title: Proangiogenic growth factors potentiate in situ angiogenesis and enhance antifungal drug activity in murine invasive aspergillosis.
abstract: 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.
authors.affiliation: Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Israel. ronenba@tasmc.health.gov.il
authors.forename: Ronen
authors.initials: R
authors.lastname: Ben-Ami
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Albert
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use; D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000472:pathogenicity*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use*
chemical_list: D043925:Angiogenesis Inducing Agents; D000935:Antifungal Agents; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000666:Amphotericin B