2009 Fiscal Year Final Research Report
Time-dependent alterations of VEGF and its signaling molecules in acute lung injury in a rat model of sepsis
| Project/Area Number |
20790296
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Experimental pathology
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| Research Institution | Hokkaido University (2009)
Research Institute, International Medical Center of Japan (2008) |
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Principal Investigator |
SUBRINA Jesmin Hokkaido University, 研究所 遺伝子診断治療研究, 室長 (60374261)
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| Project Period (FY) |
2008 – 2009
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| Keywords | Acute lung injury (ALI) / Apoptosis / endothelial nitric oxide synthase (eNOS) / Lipopolysaccharide / Vascular endothelial growth factor (VEGF) |
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| Research Abstract |
Sepsis, one of the leading causes of morbidity and mortality, is associated with the development of acute lung injury (ALI). However, molecular mechanisms of 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 (15mg/kg, I.P) endotoxemic rat model, we studied the time-line (1, 3, 6 and 10h) of pulmonary VEGF expression and its signaling machinery. Levels of pulmonary VEGF and its angiogenic-mediating receptor, Flk-1, were down regulated by LPS in a time-dependent manner ; vascular permeability-mediating receptor of VEGF, Flt-1, in contrast, was up regulated with time. Expression of signaling, pro- and or apoptotic factors after LPS administration were as follow : phosphorylated Akt, a down stream molecule was down regulated time-dependently ; endothelial nitric oxide synthase (eNOS) levels were significantly reduced ; pro-apoptotic markers Caspase-3 and Bax were up regulated, whereas, levels of Bcl-2 were down regulated. The present findings show that VEGF may not play a role in increased pulmonary vascular leakage in LPS-induced ALI. Moreover, down regulation 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. In addition, blockade of Flt-1 could improve the downregulated pulmonary VEGF level and attenuate the elevated plasma and pulmonary levels of TNF-alpha.
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