Bis(maltolato)oxovanadium(IV) Activation of STAT-1 Signaling in Fibroblasts as a Potential Therapy for Pulmonary Fibrosis.

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Title: Bis(maltolato)oxovanadium(IV) Activation of STAT-1 Signaling in Fibroblasts as a Potential Therapy for Pulmonary Fibrosis.
Author: Bost, Phillip Chapman
Advisors: James C. Bonner, Committee Chair
Philip L Sannes, Committee Member
Scott D. McCulloch, Committee Member
Abstract: The purpose of this research was to investigate the potential of a therapeutic vanadium compound in the modification and regulation of common repair mechanisms associated with pulmonary fibrosis. We hypothesized that bis(maltolato)oxovanadium(IV) (BMOV) has therapeutic potential for the treatment of pulmonary fibrosis. BMOV was formulated for the treatment of diabetes and has insulin mimetic properties, but whether it has crossover therapeutic value for the treatment of pulmonary fibrosis is currently unknown. Previous work with toxic forms of vanadium, demonstrated that despite their toxicity, these compounds exhibited interferon (IFN)-like properties which aids in regulating repair processes in fibrotic lung wounds. We sought to explore whether BMOV could represent a new and effective therapy for the treatment of pulmonary fibrosis. To test our hypothesis, we first demonstrated in chapter 1 that when used to treat pulmonary fibroblasts, BMOV behaves in a way similar to that of IFN-ï § by measuring subsequent phosphorylation of STAT-1 and upregulated expression of CXCL10. This ability to over-express CXCL10 was lost when BMOV was exposed to STAT-1-/- mice. These data indicate that BMOV initiates production of CXCL10 through a STAT-1-dependent mechanism and suggest that BMOV may have therapeutic effects when used to treat interstitial lung fibrosis. In chapter 2, we refined our in vitro model to better reflect the signaling events that take place in a lung undergoing fibrotic remodeling. To accomplish this we co-treated lung fibroblasts with both BMOV and interleukin-13 (IL-13) which is a ligand common to both asthmatic and fibrotic lungs. IL-13 acts through STAT-6 dependent signaling to mediate the production of growth factors that drive fibrosis. We found that this co-treatment significantly reduced the BMOV-induced phosphorylation of STAT-1 and subsequent production of CXCL10. Contrarily, BMOV co-treatment also reduced phosphorylation of IL-13-induced STAT-6 signaling compared to treatments of IL-13 alone. Using mouse lung fibroblasts, we attempted to determine if this co-regulation of STAT pathways occurred at or downstream of the respective phosphorylated STAT signals. To accomplish this line of inquiry we utilized fibroblasts cultured from wild type mice, STAT-1-/- mice, and STAT-6-/- mice. We found that in the absence of STAT-1, BMOV lost its ability to mitigate STAT-6 phosphorylation indicating that STAT-1 plays a fundamental role in that down-regulation. In addition, using STAT-6-/- fibroblasts we determined that IL-13 was not able to diminish STAT-1 phosphorylation or CXCL10 production. We conclude that the therapeutic potential of BMOV regarding treatment of fibrosis may be blunted if the disease has already taken root. Further studies used to investigate BMOV treatment of fibrosis should utilize whole mouse models, both knock-out and wild type. Understanding the cross talk between opposing STAT-signaling pathways will provide insight into the fibrotic process. BMOV has proven to be an invaluable tool due to its specificity and prolonged activation of STAT-1 phosphorylation.
Date: 2009-11-13
Degree: MS
Discipline: Toxicology
URI: http://www.lib.ncsu.edu/resolver/1840.16/851


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