Lactic acidosis, which is caused by an increase in blood lactic acid level due to severe shock conditions such as heart failure and sepsis, and the blood becomes extremely acidic, has a high case fatality rate of about 2%, and immediate measures are required. ..This time, the group of Yoji Minamishima, a specially appointed lecturer at Keio University School of Medicine, Tomohiro Suhara (a doctoral course at the Graduate School of Medicine, the same university), Takako Hishiki, a full-time lecturer, and Masataka Kasahara, a professor at Tokyo Dental College, will join Prolin Mizu. We discovered the mechanism by which the blood lactic acid level decreases due to the inactivation of the oxidase PHDXNUMX.The research is expected to lead to the development of new treatments for lactic acidosis.
PHD2 functions as an "intracellular oxygen concentration sensor" that switches the hypoxic response (cell response response when there is little oxygen available) on and off, and when PHD2 is inactivated, the hypoxic response occurs.Traditionally, it has been said that cells release lactic acid into the blood when the hypoxic response is activated.However, this study proves a new fact that overturns the previous perception that the hypoxic response in hepatocytes activates lactate uptake rather than enhancing lactate release.The study found that mice with disrupted PHD2 gene in the liver had lower blood lactate levels, dramatically improved survival when lactate was intraperitoneally administered, and PHD2 in septic mice. It was confirmed that oral administration of the inhibitor increases the survival rate.
The results of this research are expected to lead to the development of a completely new treatment for lactic acidosis that targets the PHD2-mediated hypoxic response in the liver, and thus to the improvement of treatment results for serious infectious diseases such as sepsis.
The research was conducted in collaboration with Keio University School of Medicine, Howard Hughes Medical Institute in the United States, and Harvard University School of Medicine Dana-Farber Cancer Research Institute as part of the JST Strategic Creative Research Promotion Project.The results of this research were published in the online bulletin version of the American scientific journal "Proceedings of the National Academy of Sciences (PNAS)" on August 2015, 8 (Eastern Time).
