TY - JOUR
T1 - Proangiogenic growth factors potentiate in situ angiogenesis and enhance antifungal drug activity in murine invasive aspergillosis
AU - Ben-Ami, Ronen
AU - Albert, Nathaniel D.
AU - Lewis, Russell E.
AU - Kontoyiannis, Dimitrios P.
N1 - Funding Information:
Financial support. This work was supported by the National Institutes of Health (NIH; grant R03 AI083733-01 to D. P. K.), an NIH Cancer Center Support Grant, and the Frances King Black endowed professorship (to D. P. K.).
Funding Information:
Potential conflicts of interest. R. B.-A. has received consulting fees and research support from Pfizer. R. E. L. has received research support from Merck. D. P. K. has received research grants from Merck, Pfizer, As-tellas, and Gilead and serves on the advisory board of Merck and on the speakers bureau of Gilead. All other authors report no potential conflicts.
PY - 2013/4/1
Y1 - 2013/4/1
N2 - In invasive pulmonary aspergillosis, direct invasion and occlusion of pulmonary vasculature by Aspergillus hyphae causes tissue hypoxia, which is enhanced by secreted fungal metabolites that downregulate compensatory angiogenic signaling pathways. We assessed the effects of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on survival rates, fungal burden, and in situ angiogenesis in a murine invasive pulmonary aspergillosis model. bFGF and VEGF monotherapy significantly increased survival rates and potentiated the activity of amphotericin B. bFGF-containing regimens were associated with reduced tissue fungal burdens. bFGF and VEGF reversed the antiangiogenic activity of Aspergillus fumigatus; however, VEGF induced the formation of immature neovessels, providing an explanation for its lesser efficacy. Treatment with bFGF plus amphotericin B was associated with neutrophil influx into Aspergillus-infected pulmonary tissue, suggesting that this combination limits fungal growth through neutrophil trafficking. Vasculogenic pathways are unexplored targets for the treatment of invasive pulmonary aspergillosis and may potentiate both innate immunity and antifungal drug activity against A. fumigatus.
AB - In invasive pulmonary aspergillosis, direct invasion and occlusion of pulmonary vasculature by Aspergillus hyphae causes tissue hypoxia, which is enhanced by secreted fungal metabolites that downregulate compensatory angiogenic signaling pathways. We assessed the effects of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on survival rates, fungal burden, and in situ angiogenesis in a murine invasive pulmonary aspergillosis model. bFGF and VEGF monotherapy significantly increased survival rates and potentiated the activity of amphotericin B. bFGF-containing regimens were associated with reduced tissue fungal burdens. bFGF and VEGF reversed the antiangiogenic activity of Aspergillus fumigatus; however, VEGF induced the formation of immature neovessels, providing an explanation for its lesser efficacy. Treatment with bFGF plus amphotericin B was associated with neutrophil influx into Aspergillus-infected pulmonary tissue, suggesting that this combination limits fungal growth through neutrophil trafficking. Vasculogenic pathways are unexplored targets for the treatment of invasive pulmonary aspergillosis and may potentiate both innate immunity and antifungal drug activity against A. fumigatus.
KW - angiogenesis inducing agents
KW - animal model
KW - fibroblast growth factor 2
KW - invasive pulmonary aspergillosis
KW - vascular endothelial growth factor A
UR - http://www.scopus.com/inward/record.url?scp=84874740459&partnerID=8YFLogxK
U2 - 10.1093/infdis/jis940
DO - 10.1093/infdis/jis940
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C2 - 23303813
AN - SCOPUS:84874740459
SN - 0022-1899
VL - 207
SP - 1066
EP - 1074
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 7
ER -