急性肺损伤（ALI）/急性呼吸窘迫综合征(ARDS)发病急、死亡率高，治疗面临巨大挑战。促炎（M1）和抗炎（M2）巨噬细胞所介导的炎症（失）平衡决定了ALI/ARDS的进程和转归，但是目前尚无可靠方法能够精准的调控M1、M2分化进而改善ALI/ARDS的预后。申请人发现，代谢重组在巨噬细胞分化中发挥关键作用。本研究拟在细胞和动物层面通过对乳酸脱氢酶a（LDHa）和线粒体丙酮酸载体（MPC）的干预来评估丙酮酸代谢如何影响M1、M2分化和ALI/ARDS的发生发展。通过药物抑制和遗传操作的方法，我们将深入研究LDHa和MPC介导的代谢途径如何通过影响线粒体活性氧-缺氧诱导因子α（mROS-HIF-1α）的产生和组蛋白的修饰来调节M1、M2分化，并进一步评估其是否为重建ALI/ARDS状态下机体促炎、抗炎平衡并改善其预后的关键靶点，从而为临床免疫治疗ALI/ARDS提供新的方法和科学依据。

Acute lung injury (ALI)/Acute respiratory distress syndrome (ARDS) is characterized by acute disease progression and high mortality. To date, effective treatment for ALI/ARDS is challenging. It is believed that the balance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophage mediated inflammation largely determines the disease progression and outcome of ALI/ARDS. To improve the outcome of ALI/ARDS, however, no reliable methods that can be used to precisely control macrophage differentiation were reported yet. We recently found that metabolic reprogramming played a pivotal role in regulating macrophage differentiation. In this study, first, we propose to perform both in vitro and in vivo experiments to investigate how interference of lactate dehydrogenase a (LDHa) and mitochondrial pyruvate carrier (MPC) will affect the differentiation of M1/M2 macrophage and subsequent disease progression of ALI/ARDS. Second, we propose to employ both pharmacologic and genetic approaches, to test the underlying mechanisms on how LDHa and MPC mediated metabolic pathway will regulate the differentiation of M1/M2 macrophage, whether through affecting the expression of mitochondrial reactive oxygen-hypoxia induced factor α (mROS-HIF-1α), and/or the histone modification. Third, in order to improve the outcome of ALI/ARDS, we further propose to test whether LDHa and MPC are two key proteins that can be targeted to restore the balance between the pro- and anti- inflammation. Successful completion of these proposed studies promises to lay a solid foundation toward developing a novel approach for effective immune treatment of ALI/ARDS.