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Thesis FAeffner 11-14-2013B.pdf (4.55 MB)

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Pathophysiologic Effects of Influenza Infection on the Murine Lung and Evaluation of Novel Therapeutic Targets

Aeffner, Famke
http://rave.ohiolink.edu/etdc/view?acc_num=osu1384440085

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Influenza viruses are a major public health concern. Seasonal influenza causes a significant number of deaths worldwide each year and sporadic pandemics have resulted in the loss of up to 3% of the human population (e.g., 1918 “Spanish flu”). Vaccination can prevent influenza infection, but slow vaccine production and low rates of compliance by the general public are problematic. Although antiviral drugs are available to treat influenza virus pneumonia, many viral strains are drug-resistant. Additionally, antiviral therapeutics are ineffective if administered late in the disease progression. Thus, novel therapies are urgently needed to prevent late-stage respiratory failure in patients with influenza. Since severe influenza infection in humans oftentimes leads to acute respiratory distress syndrome (ARDS), here we re-define the existing animal model of ARDS by adapting several functional readouts that are commonly employed in human patients for use in a mouse model of ARDS induced by H1N1 influenza infection. This includes the incorporation of variety of disciplines, including viral pathogenesis, innate immunity, cell biology, lung physiology, airway mechanics, and pulmonary critical care medicine and presents a more functionally based and meaningful assessment of potential drugs. After establishing this re-defined mouse model of ARDS, it was put to use to evaluate the treatment effects of the de novo pyrimidine synthesis inhibitor A77-1726 on H1N1 infected mice. We have previously shown that nucleotide signaling is important to development of lung dysfunction in influenza-infected mice. Nucleotide signaling can be prevented by the drug A77-1726, which blocks nucleotide synthesis. A77-1726 is an attractive therapeutic candidate because it is stable, inexpensive and suitable for administration via nebulization. We found that a single treatment with aerosolized A77-1726 significantly improved pulmonary function for at least 5 days after influenza virus infection and thereby prevented respiratory failure and providing prolonged survival. Perhaps the most promising finding was that treatment late in infection, after the onset of lung disease, significantly reduced the severity of ongoing respiratory failure. Hence, we have identified a novel and inexpensive therapeutic strategy that prevents respiratory failure and improves survival after influenza virus infection. The same work that pointed in the direction of investigating nucleotide signaling had also highlighted a potential role of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator anion channel) in the development of pulmonary failure after H1N1 influenza infection. This work demonstrated that heterozygosity for this mutation reduces severity of influenza-induced lung dysfunction and significantly alters the innate immune response to infection. These findings suggest that CFTR is a potential therapeutic target in non-cystic fibrosis patients with influenza. Specifically the role of adenosine and its signaling through the A1-adenosine receptor in the development of pulmonary pathology was investigated by utilizing previously developed techniques in the A1-adenosine receptor knockout mouse. We have been able to show that these mice display better disease outcomes and less pulmonary injury, mainly by preventing neutrophil influx and tissue destruction. Similar outcomes were seen when wild-type mice were treated with the A1-adenosine receptor antagonist DPCPX.
Ian Davis, Dr. (Advisor)
Judy Hickman-Davis, Dr. (Committee Member)
Krista La Perle, Dr. (Committee Member)
Stefan Niewiesk, Dr. (Committee Member)
Karen Wood, Dr. (Committee Member)
255 p.
Biomedical Research; Veterinary Services; Virology
Murine, mouse, lung, influenza, ARDS

Recommended Citations

Citations

  • Aeffner, F. (2013). Pathophysiologic Effects of Influenza Infection on the Murine Lung and Evaluation of Novel Therapeutic Targets [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1384440085

    APA Style (7th edition)

  • Aeffner, Famke. Pathophysiologic Effects of Influenza Infection on the Murine Lung and Evaluation of Novel Therapeutic Targets. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1384440085.

    MLA Style (8th edition)

  • Aeffner, Famke. "Pathophysiologic Effects of Influenza Infection on the Murine Lung and Evaluation of Novel Therapeutic Targets." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1384440085

    Chicago Manual of Style (17th edition)

osu1384440085
185
© 2013, some rights reserved.Creative Commons License Pathophysiologic Effects of Influenza Infection on the Murine Lung and Evaluation of Novel Therapeutic Targets by Famke Aeffner is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.