Dataset Information

Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion.

ABSTRACT:

Aims

Nitrated fatty acids (NO(2)-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO(2)) and nitro-linoleic acid (LNO(2)) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO(2) on I/R injury was evaluated.

Methods and results

In C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO(2) and LNO(2) formation was observed after 30 min of reperfusion, whereas no NO(2)-FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion. Exogenous administration of 20 nmol/g body weight OA-NO(2) during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice. Administration of OA-NO(2) inhibited activation of the p65 subunit of nuclear factor kappaB (NFkappaB) in I/R tissue. Experiments using the NFkappaB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO(2) was in part mediated by inhibition of NFkappaB. OA-NO(2) inhibition of NFkappaB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis.

Conclusion

This study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO(2) in myocardial I/R injury.

SUBMITTER: Rudolph V

PROVIDER: S-EPMC2791055 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion.

Rudolph Volker V Rudolph Tanja K TK Schopfer Francisco J FJ Bonacci Gustavo G Woodcock Steven R SR Cole Marsha P MP Baker Paul R S PR Ramani Ravi R Freeman Bruce A BA

Cardiovascular research 20100101 1

<h4>Aims</h4>Nitrated fatty acids (NO(2)-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO(2)) and nitro-linoleic acid (LNO(2)) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO(2) on I/R injury was evaluated.<h4>Methods and results</h4>In C57/BL6 mice subjected to 30 min of coronary arte ...[more]

PMID: 19666678

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Project description:Background and aimsAlthough type 2 innate lymphoid cells (ILC2s) were originally found to be liver-resident lymphocytes, the role and importance of ILC2 in liver injury remains poorly understood. In the current study, we sought to determine whether ILC2 is an important regulator of hepatic ischaemia/reperfusion injury (IRI).MethodsILC2-deficient mice (ICOS-T or NSG) and genetically modified ILC2s were used to investigate the role of ILC2s in murine hepatic IRI. Interactions between ILC2s and eosinophils or macrophages were studied in coculture. The role of human ILC2s was assessed in an immunocompromised mouse model of hepatic IRI.ResultsAdministration of IL-33 prevented hepatic IRI in association with reduction of neutrophil infiltration and inflammatory mediators in the liver. IL-33-treated mice had elevated numbers of ILC2s, eosinophils, and regulatory T cells. Eosinophils, but not regulatory T cells, were required for IL-33-mediated hepatoprotection in IRI mice. Depletion of ILC2s substantially abolished the protective effect of IL-33 in hepatic IRI, indicating that ILC2s play critical roles in IL-33-mediated liver protection. Adoptive transfer of ex vivo-expanded ILC2s improved liver function and attenuated histologic damage in mice subjected to IRI. Mechanistic studies combining genetic and adoptive transfer approaches identified a protective role of ILC2s through promoting IL-13-dependent induction of anti-inflammatory macrophages and IL-5-dependent elevation of eosinophils in IRI. Furthermore, in vivo expansion of human ILC2s by IL-33 or transfer of ex vivo-expanded human ILC2s ameliorated hepatic IRI in an immunocompromised mouse model of hepatic IRI.ConclusionsThis study provides insight into the mechanisms of ILC2-mediated liver protection that could serve as therapeutic targets to treat acute liver injury.Impact and implicationsWe report that type 2 innate lymphoid cells (ILC2s) are important regulators in a mouse model of liver ischaemia/reperfusion injury (IRI). Through manipulation of macrophage and eosinophil phenotypes, ILC2s mitigate liver inflammation and injury during liver IRI. We propose that ILC2s have the potential to serve as a therapeutic tool for protecting against acute liver injury and lay the foundation for translation of ILC2 therapy to human liver disease.

Dataset Information

Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion.

Aims

Methods and results

Conclusion

Publications

Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion.

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