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Involvement of Adenosine A2a Receptor in the Lung Fibrosis Caused by Silica Particles in Mice
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A5762 - Involvement of Adenosine A2a Receptor in the Lung Fibrosis Caused by Silica Particles in Mice
Author Block: Y. Sá1, L. B. Savio2, R. Coutinho-Silva2, V. Carregaro3, J. Alves-Filho3, C. M. Hogaboam4, M. A. Martins5, P. M. Silva5; 1Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, 2Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 3Medical Faculty of Ribeirão Preto / USP, São Paulo, Brazil, 4Dept. of Medicine Research Scientist IV, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 5Oswaldo Cruz Foundation, Rio De Janeiro, Brazil.
Introduction: Adenosine is a nucleoside that has been reported to be implicated in fibrosis, being considered as a potential therapeutic target for fibrotic diseases. In this study, we investigated the involvement of adenosine in pulmonary fibrosis in silicotic mice. Lung fibroblast reactivity was also evaluated in vitro. Methods: Mice were instilled with silica and the analyzes performed 7 and 28 days later. The parameters included lung function (resistance and elastance) and tissue morphology/morphometry. Lung fibroblast reactivity (proliferation and MCP-1) was evaluated in vitro. Results: Expression of CD39 and CD73 enzymes, responsible for adenosine generation, was increased in the lungs at 7 days of silicosis. Adenosine receptor expression was altered in the lung of the silicotic animals, reflecting increase of A1 and A2B receptors, reduction of A2A receptor and no alteration of A3. Lung fibroblasts stimulated with IL-13 and adenosine, alone or in combination, led to an increase in proliferation and MCP-1 production, phenomena sensitive to A2A receptor antagonists ZM 241385 and SCH-58261 Fibroblasts from A2A receptor knockout mice were less responsive to IL-13 and adenosine stimuli. CD39 and CD73 inhibitors also suppressed IL-13 stimulated fibroblast proliferation. Receptor A2A silicotic knockout mice showed reduction of lung function decrease and fibrotic granulomatous responses. Conclusion: Our results show that adenosine seems to be implicated in the fibrotic response associated with silicosis in mice, by a mechanism, at least partially dependent on its ability to synergize with IL-13 and its action on A2A receptor.
Author Block: Y. Sá1, L. B. Savio2, R. Coutinho-Silva2, V. Carregaro3, J. Alves-Filho3, C. M. Hogaboam4, M. A. Martins5, P. M. Silva5; 1Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, 2Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 3Medical Faculty of Ribeirão Preto / USP, São Paulo, Brazil, 4Dept. of Medicine Research Scientist IV, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 5Oswaldo Cruz Foundation, Rio De Janeiro, Brazil.
Introduction: Adenosine is a nucleoside that has been reported to be implicated in fibrosis, being considered as a potential therapeutic target for fibrotic diseases. In this study, we investigated the involvement of adenosine in pulmonary fibrosis in silicotic mice. Lung fibroblast reactivity was also evaluated in vitro. Methods: Mice were instilled with silica and the analyzes performed 7 and 28 days later. The parameters included lung function (resistance and elastance) and tissue morphology/morphometry. Lung fibroblast reactivity (proliferation and MCP-1) was evaluated in vitro. Results: Expression of CD39 and CD73 enzymes, responsible for adenosine generation, was increased in the lungs at 7 days of silicosis. Adenosine receptor expression was altered in the lung of the silicotic animals, reflecting increase of A1 and A2B receptors, reduction of A2A receptor and no alteration of A3. Lung fibroblasts stimulated with IL-13 and adenosine, alone or in combination, led to an increase in proliferation and MCP-1 production, phenomena sensitive to A2A receptor antagonists ZM 241385 and SCH-58261 Fibroblasts from A2A receptor knockout mice were less responsive to IL-13 and adenosine stimuli. CD39 and CD73 inhibitors also suppressed IL-13 stimulated fibroblast proliferation. Receptor A2A silicotic knockout mice showed reduction of lung function decrease and fibrotic granulomatous responses. Conclusion: Our results show that adenosine seems to be implicated in the fibrotic response associated with silicosis in mice, by a mechanism, at least partially dependent on its ability to synergize with IL-13 and its action on A2A receptor.
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