, Vanessa Pinho |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Chemokine Cell Transplantation Leukotriene B4 Immunology Carboxylic Acids Graft vs Host Disease Article Proinflammatory cytokine Pathogenesis 03 medical and health sciences chemistry.chemical_compound Leukocytes medicine Animals Hydroxyurea Transplantation Homologous Immunology and Allergy Benzopyrans Lipoxygenase Inhibitors Research Articles Mice Inbred BALB C Arachidonate 5-Lipoxygenase Microscopy Confocal biology business.industry MICROSCOPIA CONFOCAL Zileuton medicine.disease Mice Inbred C57BL Transplantation surgical procedures operative 030104 developmental biology Graft-versus-host disease chemistry Arachidonate 5-lipoxygenase biology.protein Cytokines Leukotriene Antagonists Chemokines business medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP The Journal of Experimental Medicine |
| Popis: | Rezende et al. report that the transplant of 5-lipoxygenase (5-LO)−deficient leukocytes protects mice from GVHD. Treatment with the 5-LO inhibitor zileuton or a LTB4 antagonist at the initial phase of the transplant achieves similar protective effects. 5-LO is a crucial contributor to tissue damage in GVHD. 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. |
| Databáze: | OpenAIRE |
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