高乳酸血症经常发生在严重脓毒症/感染性休克期间的危重病人身上，是死亡率的有力预测指标。乳酸是糖酵解的最终产物。虽然氧气输送不足导致的缺氧可能导致无氧糖酵解，但脓毒症也会在高动力循环和充足的氧气输送下增强糖酵解。然而，所涉及的分子机制尚不完全清楚。丝裂原活化蛋白激酶 (MAPK) 家族在微生物感染期间调节免疫反应的许多方面。MAPK 磷酸酶 (MKP)-1通过去磷酸化作为 p38 和 JNK MAPK 活动的反馈控制机制。在这里，我们发现小鼠缺乏Mkp-16-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) 3 的表达和磷酸化显着增强，PFKFB 3 是一种在系统性大肠杆菌感染后调节糖酵解的关键酶。在多种组织和细胞类型中观察到增强的 PFKFB3 表达，包括肝细胞、巨噬细胞和上皮细胞。在骨髓来源的巨噬细胞中，Pfkfb3被大肠杆菌和脂多糖强烈诱导，Mkp-1缺陷增强了 PFKFB3 表达，但对Pfkfb3 mRNA 稳定性没有影响。PFKFB3 诱导与 WT 和Mkp-1中的乳酸产生相关-/-脂多糖刺激后的骨髓来源的巨噬细胞。此外，我们确定 PFKFB3 抑制剂显着减弱了乳酸的产生，突出了 PFKFB3 在糖酵解程序中的关键作用。最后，p38 MAPK 而非 JNK 的药理学抑制显着减弱了 PFKFB3 表达和乳酸产生。总之，我们的研究表明 p38 MAPK 和 MKP-1 在脓毒症期间调节糖酵解中起着关键作用。

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Hyperlactatemia often occurs in critically ill patients during severe sepsis/septic shock and is a powerful predictor of mortality. Lactate is the end product of glycolysis. While hypoxia due to inadequate oxygen delivery may result in anaerobic glycolysis, sepsis also enhances glycolysis under hyperdynamic circulation with adequate oxygen delivery. However, the molecular mechanisms involved are not fully understood. Mitogen-activated protein kinase (MAPK) families regulate many aspects of the immune response during microbial infections. MAPK phosphatase (MKP)-1 serves as a feedback control mechanism for p38 and JNK MAPK activities via dephosphorylation. Here, we found that mice deficient in Mkp-1 exhibited substantially enhanced expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) 3, a key enzyme that regulates glycolysis following systemic Escherichia coli infection. Enhanced PFKFB3 expression was observed in a variety of tissues and cell types, including hepatocytes, macrophages, and epithelial cells. In bone marrow–derived macrophages, Pfkfb3 was robustly induced by both E. coli and lipopolysaccharide, and Mkp-1 deficiency enhanced PFKFB3 expression with no effect on Pfkfb3 mRNA stability. PFKFB3 induction was correlated with lactate production in both WT and Mkp-1−/− bone marrow–derived macrophage following lipopolysaccharide stimulation. Furthermore, we determined that a PFKFB3 inhibitor markedly attenuated lactate production, highlighting the critical role of PFKFB3 in the glycolysis program. Finally, pharmacological inhibition of p38 MAPK, but not JNK, substantially attenuated PFKFB3 expression and lactate production. Taken together, our studies suggest a critical role of p38 MAPK and MKP-1 in the regulation of glycolysis during sepsis.