Norisoboldine Attenuates Sepsis-Induced Acute Lung Injury by Modulating Macrophage Polarization via PKM2/HIF-1/PGC-1 Pathway
BIOLOGICAL & PHARMACEUTICAL BULLETIN(2021)
摘要
This study aimed to investigate the effect of norisopoldine (NOR) on acute lung injury in septic mice. Lipopolysaccharide (LPS) was used to establish sepsis induced acute lung injury (ALI) in mice. The dry and wet weight of mice lung was detected, and the pathological changes of lung were observed by hematoxylin and eosin (H&E) staining. Bronchoalveolar lavage fluid (BALF) was detected. Inflammatory factors in BALF were detected by enzyme-linked immunosorbent assay (ELISA). The polarization of macrophages in lung tissue was detected by flow cytometry. The markers of M1 and M2 macrophages were detected by RT-PCR. LPS induced RAW264.7 cells were treated with NOR. Inflammatory response, macrophage polarization, glycolysis, and M2 pyruvate kinase (PKM2)/hypoxia inducible factor-1 alpha (HIF-1 alpha)/peroxisome proliferator activated receptor-gamma co-activator 1-alpha (PGC-1 alpha) signaling pathway were detected. NOR could effectively alleviate sepsis induced ALI, and reduce the number of total cells, total protein concentration, neutrophils, macrophages in BALF. NOR decreased the level of inflammatory factors and promoted macrophages from M1 to M2 type in vivo and vitro. Moreover, NOR could activated PKM2, and inhibited PKM2 from cytoplasm to nuclear, attenuated HIF-1 alpha expression, and increased PGC-1 alpha and peroxisome proliferator-activated receptor (PPAR)-gamma expression. In addition, NOR inhibited glycolysis and promoted oxidative phosphorylation in RAW264.7 cells. Furthermore, PKM2 inhibitors could reverse the effect of NOR on PKM2/HIF-1 alpha/PGC-1 alpha signaling pathway in RAW264.7 cells. NOR alleviated sepsis induced AIL in mice, inhibited the inflammatory response, promote M2 polarization of macrophages through regulating PKM2/HIF-1 alpha/PGC-1 alpha signaling pathway.
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关键词
norisoboldine,sepsis-induced acute lung injury,macrophage,M2 pyruvate kinase (PKM2)
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