Nitric oxide mediates bleomycin-induced angiogenesis and pulmonary fibrosis via regulation of VEGF.
Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogenic mediator VEGF using anti-VEGF antibody CBO-P11 significantly attenuates bleomycin-induced pulmonary fibrosis in vivo. Bleomycin-induced nitric oxide (NO) was observed to be the key upstream regulator of VEGF via the PI3k/Akt pathway. VEGF regulated other important angiogenic proteins including PAI-1 and IL-8 in response to bleomycin exposure. Inhibition of NO and VEGF activity significantly mitigated bleomycin-induced angiogenic and fibrogenic responses. NO and VEGF are key mediators of bleomycin-induced pulmonary fibrosis, and could serve as important targets against this debilitating disease. Overall, our data suggests an important role for angiogenic mediators in the pathogenesis of bleomycin-induced pulmonary fibrosis.
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia.
Anand Krishnan V
AK
Iyer
Department of Obstetrics and Gynecology, The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia.
Vani
V
Ramesh
Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
Carlos A
CA
Castro
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia.
Vivek
V
Kaushik
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia.
Yogesh M
YM
Kulkarni
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia.
Clayton A
CA
Wright
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia.
Rajkumar
R
Venkatadri
Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia.
Yon
Y
Rojanasakul
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia.
Neelam
N
Azad
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000008:administration & dosage* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D016228:Endothelial Growth Factors; D010456:Peptides, Cyclic; D042461:Vascular Endothelial Growth Factor A; C478485:cyclo-VEGI; D001761:Bleomycin; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases
ANGIOGENESIS; BLEOMYCIN; NITRIC OXIDE; PULMONARY FIBROSIS; VEGF