NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A2A Receptor to Inhibit Lung Ischemia-Reperfusion Injury.
Am J Respir Crit Care Med
; 193(9): 988-99, 2016 05 01.
Article
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| MEDLINE
| ID: mdl-26757359
ABSTRACT
RATIONALE Ischemia-reperfusion (IR) injury after lung transplantation, which affects both short- and long-term allograft survival, involves activation of NADPH oxidase 2 (NOX2) and activation of invariant natural killer T (iNKT) cells to produce IL-17. Adenosine A2A receptor (A2AR) agonists are known to potently attenuate lung IR injury and IL-17 production. However, mechanisms for iNKT cell activation after IR and A2AR agonist-mediated protection remain unclear. OBJECTIVES:
We tested the hypothesis that NOX2 mediates IL-17 production by iNKT cells after IR and that A2AR agonism prevents IR injury by blocking NOX2 activation in iNKT cells.METHODS:
An in vivo murine hilar ligation model of IR injury was used, in which left lungs underwent 1 hour of ischemia and 2 hours of reperfusion. MEASUREMENTS AND MAINRESULTS:
Adoptive transfer of iNKT cells from p47(phox-/-) or NOX2(-/-) mice to Jα18(-/-) (iNKT cell-deficient) mice significantly attenuated lung IR injury and IL-17 production. Treatment with an A2AR agonist attenuated IR injury and IL-17 production in wild-type (WT) mice and in Jα18(-/-) mice reconstituted with WT, but not A2AR(-/-), iNKT cells. Furthermore, the A2AR agonist prevented IL-17 production by murine and human iNKT cells after acute hypoxia-reoxygenation by blocking p47(phox) phosphorylation, a critical step for NOX2 activation.CONCLUSIONS:
NOX2 plays a key role in inducing iNKT cell-mediated IL-17 production and subsequent lung injury after IR. A primary mechanism for A2AR agonist-mediated protection entails inhibition of NOX2 in iNKT cells. Therefore, agonism of A2ARs on iNKT cells may be a novel therapeutic strategy to prevent primary graft dysfunction after lung transplantation.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Glicoproteínas de Membrana
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Daño por Reperfusión
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NADPH Oxidasas
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Receptor de Adenosina A2A
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Células T Asesinas Naturales
Límite:
Animals
Idioma:
En
Revista:
Am J Respir Crit Care Med
Asunto de la revista:
TERAPIA INTENSIVA
Año:
2016
Tipo del documento:
Article