RESUMEN
BACKGROUND & AIMS: Sepsis, a globally prevalent and highly lethal condition, remains a critical medical challenge. This investigation aims to assess the relevance of FGF1 as a potential therapeutic target for sepsis. METHODS: Sepsis was induced in C57BL/6 mice through LPS administration to establish an in vivo animal model. Various in vitro assays were conducted using human umbilical vein endothelial cells to elucidate the role of FGF1 in the disruption of the coagulation system and liver injury associated with sepsis, as well as to explore its underlying molecular mechanisms. RESULTS: In in vivo experiments, FGF1 ameliorated coagulation system disruption in septic mice by reducing the levels of pro-inflammatory and coagulation-related factors in the bloodstream. FGF1 also enhanced liver function in septic mice, mitigating liver inflammation and cell apoptosis, fostering liver vascular regeneration, increasing liver blood perfusion, and improving mouse survival. In vitro experiments demonstrated that FGF1 could inhibit LPS-induced inflammatory responses and apoptosis in endothelial cells, fortify endothelial cell barrier function, decrease endothelial cell permeability, promote endothelial cell proliferation, and restore endothelial cell tube-forming ability. Both in vivo and in vitro experiments substantiated that FGF1 improved sepsis by inhibiting the IL-6/STAT3 signaling pathway. CONCLUSION: In summary, our study indicates that FGF1 mitigates excessive inflammatory responses in sepsis by suppressing the IL-6/STAT3 signaling pathway, thereby improving systemic blood circulation and ameliorating liver damage in septic organisms. Consequently, this research identifies FGF1 as a potential clinical target for the treatment of human sepsis.
Asunto(s)
Factor 1 de Crecimiento de Fibroblastos , Células Endoteliales de la Vena Umbilical Humana , Interleucina-6 , Ratones Endogámicos C57BL , Factor de Transcripción STAT3 , Sepsis , Transducción de Señal , Animales , Factor de Transcripción STAT3/metabolismo , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/tratamiento farmacológico , Humanos , Interleucina-6/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Factor 1 de Crecimiento de Fibroblastos/farmacología , Masculino , Hígado/metabolismo , Hígado/patología , Lipopolisacáridos/toxicidad , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Coagulación Sanguínea/efectos de los fármacosRESUMEN
Purpose: 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)-1ß, 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-1ß and IL-6, as well as TF, plasminogen activator inhibitor 1 (PAI-1), D-dimer, thrombin-antithrombin 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.
RESUMEN
BACKGROUND: Sepsis is defined as a life-threatening organ dysfunction caused by dysregulation of the host response to infection. There is still a lack of specific treatment for sepsis. Here, we report that Fibroblast growth factor-2 (FGF2) can reduce the mortality of sepsis by ameliorating the coagulation abnormalities. METHODS: FGF2 was intraperitoneally injected into septic mice induced by lipopolysaccharide (LPS) and then assessed for coagulation response, organ damage and survival. RAW264.7 cells with or without FGF2 pretreating were exposed to LPS, and then changes in coagulation related factors expression and signaling were tested. RESULTS: The findings showed that intraperitoneal injection of FGF2 inhibited coagulation activity, reduced lung and liver damage, and increased survival in septic mice. In RAW264.7 cells, LPS upregulated the expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); however, pretreatment with FGF2 prevented this upregulation, while FGF2 knockdown exacerbated TF upregulation. Moreover, FGF2 suppressing the AKT/mTOR/S6K1 signaling pathway in septic mice and RAW264.7 cells stimulated by LPS. CONCLUSIONS: This study revealed a therapeutic role of FGF2 in ameliorating the coagulation abnormalities during sepsis.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos , Sepsis , Ratones , Animales , Factor 2 de Crecimiento de Fibroblastos/uso terapéutico , Lipopolisacáridos/farmacología , Transducción de Señal , Coagulación SanguíneaRESUMEN
Excessive inflammation and coagulation contribute to high morbidity and mortality in sepsis. Many studies have indicated the role of piperlongumine (PL) in anti-inflammation, but its effect on coagulation remains uncertain. Here, we explore whether PL could moderate coagulation indicators and alleviate lung inflammation during sepsis. RAW264.7 cells were induced by lipopolysaccharide (LPS) and treated with PL. Inflammatory and coagulation indicators, cell function and signaling, were evaluated in cells. Cecal ligation and puncture (CLP) mice were treated with PL by gavage. The harvested lungs and plasma were used to assess inflammation and coagulation indicators. As a result, PL increased the survival rate and reduced the concentrations of tissue factor (TF), plasminogen activator inhibitor 1 (PAI-1), thrombin-antithrombin complex (TAT), D-dimer, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α in CLP mice, with fibrinogen in reverse. Moreover, the PL alleviated inflammation, fibrin deposition, and lung injury in the lungs of CLP mice. In vitro, PL downregulated the expression of TF, PAI-1, IL-6, TNF-α, and IL-1ß in RAW264.7 cells induced by LPS. Furthermore, PL inhibited the phosphorylation of the AKT/mTOR signaling pathway's key proteins and suppressed the nuclear translocation of p-STAT3 in LPS-stimulated RAW264.7 cells. In conclusion, this study suggests that PL may modulate coagulation indicators and improve lung inflammation through AKT/mTOR signaling pathway in sepsis.