Pretreatment with Eupatilin Attenuates Inflammation and Coagulation in Sepsis by Suppressing JAK2/STAT3 Signaling Pathway

Abstract

Sepsis is an aggressive and life-threatening organ dysfunction induced by infection. Excessive inflammation and coagulation contribute to the negative outcomes for sepsis, resulting in high morbidity and mortality. In this study, we explored whether Eupatilin could alleviate lung injury, reduce inflammation and coagulation during sepsis. Methods: We constructed an in vitro sepsis model by stimulating RAW264.7 cells with 1 μg/mL lipopolysaccharide (LPS) for 6 hours. The cells were divided into control group, LPS group, LPS+ Eupatilin (Eup) group, and Eup group to detect their cell activity and inflammatory cytokines and coagulation factor levels. Cells in LPS+Eup and Eup group were pretreated with Eupatilin (10μM) for 2 hours. In vivo, mice were divided into sham operation group, cecal ligation and puncture (CLP) group and Eup group. Mice in the CLP and Eup groups were pretreated with Eupatilin (10mg/kg) for 2 hours by gavage. Lung tissue and plasma were collected and inflammatory cytokines, coagulation factors and signaling were measured. Results: In vitro, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and tissue factor (TF) expression in LPS-stimulated RAW264.7 cells was downregulated by Eupatilin (10μM). Furthermore, Eupatilin inhibited phosphorylation of the JAK2/STAT3 signaling pathway and suppressed p-STAT3 nuclear translocation. In vivo, Eupatilin increased the survival rate of the mice. In septic mice, plasma concentrations of TNF-α, IL-1β and IL-6, as well as TF, plasminogen activator inhibitor 1 (PAI-1), D-dimer, thrombinantithrombin complex (TAT) and fibrinogen were improved by Eupatilin. Moreover, Eupatilin alleviated lung injury by improving the expression of inflammatory cytokines and TF, fibrin deposition and macrophage infiltration in lung tissue. Conclusion:Our results revealed that Eupatilin may modulate inflammation and coagulation indicators as well as improve lung injury in sepsis via the JAK2/STAT3 signaling pathway.

Eupatilin Ameliorates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting Inflammation, Oxidative Stress, and Apoptosis in Mice

“…We found that EUP significantly inhibited activation of MAPK and NF-κB cascades. Similar to our findings, recent studies reported that EUP alleviated septic lung injury by reducing cytokine production and macrophage infiltration [ 46 , 47 ]. EUP inhibited pro-inflammatory cytokine production in LPS-treated macrophages by suppressing the NF-κB pathway [ 48 ].…”

Plant-Derived Senotherapeutics for the Prevention and Treatment of Intervertebral Disc Degeneration and Aging

“…Eupatilin (5,7-dihydroxy-3′,4′,6-trimethoxyflavone) ( Figure 1 ) is the primary flavonoid extracted from the herbaceous perennial plant Artemisia argyi of the Asteraceae family with pharmacological potential due to its anti-cancer, anti-oxidant and anti-inflammatory properties [ 132 ]. Eupatilin’s biological activities have been shown to be mediated by the regulation of several signaling pathways, including NF-κB, MAPK, Nrf2 and JAK2/signal transducer and activator of transcription (STAT) 3, through which the compound has been reported to suppress allergic inflammatory responses, lung injury in sepsis and ovalbumin-induced asthma [ 133 , 134 , 135 , 136 ]. Furthermore, eupatilin has been reported to exert chondroprotective effects in IL-1β-stimulated human OA chondrocytes in vitro and antinociceptive and chondroprotective properties in a rat model of OA in vivo by downregulating phosphorylated levels of JNK, oxidative damage and catabolic activity [ 137 ].…”

Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications

“…Leukocyte-generated thrombin can activate PARs found on both ECs and leukocytes, prompting ECs to release inflammatory factors such as IL-6. Thrombin's effect on ECs increases the expression of selectin E and P on the EC surface, thereby augmenting leukocyte adhesion to ECs and facilitating leukocyte exudation and chemotaxis [199]. Conversely, inflammatory factors and chemokines can attract a substantial number of inflammatory cells to accumulate at the site of inflammation, which produce numerous cytokines within the inflamed area, culminating in a cytokine storm.…”