Myeloid Knockout GGPPS1 Ease Acute Lung Injury Induced By Endotoxin Complications

Acute lung injury (ALI) is a non-cardiogenic and extra pulmonary disease causing acute progressive hypoxic respiratory failure, further development of the disease will become acute respiratory distress syndrome (ARDS), eventually lead to multiple organ dysfunction, which is a very common clinical phenomenon.Due to insufficient understanding of the development of the disease, currently the clinical measures for improving ARDS patients’severe refractory hypoxemia is very limited, there is no ideal treatment, ARDS mortality remains high. So study of the pathogenesis of the disease is particularly important to improve the prognosis in the treatment of ALI/ARDS.ARDS pathogenesis is complicated, research shows that the mechanism of ARDS may be related to the excessive expression of the inflammatory response in the human. A variety of inflammatory cells and inflammatory mediators participate in this excessive inflammation. When inflammatory cells exposed to all kinds of exogenous and endogenous stimulation, this can cause their own activation, and release more inflammatory factors causing more cells activated, so this process is closely associated with the activation of membrane proteins. An important way of membrane proteins is activating the isoprene modification. Common way of isoprene modification in eukaryotic cells is mainly GGPP modification and FPP modification two ways,GGPP and FPP derived from the mevalonate pathway. Found in previous study using statins (HMG CoA reductase inhibitor) has the effect that releases inflammation, but the specific mechanism remains unclear, one possibility is that statins inhibits downstream GGPP and FPP synthesis, reducing membrane protein isoprene, and thus regulates inflammatory.Our research team prior experiment has confirmed that alveolar epithelial cells GGPPS1 expression level changed in ARDS, and GGPPS1 expression changes and lung inflammation levels have direct correlation. Through literature, in the SCI has not yet reported the change and role of inflammatory cells in this phenomenon.In all kinds of inflammatory cells, peripheral blood macrophages activated in the early inflammtion, and they will release inflammatory factors. Through the study of this article we found:1. In ARDS patients or endotoxin (LPS) induced acute lung injury mice model GGPPS1 expression significantly higher in peripheral blood macrophages; 2. In vitro experiment we found that LPS caused human/mice macrophage GGPPS1 expression elevated through p38/MAPK pathway.3. The myeloid knockout GGPPS1 will reduce neutrophil recruitment in the mice acute lung injury model induced by LPS, at the same time reduce the exudation of protein, inflammation factors, alleviating the excessive inflammation.In conclusion, our findings suggest that in ARDS the peripheral blood macrophage GGPPS1 expression increased significantly, and may exacerbate inflammatory. Our experimental results, to a certain extent explains the role of protein isoprene in acute lung injury and the possible anti-inflammatory mechanism of statins, widen new research idea in the treatment of acute lung injury.