Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury

Lucas Liaudet, Jon G. Mabley, Pál Pacher, László Virág, Francisco G. Soriano, Anita Marton, György Haskó, Edwin A. Deitch, Csaba Szabo

Research output: Contribution to journalArticle

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Abstract

Objective: To investigate the effects of inosine on the acute lung inflammation induced by lipopolysaccharide (LPS) in vivo and on the activation and cytotoxicity elicited by proinflammatory cytokines on human lung epithelial (A549) cells in vitro. Summary Background Data: Inosine is an endogenous purine recently shown to exert immunomodulatory and antiinflammatory effects. Methods: Mice challenged with intratracheal LPS (50 μg) were treated after 1, 6, and 12 hours with inosine (200 mg/kg intraperitoneal) or vehicle. After 24 hours, bronchoalveolar lavage fluid was obtained to measure proinflammatory (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, IL-6), and antiinflammatory (IL-10, IL-4) cytokines, chemokines (MIP-1 α and MIP-2), myeloperoxidase activity and total cell counts, nitric oxide production, and proteins. Lung histology and immunohistochemical detection of 3-nitrotyrosine, a marker of nitrosative stress, were performed in inflated-fixed lungs. In vitro, cell viability and production of the chemokine IL-8 were evaluated in A549 cells stimulated with a mixture of cytokines in the presence or absence of inosine. Results: Inosine downregulated the LPS-induced expression of TNF-α, IL-1β, IL-6 and MIP-2 and tended to reduce MIP-1α, whereas it enhanced the production of IL-4. Total leukocyte counts, myeloperoxidase, nitric oxide production, and proteins were all significantly decreased by inosine. The purine also improved lung morphology and suppressed 3-nitrotyrosine staining in the lungs after LPS. Inosine attenuated the cytotoxicity and the expression of IL-8 induced by proinflammatory cytokines in A549 cells. Conclusions: Inosine largely suppressed LPS-induced lung inflammation in vivo and reduced the toxicity of cytokines in lung cells in vitro. These data support the proposal that inosine might represent a useful adjunct in the therapy of acute respiratory distress syndrome.

Original languageEnglish (US)
Pages (from-to)568-578
Number of pages11
JournalAnnals of Surgery
Volume235
Issue number4
DOIs
StatePublished - 2002
Externally publishedYes

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Inosine
Acute Lung Injury
Anti-Inflammatory Agents
Lipopolysaccharides
Lung
Cytokines
Interleukin-8
Interleukin-1
Chemokines
Interleukin-4
Peroxidase
Interleukin-6
Pneumonia
Nitric Oxide
Tumor Necrosis Factor-alpha
Adult Respiratory Distress Syndrome
Bronchoalveolar Lavage Fluid
Leukocyte Count
Interleukin-10
Cell Survival

ASJC Scopus subject areas

  • Surgery

Cite this

Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury. / Liaudet, Lucas; Mabley, Jon G.; Pacher, Pál; Virág, László; Soriano, Francisco G.; Marton, Anita; Haskó, György; Deitch, Edwin A.; Szabo, Csaba.

In: Annals of Surgery, Vol. 235, No. 4, 2002, p. 568-578.

Research output: Contribution to journalArticle

Liaudet, L, Mabley, JG, Pacher, P, Virág, L, Soriano, FG, Marton, A, Haskó, G, Deitch, EA & Szabo, C 2002, 'Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury', Annals of Surgery, vol. 235, no. 4, pp. 568-578. https://doi.org/10.1097/00000658-200204000-00016
Liaudet, Lucas ; Mabley, Jon G. ; Pacher, Pál ; Virág, László ; Soriano, Francisco G. ; Marton, Anita ; Haskó, György ; Deitch, Edwin A. ; Szabo, Csaba. / Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury. In: Annals of Surgery. 2002 ; Vol. 235, No. 4. pp. 568-578.
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T1 - Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury

AU - Liaudet, Lucas

AU - Mabley, Jon G.

AU - Pacher, Pál

AU - Virág, László

AU - Soriano, Francisco G.

AU - Marton, Anita

AU - Haskó, György

AU - Deitch, Edwin A.

AU - Szabo, Csaba

PY - 2002

Y1 - 2002

N2 - Objective: To investigate the effects of inosine on the acute lung inflammation induced by lipopolysaccharide (LPS) in vivo and on the activation and cytotoxicity elicited by proinflammatory cytokines on human lung epithelial (A549) cells in vitro. Summary Background Data: Inosine is an endogenous purine recently shown to exert immunomodulatory and antiinflammatory effects. Methods: Mice challenged with intratracheal LPS (50 μg) were treated after 1, 6, and 12 hours with inosine (200 mg/kg intraperitoneal) or vehicle. After 24 hours, bronchoalveolar lavage fluid was obtained to measure proinflammatory (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, IL-6), and antiinflammatory (IL-10, IL-4) cytokines, chemokines (MIP-1 α and MIP-2), myeloperoxidase activity and total cell counts, nitric oxide production, and proteins. Lung histology and immunohistochemical detection of 3-nitrotyrosine, a marker of nitrosative stress, were performed in inflated-fixed lungs. In vitro, cell viability and production of the chemokine IL-8 were evaluated in A549 cells stimulated with a mixture of cytokines in the presence or absence of inosine. Results: Inosine downregulated the LPS-induced expression of TNF-α, IL-1β, IL-6 and MIP-2 and tended to reduce MIP-1α, whereas it enhanced the production of IL-4. Total leukocyte counts, myeloperoxidase, nitric oxide production, and proteins were all significantly decreased by inosine. The purine also improved lung morphology and suppressed 3-nitrotyrosine staining in the lungs after LPS. Inosine attenuated the cytotoxicity and the expression of IL-8 induced by proinflammatory cytokines in A549 cells. Conclusions: Inosine largely suppressed LPS-induced lung inflammation in vivo and reduced the toxicity of cytokines in lung cells in vitro. These data support the proposal that inosine might represent a useful adjunct in the therapy of acute respiratory distress syndrome.

AB - Objective: To investigate the effects of inosine on the acute lung inflammation induced by lipopolysaccharide (LPS) in vivo and on the activation and cytotoxicity elicited by proinflammatory cytokines on human lung epithelial (A549) cells in vitro. Summary Background Data: Inosine is an endogenous purine recently shown to exert immunomodulatory and antiinflammatory effects. Methods: Mice challenged with intratracheal LPS (50 μg) were treated after 1, 6, and 12 hours with inosine (200 mg/kg intraperitoneal) or vehicle. After 24 hours, bronchoalveolar lavage fluid was obtained to measure proinflammatory (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, IL-6), and antiinflammatory (IL-10, IL-4) cytokines, chemokines (MIP-1 α and MIP-2), myeloperoxidase activity and total cell counts, nitric oxide production, and proteins. Lung histology and immunohistochemical detection of 3-nitrotyrosine, a marker of nitrosative stress, were performed in inflated-fixed lungs. In vitro, cell viability and production of the chemokine IL-8 were evaluated in A549 cells stimulated with a mixture of cytokines in the presence or absence of inosine. Results: Inosine downregulated the LPS-induced expression of TNF-α, IL-1β, IL-6 and MIP-2 and tended to reduce MIP-1α, whereas it enhanced the production of IL-4. Total leukocyte counts, myeloperoxidase, nitric oxide production, and proteins were all significantly decreased by inosine. The purine also improved lung morphology and suppressed 3-nitrotyrosine staining in the lungs after LPS. Inosine attenuated the cytotoxicity and the expression of IL-8 induced by proinflammatory cytokines in A549 cells. Conclusions: Inosine largely suppressed LPS-induced lung inflammation in vivo and reduced the toxicity of cytokines in lung cells in vitro. These data support the proposal that inosine might represent a useful adjunct in the therapy of acute respiratory distress syndrome.

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