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Am J Resp Cell Mol Biol. Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice
[Source: American Journal of Respiratory Cell and Molecular Biology, full page: (LINK). Abstract, edited.]
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Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice
Famke Aeffner<SUP>1</SUP>, Anna Bratasz<SUP>2</SUP>, Emilio Fla?o<SUP>3</SUP>, Kimerly A. Powell<SUP>2</SUP> and Ian C. Davis<SUP>1</SUP>
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Author Affiliations: <SUP>1</SUP>Department of Veterinary Biosciences, and <SUP>2</SUP>Department of Biomedical Informatics, Ohio State University, Columbus, Ohio; and <SUP>3</SUP>Research Institute, Nationwide Children?s Hospital, Columbus, Ohio
Correspondence and requests for reprints should be addressed to Ian C. Davis, D.V.M., Ph.D., Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210. E-mail: Ian.Davis@cvm.osu.edu
Abstract
Acute respiratory disease is associated with significant morbidity and mortality in influenza. Because antiviral drugs are only effective early in infection, new agents are needed to treat nonvaccinated patients presenting with late-stage disease, particularly those who develop acute respiratory distress syndrome. We found previously that the de novo pyrimidine synthesis inhibitor A77-1726 reversed the influenza-induced impairment of alveolar fluid clearance. Patients with acute respiratory distress syndrome and intact alveolar fluid clearance demonstrate lower mortality than those with compromised fluid clearance. We therefore investigated the effects of treatment with nebulized A77-1726 (67.5 mg/kg) on indices of cardiopulmonary function relevant to the diagnosis of acute respiratory distress syndrome. BALB/cAnNCr mice (8?12 wk old) were inoculated intranasally with 10,000 plaque-forming units/mouse influenza A/WSN/33 (H1N1). Pulse oximetry was performed daily. Alveolar fluid clearance, lung water, and lung mechanics were measured at 2 and 6 days after inoculation in live, ventilated mice by BSA instillation, magnetic resonance imaging, and forced-oscillation techniques, respectively. A77-1726 treatment at 1 day after inoculation delayed mortality. Treatment on Days 1 or 5 reduced viral replication on Day 6, and improved alveolar fluid clearance, peripheral oxygenation, and cardiac function. Nebulized A77-1726 also reversed influenza-induced increases in lung water content and volume, improved pulmonary mechanics, reduced bronchoalveolar lavage fluid ATP and neutrophil content, and increased IL-6 concentrations. The ability of A77-1726 to improve cardiopulmonary function in influenza-infected mice and to reduce the severity of ongoing acute respiratory distress syndrome late in infection suggests that pyrimidine synthesis inhibitors are promising therapeutic candidates for the management of severe influenza.
Keywords
Footnotes
This work was sponsored by the National Institutes of Health/National Institute of Allergy and Infectious Diseases Regional Center of Excellence for Bio-Defense and Emerging Infectious Diseases Research Program. The authors acknowledge their membership within and support from the Region V ?Great Lakes? Regional Center of Excellence (National Institutes of Health grant 2-U54-AI-057153). Additional support to I.C.D. was provided by the Ohio State University Public Health Preparedness in Infectious Diseases Program.
F.A. was supported by a nonconditional fellowship from the Eli Lilly and Co. Foundation.
This article has an online supplement, which is accessible from this issue?s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1165/rcmb.2012-0112OC on June 7, 2012
Author disclosures are available with the text of this article at www.atsjournals.org.
Received March 21, 2012. / Accepted May 28, 2012.
Copyright ? 2012 by the American Thoracic Society
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Author Affiliations: <SUP>1</SUP>Department of Veterinary Biosciences, and <SUP>2</SUP>Department of Biomedical Informatics, Ohio State University, Columbus, Ohio; and <SUP>3</SUP>Research Institute, Nationwide Children?s Hospital, Columbus, Ohio
Correspondence and requests for reprints should be addressed to Ian C. Davis, D.V.M., Ph.D., Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210. E-mail: Ian.Davis@cvm.osu.edu
Abstract
Acute respiratory disease is associated with significant morbidity and mortality in influenza. Because antiviral drugs are only effective early in infection, new agents are needed to treat nonvaccinated patients presenting with late-stage disease, particularly those who develop acute respiratory distress syndrome. We found previously that the de novo pyrimidine synthesis inhibitor A77-1726 reversed the influenza-induced impairment of alveolar fluid clearance. Patients with acute respiratory distress syndrome and intact alveolar fluid clearance demonstrate lower mortality than those with compromised fluid clearance. We therefore investigated the effects of treatment with nebulized A77-1726 (67.5 mg/kg) on indices of cardiopulmonary function relevant to the diagnosis of acute respiratory distress syndrome. BALB/cAnNCr mice (8?12 wk old) were inoculated intranasally with 10,000 plaque-forming units/mouse influenza A/WSN/33 (H1N1). Pulse oximetry was performed daily. Alveolar fluid clearance, lung water, and lung mechanics were measured at 2 and 6 days after inoculation in live, ventilated mice by BSA instillation, magnetic resonance imaging, and forced-oscillation techniques, respectively. A77-1726 treatment at 1 day after inoculation delayed mortality. Treatment on Days 1 or 5 reduced viral replication on Day 6, and improved alveolar fluid clearance, peripheral oxygenation, and cardiac function. Nebulized A77-1726 also reversed influenza-induced increases in lung water content and volume, improved pulmonary mechanics, reduced bronchoalveolar lavage fluid ATP and neutrophil content, and increased IL-6 concentrations. The ability of A77-1726 to improve cardiopulmonary function in influenza-infected mice and to reduce the severity of ongoing acute respiratory distress syndrome late in infection suggests that pyrimidine synthesis inhibitors are promising therapeutic candidates for the management of severe influenza.
Keywords
- alveolar fluid clearance
- pulmonary edema
- antiviral agents
- lung function
- ARDS
Footnotes
This work was sponsored by the National Institutes of Health/National Institute of Allergy and Infectious Diseases Regional Center of Excellence for Bio-Defense and Emerging Infectious Diseases Research Program. The authors acknowledge their membership within and support from the Region V ?Great Lakes? Regional Center of Excellence (National Institutes of Health grant 2-U54-AI-057153). Additional support to I.C.D. was provided by the Ohio State University Public Health Preparedness in Infectious Diseases Program.
F.A. was supported by a nonconditional fellowship from the Eli Lilly and Co. Foundation.
This article has an online supplement, which is accessible from this issue?s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1165/rcmb.2012-0112OC on June 7, 2012
Author disclosures are available with the text of this article at www.atsjournals.org.
Received March 21, 2012. / Accepted May 28, 2012.
Copyright ? 2012 by the American Thoracic Society
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