NF-кB信号通路在间充质干细胞调节巨噬细胞治疗烧伤脓毒症的作用研究
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摘要
烧伤脓毒症的发生机制及治疗方法一直是研究的热点与重点。间充质干细胞具有较强的抗炎、免疫调节作用，可通过旁分泌各种细胞因子或与各种免疫细胞相互调节而发挥作用，用于炎症性或免疫性疾病的治疗。近年来已经在GVHD、系统性红斑狼疮、类风湿性关节炎、急性肺损伤、急性肾功能损害、急性免疫性肝损伤等疾病，脂肪间充质干细胞取得了明显的治疗效果，但是针对严重烧伤脓毒症的治疗研究仍然甚少，且具体机制仍不十分清楚。
首先，建立一个有效的完全模拟脓毒症发病机制的动物模型及分离扩增培养获得大量脂肪间充质干细胞非常关键。在第一部分实验，以C57/BL6J小鼠10%III°烫伤创面，接种2×10~5CFU铜绿假单胞菌建立小鼠烧伤脓毒症模型。实验结果：具有稳定的脓毒症发病率及死亡率，死亡率达50%-80%，；IL-1、IL-6、TNF-a及CRP等炎性因子明显升高，IL-6最高达20ng/ml；心、肝、脾、肺及肾脏细菌含量增高，其中脾脏含量最高；各脏器炎性细胞浸润及炎症损伤严重，可见大量的炎性细胞浸润及血性渗出；ALT、AST、BUN、Cr持续升高，肾功及肝功能明显下降。该实验表明该烧伤脓毒症模型有较高的死亡率和可重复的稳定性，并可进一步可发展为SIRS和MODS；该模型较好的反应了烧伤脓毒症的病理机制及临床特征。
在第二部分实验采用酶消化、贴壁筛选以及差速离心法分离培养小鼠脂肪间充质干细胞，通过流式细胞分析获得90%以上的CD90、CD105、CD44表达阳性，以及90%以上的CD34、CD45表达阴性的；同时通过油红O及碱性磷酸酶染色证明该细胞是有向成脂、成骨多向分化能力的脂肪来源的间充质干细胞。
在第三部分实验在脓毒症模型制备6h后，运用2×105脂肪间充质干细胞输注治疗小鼠烧伤脓毒症，观察小鼠的一般状况、生存率，检测全身各脏器细菌及内毒素定量、各脏器功能，以及促炎/抗炎因子的改变，明确脂肪间充质干细胞在烧伤脓毒症的治疗作用。实验结果表明：1、小鼠一般状况、自主活动及对外界的反应都有明显改善；2、小鼠24h、48h至72h脏器的细菌含量明显减少，而脾脏细菌定量变化最大，心脏的变化最小；3、随时间延长，TNF-、IL-12表达明显下降及抗炎因子IL-10表达明显升高，血清中TNF-、IL-6等促炎症因子及抗炎因子IL-10变化也是相同的。4、各脏器组织HE染色示炎性细胞浸润明显减少，肝小叶放射状结构保持完整；肾脏组织肾小管坏死细胞明显减少，肺间质增厚及肺泡内的血性渗出明显改善，肝、肺及肾脏组织细胞坏死凋亡明显减少，脏器功能得到改善。这些实验结果表明，脂肪间充质干细胞治疗烧伤脓毒症得到了肯定的疗效。
在第四部分实验体外单独或共培养脂肪间充质干细胞与Raw264.7小鼠巨噬细胞，以探讨脂肪间充质干细胞调节巨噬细胞及其NF-кB信号通路在干细胞治疗脓毒症可能的作用机制。将细胞分为四组：正常对照组、LPS刺激组、Transwell组、混合细胞组。实验结果证明：1、经LPS刺激后，促炎因子TNF-a、IL-6及抗炎因子TGF-b均有明显升高，但随时间延长，抗炎因子迅速下降，而促炎因子持续升高；当细胞共培养时，促炎因子明显下降，抗炎因子明显升高，其中促炎因子TNF-a，及抗炎因子COX-2变化最明显。2、经LPS刺激24h后，CD206阳性细胞增幅10%；随时间延长，LPS刺激组CD206阳性细胞无明显变化；但细胞Transwell及混合细胞共培养组，分别由23.3%增至38.5%，24.2%增至52.7%，较LPS刺激组有显著的提高，且发现，混合细胞组CD206的细胞比例最高，具有统计学差异。3、间充质干细胞共培养组，细胞内的P65的核转位及其上游分子p-IKB-a、p-IKK-a的磷酸化水平明显抑制。该实验结果表明，脂肪间充质干细胞可能不仅通过旁分泌的作用来调节巨噬细胞，还可通过与巨噬细胞间接触而发挥调节的作用。其中PGE2及NF-кB信号通路可能是间充质干细胞调节巨噬细胞变化的关键性因素，也是间充质干细胞
The mechanism and treatment of burn sepsis has been a difficult research focus.Mesenchymal stem cells (MSCs) are multipotent cells that are being clinically explored asa new therapeutic for treating a variety of immune-mediated diseases. The alternativefunctions are now being characterized in the context of MSC transplantation, wherebyparacrine interactions between MSCs and host cells of both the innate and adaptiveimmune systems have been shown to relate directly to the therapeutic activity of MSCs. Inrecent years, it has pioneered studies to investigate systemic administration of MSCs as atherapy for steroid-refractive graft-versus-host disease (GvHD), Crohn’s disease, type Idiabetes mellitus (IDDM), myocardial infarction (MI), and chronic obstructive pulmonarydisease (COPD) and other diseases. Because early has been in GVHD, systemic lupuserythematosus, rheumatoid arthritis, acute lung injury, acute renal dysfunction, acuteautoimmune liver damage, adipose mesenchymal stem cells made significant therapeuticeffect. However, there is still little research about MSC therapeutic on burn sepsis. And its therapeutic mechanism is still not very clear.
First, it is a very important to establish an stable, high replicated burn sepsis modeland harvest a large mount of mesenchymal stem cells. In the first experiment, weestablished a mouse model of burn sepsis with a III°burn wound of about10%ofTBSA, followed by inoculating with2×105CFU Pseudomonas aeruginosa in femaleC57BL/6mice. The mice with burn sepsis developed SIRS and MODS and had a50%-80%high rate of mortality,, which were reproducible. This novel mouse model of burnsepsis assembled the pathogenesis and clinical characteristics of human with burn sepsis.
In the second part of the experiment, it aim to harvest Adipose-derived stem cells ofC57mice in vitro. ADSCs were isolated by enzyme digestion. And ADSCs within3passages were used to verify the mult-potential differentiation capacity and FACS analysis.It showed us the cells had typical morphological characters of stem cells and were positivein the ADSCs’markers CD90, CD105, CD44, negative in CD34, CD45.
In the third experiment，it aim to investigate ADSCs therapeutic function on burnsepsis. After administration of2×105ADSCs, we obeseved clinical severity score forevaluation of the clinical status and tested mortality, organ bacteria quantitation, liver andkidney function, as well as changes in proinflammatory/anti-inflammatory cytokines inorgans or blood. Experimental results show that:1, the general condition of mice,spontaneous activity, and the reaction of the outside has improved significantly; After24h,48h to72h, organs bacteria quantitation were significantly reduced;3, TNF-, IL-12expression decreased significantly and anti-inflammatory cytokines IL-10expression wassignificantly elevated in liver and lung mRNA. The serum TNF-, IL-6and otherproinflammatory cytokines and anti-inflammatory cytokines IL-10changes have the sameresults.4, HE staining of liver, lung and kidney organs is shown the infiltration ofinflammatory cells significantly reduce, cell necrosis and apoptosis was significantlyreduced, improved organ function. These results suggest that intravenous administration ofADSCs improves SIRS and MODS with burn sepsis. These demonstrated that thefeasibility and effectiveness of ADSCs administration for experimental burn sepsis,providing the basis for development of a potentially effective immunomodulatory strategy to decrease morbidity and mortality in clinical sepsis.
In the fourth experiment, it aims to investigate interaction of ADSCs withRaw264.7macrophages and interaction of ADSCs with NF-кB signaling pathway in theirantiinfammatory/immune modulatory effects. We co-culture ADSCs with Raw264.7macrophages after stimulated by LPS. And We used cell surface antigen CD206expression and intracellular cytokine expression patterns to study the immunophenotypeof macrophages at the end of this coculture period in vitro. They were divided into fourgroups: normal control group, LPS stimulation group Transwell group, mixed group.Experimental results show that:1, Macrophages cocultured with ADSCs consistentlyshowed high-level expression of CD206, a marker of alternatively activated macrophages.However, macrophages cocultured with MSCs also expressed high levels of TGF-b,COX-2and low levels of tumor necrosis factor alpha (TNF-a) and IL-6compared tocontrols.2, ADSCs co-cultured group, nuclear translocation of P65cells and its upstreammolecular p-IKB-a, p-of IKK-phosphorylation significantly inhibited. The experimentalresults show that the ADSCs may be adjusted not only by paracrine role of macrophages,but also by contact between macrophages play a regulating role. PGE2and NF-кBsignaling pathway may be key factors, it is also the key point in therapy for sepsis withADSCs.
首先，建立一个有效的完全模拟脓毒症发病机制的动物模型及分离扩增培养获得大量脂肪间充质干细胞非常关键。在第一部分实验，以C57/BL6J小鼠10%III°烫伤创面，接种2×10~5CFU铜绿假单胞菌建立小鼠烧伤脓毒症模型。实验结果：具有稳定的脓毒症发病率及死亡率，死亡率达50%-80%，；IL-1、IL-6、TNF-a及CRP等炎性因子明显升高，IL-6最高达20ng/ml；心、肝、脾、肺及肾脏细菌含量增高，其中脾脏含量最高；各脏器炎性细胞浸润及炎症损伤严重，可见大量的炎性细胞浸润及血性渗出；ALT、AST、BUN、Cr持续升高，肾功及肝功能明显下降。该实验表明该烧伤脓毒症模型有较高的死亡率和可重复的稳定性，并可进一步可发展为SIRS和MODS；该模型较好的反应了烧伤脓毒症的病理机制及临床特征。
在第二部分实验采用酶消化、贴壁筛选以及差速离心法分离培养小鼠脂肪间充质干细胞，通过流式细胞分析获得90%以上的CD90、CD105、CD44表达阳性，以及90%以上的CD34、CD45表达阴性的；同时通过油红O及碱性磷酸酶染色证明该细胞是有向成脂、成骨多向分化能力的脂肪来源的间充质干细胞。
在第三部分实验在脓毒症模型制备6h后，运用2×105脂肪间充质干细胞输注治疗小鼠烧伤脓毒症，观察小鼠的一般状况、生存率，检测全身各脏器细菌及内毒素定量、各脏器功能，以及促炎/抗炎因子的改变，明确脂肪间充质干细胞在烧伤脓毒症的治疗作用。实验结果表明：1、小鼠一般状况、自主活动及对外界的反应都有明显改善；2、小鼠24h、48h至72h脏器的细菌含量明显减少，而脾脏细菌定量变化最大，心脏的变化最小；3、随时间延长，TNF-、IL-12表达明显下降及抗炎因子IL-10表达明显升高，血清中TNF-、IL-6等促炎症因子及抗炎因子IL-10变化也是相同的。4、各脏器组织HE染色示炎性细胞浸润明显减少，肝小叶放射状结构保持完整；肾脏组织肾小管坏死细胞明显减少，肺间质增厚及肺泡内的血性渗出明显改善，肝、肺及肾脏组织细胞坏死凋亡明显减少，脏器功能得到改善。这些实验结果表明，脂肪间充质干细胞治疗烧伤脓毒症得到了肯定的疗效。
在第四部分实验体外单独或共培养脂肪间充质干细胞与Raw264.7小鼠巨噬细胞，以探讨脂肪间充质干细胞调节巨噬细胞及其NF-кB信号通路在干细胞治疗脓毒症可能的作用机制。将细胞分为四组：正常对照组、LPS刺激组、Transwell组、混合细胞组。实验结果证明：1、经LPS刺激后，促炎因子TNF-a、IL-6及抗炎因子TGF-b均有明显升高，但随时间延长，抗炎因子迅速下降，而促炎因子持续升高；当细胞共培养时，促炎因子明显下降，抗炎因子明显升高，其中促炎因子TNF-a，及抗炎因子COX-2变化最明显。2、经LPS刺激24h后，CD206阳性细胞增幅10%；随时间延长，LPS刺激组CD206阳性细胞无明显变化；但细胞Transwell及混合细胞共培养组，分别由23.3%增至38.5%，24.2%增至52.7%，较LPS刺激组有显著的提高，且发现，混合细胞组CD206的细胞比例最高，具有统计学差异。3、间充质干细胞共培养组，细胞内的P65的核转位及其上游分子p-IKB-a、p-IKK-a的磷酸化水平明显抑制。该实验结果表明，脂肪间充质干细胞可能不仅通过旁分泌的作用来调节巨噬细胞，还可通过与巨噬细胞间接触而发挥调节的作用。其中PGE2及NF-кB信号通路可能是间充质干细胞调节巨噬细胞变化的关键性因素，也是间充质干细胞
The mechanism and treatment of burn sepsis has been a difficult research focus.Mesenchymal stem cells (MSCs) are multipotent cells that are being clinically explored asa new therapeutic for treating a variety of immune-mediated diseases. The alternativefunctions are now being characterized in the context of MSC transplantation, wherebyparacrine interactions between MSCs and host cells of both the innate and adaptiveimmune systems have been shown to relate directly to the therapeutic activity of MSCs. Inrecent years, it has pioneered studies to investigate systemic administration of MSCs as atherapy for steroid-refractive graft-versus-host disease (GvHD), Crohn’s disease, type Idiabetes mellitus (IDDM), myocardial infarction (MI), and chronic obstructive pulmonarydisease (COPD) and other diseases. Because early has been in GVHD, systemic lupuserythematosus, rheumatoid arthritis, acute lung injury, acute renal dysfunction, acuteautoimmune liver damage, adipose mesenchymal stem cells made significant therapeuticeffect. However, there is still little research about MSC therapeutic on burn sepsis. And its therapeutic mechanism is still not very clear.
First, it is a very important to establish an stable, high replicated burn sepsis modeland harvest a large mount of mesenchymal stem cells. In the first experiment, weestablished a mouse model of burn sepsis with a III°burn wound of about10%ofTBSA, followed by inoculating with2×105CFU Pseudomonas aeruginosa in femaleC57BL/6mice. The mice with burn sepsis developed SIRS and MODS and had a50%-80%high rate of mortality,, which were reproducible. This novel mouse model of burnsepsis assembled the pathogenesis and clinical characteristics of human with burn sepsis.
In the second part of the experiment, it aim to harvest Adipose-derived stem cells ofC57mice in vitro. ADSCs were isolated by enzyme digestion. And ADSCs within3passages were used to verify the mult-potential differentiation capacity and FACS analysis.It showed us the cells had typical morphological characters of stem cells and were positivein the ADSCs’markers CD90, CD105, CD44, negative in CD34, CD45.
In the third experiment，it aim to investigate ADSCs therapeutic function on burnsepsis. After administration of2×105ADSCs, we obeseved clinical severity score forevaluation of the clinical status and tested mortality, organ bacteria quantitation, liver andkidney function, as well as changes in proinflammatory/anti-inflammatory cytokines inorgans or blood. Experimental results show that:1, the general condition of mice,spontaneous activity, and the reaction of the outside has improved significantly; After24h,48h to72h, organs bacteria quantitation were significantly reduced;3, TNF-, IL-12expression decreased significantly and anti-inflammatory cytokines IL-10expression wassignificantly elevated in liver and lung mRNA. The serum TNF-, IL-6and otherproinflammatory cytokines and anti-inflammatory cytokines IL-10changes have the sameresults.4, HE staining of liver, lung and kidney organs is shown the infiltration ofinflammatory cells significantly reduce, cell necrosis and apoptosis was significantlyreduced, improved organ function. These results suggest that intravenous administration ofADSCs improves SIRS and MODS with burn sepsis. These demonstrated that thefeasibility and effectiveness of ADSCs administration for experimental burn sepsis,providing the basis for development of a potentially effective immunomodulatory strategy to decrease morbidity and mortality in clinical sepsis.
In the fourth experiment, it aims to investigate interaction of ADSCs withRaw264.7macrophages and interaction of ADSCs with NF-кB signaling pathway in theirantiinfammatory/immune modulatory effects. We co-culture ADSCs with Raw264.7macrophages after stimulated by LPS. And We used cell surface antigen CD206expression and intracellular cytokine expression patterns to study the immunophenotypeof macrophages at the end of this coculture period in vitro. They were divided into fourgroups: normal control group, LPS stimulation group Transwell group, mixed group.Experimental results show that:1, Macrophages cocultured with ADSCs consistentlyshowed high-level expression of CD206, a marker of alternatively activated macrophages.However, macrophages cocultured with MSCs also expressed high levels of TGF-b,COX-2and low levels of tumor necrosis factor alpha (TNF-a) and IL-6compared tocontrols.2, ADSCs co-cultured group, nuclear translocation of P65cells and its upstreammolecular p-IKB-a, p-of IKK-phosphorylation significantly inhibited. The experimentalresults show that the ADSCs may be adjusted not only by paracrine role of macrophages,but also by contact between macrophages play a regulating role. PGE2and NF-кBsignaling pathway may be key factors, it is also the key point in therapy for sepsis withADSCs.
引文
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