氟苯尼考抗炎活性及对炎性信号传导通路的调控
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摘要
氟苯尼考为一新型的氯霉素类动物专用广谱抗菌药,主要用于治疗动物细菌性疾病,多病原、多病因引起的严重混合感染及母畜子宫内膜炎、乳腺炎等。本研究通过建立LPS诱导体外炎症反应和体内炎症模型,证实它的抗炎作用及抗炎作用机制。在体外试验中,采用MTT、ABC-夹心ELISA、Griess reagent、RT-PCR、免疫蛋白印迹、免疫荧光等方法,研究了氟苯尼考对主要细胞因子、炎性介质及炎性信号传导通路NF-κB和MAPK的影响;体内通过建立LPS所致的小鼠内毒血症和急性肺损伤模型,检测了氟苯尼考对两种动物模型的保护作用。体外研究结果表明,氟苯尼考通过调控NF-κB和MAPK通路抑制了炎性细胞因子TNF-α、IL-6的分泌,抑制了炎性介质NO和PGE2合成及iNOS和COX-2的mRNA和蛋白表达水平;体内研究结果表明,氟苯尼考通过调节小鼠血清中细胞因子水平提高了LPS诱导的小鼠内毒血症的生存率。氟苯尼考通过减轻肺水肿、抑制炎性细胞趋化、降低炎性细胞因子表达等多方面作用改善了LPS诱导的小鼠急性肺损伤。结论:首次证实氟苯尼考具有体内外抗炎活性,并借助信号传导通路平台探讨了其抗炎分子机制,从而为该药在临床上的合理应用提供理论和实验依据。
It has been shown that some antibacterials modulate the inflammatory responses by directly affecting host cell function in addition to exerting their antibacterial activity. In particular, drugs that target protein synthesis or DNA replication processes in bacteria have been suspected of causing this effect. Florfenicol is a new type broad-spectrum antibacterial that is used in the veterinary clinic. It has been widely used to treat a broad array of infectious diseases, such as for the treatments of bovine and porcine respiratory tract infections, actinobacillus pleuropneumonia in pigs, endometritis and mastitisand in female livestocks. However, florfenicol is widely used only as antibacterial in veterinary clinic. In order to fully educe clinical value and expand applied scope of florfenicol, we built in vitro inflammatory model by LPS-stimulated murine RAW 264.7 macrophages, and further explored anti-inflammatory molecular mechanism of florfenicol by inflammatory signal transduction pathway. Meanwhile, we studied the effects of florfenicol on LPS-induced murine toxicemia and ALI.
First, we investigated the effect of different concentrations of florfenicol on cytokine TNF-α, IL-1β, IL-6 and IL-10, inflammatory mediator NO and PGE2 secretions in LPS-stimulated murine RAW 264.7 macrophages. The result showed that florfenicol inhibited TNF-α, IL-6 and IL-1βsecretion and increased IL-10 level in a dose-dependent manner, but had no significant effect on IL-1βand IL-10. Florfenicol also inhibited NO and PGE2 synthesis, iNOS and COX-2 mRNA and protein expressions in a dose-dependent manner. These indicated florfenicol may educe anti-inflammatory effect through regulating the secretion of cytokines and inflammatory mediators in inflammatory process.
The mechanism by which LPS induces the production of cytokines and inflammatory mediators has been intensively investigated. There are several well-characterised signalling pathways involved. Among these, the mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) pathways may play an essential role. NF-κB is one of the most ubiquitous transcription factors and regulates the genes involved in cellular proliferation, inflammatory responses, and cell adhesion. The other major extracellular signal transduction pathway stimulated by inflammatory mediators is the MAPK pathway. The MAPKs are a family that includes ERK, p38 and JNK. They participate in LPS-induced intracellular signaling transmission and cytobiological response. Therefore, NF-κB and MAPKs are known as important targets for anti-inflammatory molecular mechanism. In order to study anti-infalmmatory molecular mechanism, we further investigated the effect of florfenicol on NF-κB and MAPKs signal transduction pathways in LPS-stimulated murine RAW264.7 macrophages. The result showed that florfenicol inhibited NF-κB activity, p38 and ERK1/2 protein phosphorylation in a dose-dependent manner. It suggested that florfenicol inhibited cytokine TNF-α, IL-6, NO and PGE2 secretion by regulating both NF-κB and p38, ERK1/2 MAPKs pathways.
To provide objective evaluation index on clinical therapeutic of florfenicol, we further studied in vivo ant-inflammatory of florfenicol. We investigated the effect of different concentrations of florfenicol on preventive and therapeutic effect in LPS-induced toxicemia mice, and the effect on cytokine TNF-α,IL-1β,IL-6 and IL-10 production in murine serum. The result showed that florfenicol significantly improved murine survival rate and decreased TNF-αand IL-6, increased IL-10 level in serum, but had little effect on IL-1β. It suggested that florfenicol improved murine survival rate through regulating the level of cytokines.
LPS-toxicemia will further cause systemic inflammatory response syndrome (SIRS) and most common and severe ALI, and lungs are involved in and first attacted organ by LPS because of its physiological characteristic. Therefore, we also studied the protection of florfenicol on murine ALI by building LPS-induced ALI model. The result showed that flrofenicol inhibited W/D ratio of lung, protein concentration and cellular scores of BALF; florfenicol significantly inhibited TNF-α, IL-1βand IL-6 level of BALF in LPS-induced ALI mice; lung histopathology also showed that florfenicol had certain protection on inflammatory infiltration of ALI.
We first time demonstrate that florfenicol has anti-inflammatory effect through regulating NF-κB, p38 and ERK1/2 MAPKs signal pathway in addition to exerting its antibacterial activity, it will provide foundation for reasonable application of florfenicol in clinic and improve clinical value, and it may be of importance as a therapeutics in treatment of excessive inflammatory reaction, SIRS and MODS in macrophages.
It has been shown that some antibacterials modulate the inflammatory responses by directly affecting host cell function in addition to exerting their antibacterial activity. In particular, drugs that target protein synthesis or DNA replication processes in bacteria have been suspected of causing this effect. Florfenicol is a new type broad-spectrum antibacterial that is used in the veterinary clinic. It has been widely used to treat a broad array of infectious diseases, such as for the treatments of bovine and porcine respiratory tract infections, actinobacillus pleuropneumonia in pigs, endometritis and mastitisand in female livestocks. However, florfenicol is widely used only as antibacterial in veterinary clinic. In order to fully educe clinical value and expand applied scope of florfenicol, we built in vitro inflammatory model by LPS-stimulated murine RAW 264.7 macrophages, and further explored anti-inflammatory molecular mechanism of florfenicol by inflammatory signal transduction pathway. Meanwhile, we studied the effects of florfenicol on LPS-induced murine toxicemia and ALI.
First, we investigated the effect of different concentrations of florfenicol on cytokine TNF-α, IL-1β, IL-6 and IL-10, inflammatory mediator NO and PGE2 secretions in LPS-stimulated murine RAW 264.7 macrophages. The result showed that florfenicol inhibited TNF-α, IL-6 and IL-1βsecretion and increased IL-10 level in a dose-dependent manner, but had no significant effect on IL-1βand IL-10. Florfenicol also inhibited NO and PGE2 synthesis, iNOS and COX-2 mRNA and protein expressions in a dose-dependent manner. These indicated florfenicol may educe anti-inflammatory effect through regulating the secretion of cytokines and inflammatory mediators in inflammatory process.
The mechanism by which LPS induces the production of cytokines and inflammatory mediators has been intensively investigated. There are several well-characterised signalling pathways involved. Among these, the mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) pathways may play an essential role. NF-κB is one of the most ubiquitous transcription factors and regulates the genes involved in cellular proliferation, inflammatory responses, and cell adhesion. The other major extracellular signal transduction pathway stimulated by inflammatory mediators is the MAPK pathway. The MAPKs are a family that includes ERK, p38 and JNK. They participate in LPS-induced intracellular signaling transmission and cytobiological response. Therefore, NF-κB and MAPKs are known as important targets for anti-inflammatory molecular mechanism. In order to study anti-infalmmatory molecular mechanism, we further investigated the effect of florfenicol on NF-κB and MAPKs signal transduction pathways in LPS-stimulated murine RAW264.7 macrophages. The result showed that florfenicol inhibited NF-κB activity, p38 and ERK1/2 protein phosphorylation in a dose-dependent manner. It suggested that florfenicol inhibited cytokine TNF-α, IL-6, NO and PGE2 secretion by regulating both NF-κB and p38, ERK1/2 MAPKs pathways.
To provide objective evaluation index on clinical therapeutic of florfenicol, we further studied in vivo ant-inflammatory of florfenicol. We investigated the effect of different concentrations of florfenicol on preventive and therapeutic effect in LPS-induced toxicemia mice, and the effect on cytokine TNF-α,IL-1β,IL-6 and IL-10 production in murine serum. The result showed that florfenicol significantly improved murine survival rate and decreased TNF-αand IL-6, increased IL-10 level in serum, but had little effect on IL-1β. It suggested that florfenicol improved murine survival rate through regulating the level of cytokines.
LPS-toxicemia will further cause systemic inflammatory response syndrome (SIRS) and most common and severe ALI, and lungs are involved in and first attacted organ by LPS because of its physiological characteristic. Therefore, we also studied the protection of florfenicol on murine ALI by building LPS-induced ALI model. The result showed that flrofenicol inhibited W/D ratio of lung, protein concentration and cellular scores of BALF; florfenicol significantly inhibited TNF-α, IL-1βand IL-6 level of BALF in LPS-induced ALI mice; lung histopathology also showed that florfenicol had certain protection on inflammatory infiltration of ALI.
We first time demonstrate that florfenicol has anti-inflammatory effect through regulating NF-κB, p38 and ERK1/2 MAPKs signal pathway in addition to exerting its antibacterial activity, it will provide foundation for reasonable application of florfenicol in clinic and improve clinical value, and it may be of importance as a therapeutics in treatment of excessive inflammatory reaction, SIRS and MODS in macrophages.
引文
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