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Anti-inflammatory effects of inosine in allergic lung inflammation in mice: evidence for the participation of adenosine A2A and A3 receptors

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Abstract

Inosine, a naturally occurring purine formed from the breakdown of adenosine, is associated with immunoregulatory effects. Evidence shows that inosine modulates lung inflammation and regulates cytokine generation. However, its role in controlling allergen-induced lung inflammation has yet to be identified. In this study, we aimed to investigate the role of inosine and adenosine receptors in a murine model of lung allergy induced by ovalbumin (OVA). Intraperitoneal administration of inosine (0.001–10 mg/kg, 30 min before OVA challenge) significantly reduced the number of leukocytes, macrophages, lymphocytes and eosinophils recovered in the bronchoalveolar lavage fluid of sensitized mice compared with controls. Interestingly, our results showed that pre-treatment with the selective A2A receptor antagonist (ZM241385), but not with the selective A2B receptor antagonist (alloxazine), reduced the inhibitory effects of inosine against macrophage count, suggesting that A2A receptors mediate monocyte recruitment into the lungs. In addition, the pre-treatment of mice with selective A3 antagonist (MRS3777) also prevented inosine effects against macrophages, lymphocytes and eosinophils. Histological analysis confirmed the effects of inosine and A2A adenosine receptors on cell recruitment and demonstrated that the treatment with ZM241385 and alloxazine reverted inosine effects against mast cell migration into the lungs. Accordingly, the treatment with inosine reduced lung elastance, an effect related to A2 receptors. Moreover, inosine reduced the levels of Th2-cytokines, interleukin-4 and interleukin-5, an effect that was not reversed by A2A or A2B selective antagonists. Our data show that inosine acting on A2A or A3 adenosine receptors can regulate OVA-induced allergic lung inflammation and also implicate inosine as an endogenous modulator of inflammatory processes observed in the lungs of asthmatic patients.

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Acknowledgments

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), Programa de Reestruturação e Expansão das Universidades Federais (REUNI); Programa Nacional de Cooperação Acadêmica (PROCAD) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).

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Authors and Affiliations

  1. Department of Pharmacology, Center of Biological Sciences, Federal University of Paraná, Curitiba, 88015-420, Paraná, Brazil

    Fernanda da Rocha Lapa & Daniela de Almeida Cabrini

  2. Department of Health Sciences, Universidade Nove de Julho, São Paulo, São Paulo, 04752-005, Brazil

    Ana Paula Ligeiro de Oliveira

  3. Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, São Paulo, São Paulo, 05508-900, Brazil

    Beatriz Golega Accetturi, Isabelli de Oliveira Martins, Helory Vanni Domingos & Wothan Tavares de Lima

  4. Department of Physiological Sciences, Federal University of Santa Catarina, Trindade, 88040-900, Florianópolis, Santa Catarina, Brazil

    Adair Roberto Soares Santos

  5. Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, 88040-900, Santa Catarina, Brazil

    Fernanda da Rocha Lapa

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  1. Fernanda da Rocha Lapa
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Correspondence to Adair Roberto Soares Santos.

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da Rocha Lapa, F., de Oliveira, A.P.L., Accetturi, B.G. et al. Anti-inflammatory effects of inosine in allergic lung inflammation in mice: evidence for the participation of adenosine A2A and A3 receptors. Purinergic Signalling 9, 325–336 (2013). https://doi.org/10.1007/s11302-013-9351-x

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  • DOI: https://doi.org/10.1007/s11302-013-9351-x

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