title: Time-dependent alterations of VEGF and its signaling molecules in acute lung injury in a rat model of sepsis.
abstract: Molecular mechanisms of sepsis-associated acute lung injury (ALI) are poorly defined. Since vascular endothelial growth factor (VEGF) is a potent vascular permeability and mitogenic factor, it might contribute to the development of ALI in sepsis. Thus, using lipopolysaccharide (LPS)-induced (15 mg/kg, intraperitoneal) endotoxemic rat model, we studied the timeline (1, 3, 6, and 10 h) of pulmonary VEGF expression and its signaling machinery. Levels of pulmonary VEGF and its angiogenic-mediating receptor, Flk-1, were downregulated by LPS in a time-dependent manner; levels of plasma VEGF and its permeability-mediating receptor, Flt-1, in contrast, was upregulated with time. In addition, blockade of Flt-1 could improve the downregulated pulmonary VEGF level and attenuate the elevated plasma and pulmonary levels of TNF-α, followed by improvement of arterial oxygenation and wet-to-dry weight ratio of the lung. Expression of signaling, pro- and or apoptotic factors after LPS administration were as follows: phosphorylated Akt, a downstream molecule was downregulated time dependently; endothelial nitric oxide synthase levels were significantly reduced; pro-apoptotic markers caspase 3 and Bax were upregulated whereas levels of Bcl-2 were downregulated. The present findings show that VEGF may play a role through the expression of Flt-1 in LPS-induced ALI. Moreover, downregulation of VEGF signaling cascade may account for LPS-induced apoptosis and impaired physiological angiogenesis in lung tissues, which in turn may contribute to the development of ALI induced by LPS.
authors.affiliation: Division of Gene Therapeutics, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.forename: Sohel
authors.initials: S
authors.lastname: Zaedi
authors.forename: A M Shahidul
authors.initials: AM
authors.lastname: Islam
authors.forename: S Nusrat
authors.initials: SN
authors.lastname: Sultana
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Iwashima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wada
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Gando
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D053148:Caspase 3 / Q000096:biosynthesis; D015536:Down-Regulation; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D018919:Neovascularization, Physiologic; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000097:blood; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; C467498:vascular endothelial growth factor A, rat; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3