The protease/antiprotease balance determines influenza susceptibility and can be modified by oxidants and antioxidants Public Deposited

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  • March 19, 2019
Creator
  • Meyer, Megan
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The respiratory epithelium functions as a central orchestrator to initiate and organize responses to inhaled stimuli. Proteases and antiproteases are secreted from the respiratory epithelium and are involved in respiratory homeostasis. Modifications to the protease/antiprotease balance can lead to the development of lung diseases such as emphysema or chronic obstructive pulmonary disease. Furthermore, altered protease/antiprotease balance, in favor for increased protease activity, is associated with increased susceptibility to respiratory viral infections such as influenza virus. We demonstrated that inhaled oxidants, such as cigarette smoke, alters intracellular regulation and extracellular modifications of a key respiratory antiprotease, secretory leukocyte protease inhibitor (SLPI). Additionally, we established that SLPI is a novel anti-influenza biomarker that restricts influenza infection in vivo and in vitro. Furthermore, we investigated the effect of nutritional antioxidants, such as sulforaphane (SFN), on SLPI expression and found that SFN induced SLPI expression and secretion using in vivo and in vitro models. Finally, we detailed that smokers have increased secretions of an influenza-activating protease, transmembrane protease serine 2 (TMPRSS2) and that SFN supplementation reduced TMPRSS2 secretion, which protected against influenza infection in vitro. Taken together, these studies establish the integral role of the respiratory protease/antiprotease balance in the context of an influenza infection and after oxidant/antioxidant exposure. Further, these findings have broad implications for other inhaled oxidants, such as wood smoke and ozone, and offer the use of SFN as possible nutritional therapeutic to boost respiratory mucosal responses and/or protect against influenza infection.
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  • In Copyright
Advisor
  • Cotter, Peggy
  • Noah, Terry
  • Heise, Mark
  • Abel, Kristina
  • Jaspers, Ilona
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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