2018 Fiscal Year Annual Research Report
Exploration of mechanisms underlying organ protective role of blockade of protease activated receptor 2 in sepsis through the modulation of VEGF angiogenic system and associated microcirculation
| Project/Area Number |
16K11394
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | Sepsis / MODS / PAR2 blockade / VEGF / mechanism |
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| Outline of Annual Research Achievements |
We completed three years of this project. We could complete all planned experiments withour PAR2 knockout mice study because of the technical problem of mouse breeding. We conducted experiment both generating acute and chronic model of sepsis by LPS (Escherichia coli serotype 0111:B4) in rats. We also conducted time course study of acute model of sepsis upto 72 hours duration in rat. In our experiment, it seems that only three hours treatment of PAR2 blockade is effective in acute sepsis for the improvment and arrest of multiple organ dysfunction syndrome (MODS) in sepsis through modulation of VEGF system. Indeed, in our research over last decade we found that PAR2 is a critical player and trigger for MODS in sepsis, in some cases equally important as of TNF-alpha. This PAR2 is closely associated with angiogenic system (VEGF), endothelin (ET) and inflammayory (TNF) cascade from the early hours of sepsis in connection to MODS development and progression. From in vitro studies, using cardiomyocytes and lung macrophages, we also confirmed the relation between VEGF and PAR2 in LPS administered cells using PAR2 blocker and also using VEGF antagonist. From our series of experiments, now we can conclude that PAR2 inhibition from early hours of sepsis might be effective in the treatment and prevention of lung injusry and myocardial dysfunction through amelioration of VEGF signaling.
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