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VITAMIN D3 IS AN EFFECTIVE COUNTERMEASURE AGAINST NITROGEN MUSTARD EXPOSURE

Au, Liemin
http://rave.ohiolink.edu/etdc/view?acc_num=case1396609569

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Chemical Engineering.
Exposure to mustard gas and mustard gas-related compounds has detrimental local and systemic effects1, 2. In recent history, these compounds have not only been used as chemical warfare agents3 but also medicinally as chemotherapeutic agents against blood cancers such as leukemia and lymphoma4. Exposure to these powerful alkylating agents suppresses the bone marrow from producing circulating cells vital for survival5. The cellular mechanisms responsible for nitrogen mustard (NM)-induced toxicity remain unknown; moreover, there are no countermeasures to mitigate the detrimental effects of NM exposure. Here we show a skin and bone marrow connection mediated by inflammatory macrophages that is critical for NM-induced marrow toxicity. Using a murine model of topical exposure to NM, we identify inducible nitric oxide synthase (iNOS)-expressing macrophages as critical mediators responsible for exacerbating local tissue damage. These cells of the innate immune system accumulate at the site of NM exposure then exit the injured skin and traffic to the bone marrow where they contribute to bone marrow suppression, peripheral blood pancytopenia, and mortality. Direct inhibition of iNOS with a specific pharmacological inhibitor or with 25-hydroxyvitamin D3 (25(OH)D), known to suppress macrophage inflammation6-9, protects mice from local and systemic effects of NM. Additionally, local depletion of skin recruited macrophages not only accelerates healing of wounds inflicted by NM but also rescues mice from bone marrow suppression and blood cytopenia. In this report, we present findings which suggest that 25(OH)D is an effective and practical countermeasure to prevent detrimental effects of NM exposure. Furthermore, once assumed to be solely mediated by the direct alkylating effects of NM, our observations establish a novel and critical role of the innate immune system in linking local tissue inflammation with systemic pathologies.
Kurt Lu (Advisor)
Thomas McCormick (Committee Member)
Harihara Baskaran (Committee Member)
Eric Pearlman (Committee Member)
Heidi Martin (Committee Member)
C.C Liu (Committee Member)
127 p.
Immunology; Toxicology
Vitamin D, Nitrogen mustard, Macrophages

Recommended Citations

Citations

  • Au, L. (2014). VITAMIN D3 IS AN EFFECTIVE COUNTERMEASURE AGAINST NITROGEN MUSTARD EXPOSURE [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1396609569

    APA Style (7th edition)

  • Au, Liemin. VITAMIN D3 IS AN EFFECTIVE COUNTERMEASURE AGAINST NITROGEN MUSTARD EXPOSURE. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1396609569.

    MLA Style (8th edition)

  • Au, Liemin. "VITAMIN D3 IS AN EFFECTIVE COUNTERMEASURE AGAINST NITROGEN MUSTARD EXPOSURE." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396609569

    Chicago Manual of Style (17th edition)

case1396609569
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© 2014, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.