利福喷丁联合氟康唑对耐药白念珠菌感染小鼠的作用及免疫机制分析
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摘要
目的:观察利福喷丁联合氟康唑对耐药白念珠菌感染小鼠的保护作用,并探讨其作用机制。方法:100只ICR小鼠随机分为5组:空白对照组、模型组、利福喷丁组(0. 9 mg·kg~(-1))、氟康唑组(0. 5 mg·kg~(-1))、利福喷丁+氟康唑组(0. 9 mg·kg~(-1)+0. 5 mg·kg~(-1))。除空白对照组外,给予各组小鼠尾静脉注射耐药白念珠菌100悬液处理,构建真菌感染模型。感染2h后,利福喷丁组、氟康唑组、利福喷丁+氟康唑组分别腹腔注射给药,空白对照组和模型组腹腔注射等体积生理盐水,1次/d,连续给药7 d。真菌感染后连续观察30 d,统计各组大鼠生存情况,检测Th1、Th17、Th2细胞比例,观察肾脏组织病变情况及肾脏载菌量。结果:与空白对照组比较,模型组小鼠平均存活时间明显缩短,肾脏组织现大量真菌菌丝、孢子和炎症性病变,肾脏载菌量明显增多,外周血Th1、Th17细胞比例明显降低,Th2细胞比例明显增高(P <0. 05)。与模型组比较,利福喷丁组小鼠平均存活时间、肾脏组织病变程度及肾脏载菌量差异均无统计学意义(P> 0. 05);氟康唑组及利福喷丁+氟康唑组小鼠平均存活时间显著延长,肾脏组织中菌丝和孢子减少,肾脏组织病变程度减轻,肾脏载菌量显著减少,外周血Th1、Th17细胞比例显著升高,Th2细胞比例显著降低(P <0. 05);且联合作用效果显著优于氟康唑单独作用(P <0. 05)。结论:利福喷丁联合氟康唑可增强氟康唑对耐药白念珠菌的抗菌作用,其机制可能与调节Th1、Th17、Th2细胞分化有关。
Objective: To observe the protective effect of rifapentine combined with fluconazole in mice infected with drug-resistant Candida albicans,and explore the underlying mechanism. Methods: Totally 100 ICR mice were randomly divided into 5 groups: the blank control group,the model group,rifapentine group(0. 9 mg·kg~(-1)),fluconazole group(0. 5 mg·kg~(-1)),rifapentine + fluconazole group(0. 9 mg·kg~(-1)+ 0. 5 mg·kg~(-1)). Except for the blank control group,the mice in the other groups were injected with drug-resistant Candida albicans 100 suspension via tail vein,and a fungal infection model was established. After 2-hour infection,rifapentin group,fluconazole group and rifapentin + fluconazole group was given 0. 9 mg·kg~(-1)rifapentin,0. 5 mg·kg~(-1)fluconazole and0. 9 mg·kg~(-1)rifapentin + 0. 5 mg·kg~(-1)fluconazole,respectively. The blank control group and the model group were injected with saline at the same volume,once a day for 7 days. After the fungal infection,the mice were under 30-day continuous observation,the survival time in each group was statistically analyzed,the proportions of Th1,Th17 and Th2 cells were detected,and the renal tissue lesion and the loaded amount of bacteria were observed. Results: Compared with that in the blank control group,the average survival time of the mice in the model group was significantly shortened,a large number of fungal hyphae and spores and inflammatory lesions were presented in kidney,the amount of bacteria loaded in kidney was significantly increased,and the proportions of Th1 and Th17 cells in peripheral blood decreased significantly,the proportion of Th2 cells increased significantly( P < 0. 05). Compared with the model group,there were no significant differences in the average survival time,the degree of renal tissue lesion and the renal bacteria carrying capacity in rifapentine group( P > 0. 05). The average survival time of fluconazole group and rifapentine + fluconazole group was significantly prolonged,mycelium and spores decreased in renal tissue,the degree of renal tissue lesion was relieved,the amount of bacteria loaded in kidney decreased significantly,the proportions of Th1 and Th17 cells in peripheral blood significantly increased,and the proportion of Th2 cells decreased significantly( P < 0. 05). The combined effect was significantly better than that of fluconazole alone( P < 0. 05). Conclusion: Rifapentin combined with fluconazole can enhance the antibacterial effect of fluconazole on drug-resistant Candida albicans,and the mechanism may be related to regulating the differentiations of Th1,Th17 and Th2 cells.
Objective: To observe the protective effect of rifapentine combined with fluconazole in mice infected with drug-resistant Candida albicans,and explore the underlying mechanism. Methods: Totally 100 ICR mice were randomly divided into 5 groups: the blank control group,the model group,rifapentine group(0. 9 mg·kg~(-1)),fluconazole group(0. 5 mg·kg~(-1)),rifapentine + fluconazole group(0. 9 mg·kg~(-1)+ 0. 5 mg·kg~(-1)). Except for the blank control group,the mice in the other groups were injected with drug-resistant Candida albicans 100 suspension via tail vein,and a fungal infection model was established. After 2-hour infection,rifapentin group,fluconazole group and rifapentin + fluconazole group was given 0. 9 mg·kg~(-1)rifapentin,0. 5 mg·kg~(-1)fluconazole and0. 9 mg·kg~(-1)rifapentin + 0. 5 mg·kg~(-1)fluconazole,respectively. The blank control group and the model group were injected with saline at the same volume,once a day for 7 days. After the fungal infection,the mice were under 30-day continuous observation,the survival time in each group was statistically analyzed,the proportions of Th1,Th17 and Th2 cells were detected,and the renal tissue lesion and the loaded amount of bacteria were observed. Results: Compared with that in the blank control group,the average survival time of the mice in the model group was significantly shortened,a large number of fungal hyphae and spores and inflammatory lesions were presented in kidney,the amount of bacteria loaded in kidney was significantly increased,and the proportions of Th1 and Th17 cells in peripheral blood decreased significantly,the proportion of Th2 cells increased significantly( P < 0. 05). Compared with the model group,there were no significant differences in the average survival time,the degree of renal tissue lesion and the renal bacteria carrying capacity in rifapentine group( P > 0. 05). The average survival time of fluconazole group and rifapentine + fluconazole group was significantly prolonged,mycelium and spores decreased in renal tissue,the degree of renal tissue lesion was relieved,the amount of bacteria loaded in kidney decreased significantly,the proportions of Th1 and Th17 cells in peripheral blood significantly increased,and the proportion of Th2 cells decreased significantly( P < 0. 05). The combined effect was significantly better than that of fluconazole alone( P < 0. 05). Conclusion: Rifapentin combined with fluconazole can enhance the antibacterial effect of fluconazole on drug-resistant Candida albicans,and the mechanism may be related to regulating the differentiations of Th1,Th17 and Th2 cells.
引文
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6王玉连,张璐璐,秦玉璘,等.利福喷丁对氟康唑体外抗耐药白念珠菌的增效作用[J].中国真菌学杂志,2016,11(3):156-159
7 Voigt J,Hünniger K,Bouzani M,et al.Human natural killer cells acting asphagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity[J].JInfect Dis,2014,209(4):616-626
8 Jaechen S,Youngjoo J,Seonmin P,et al.Mechanism underlying renal failure caused by pathogenic Candida albicans infection[J].Biomed Rep,2015,3(2):179-182
9 Katragkou A,Alexander EL,Eoh H,et al.Effects of fluconazole on the metabolomic profile of Candida albicans[J].J Antimicrob Chemother,2016,71(3):635-640
10 Dovigo LN,Pavarina AC,Mima EG,et al.Fungicidal effect of photodynamic therapy against fluconazole-resistant Candida albicans and Candida glabrata[J].Mycoses,2015,54(2):123-130
11 Bulik CC,Sobel JD,Nailor MD.Susceptibility profile of vaginal isolates of Candida albicans prior to and following fluconazole introduction-impact of two decades[J].Mycoses,2015,54(1):34-38
12 Jindani A,Harrison TS,Nunn AJ,et al.High-dose rifapentine with moxifloxacin for pulmonary tuberculosis[J].N Engl J Med,2014,371(17):1599-1608
13 Chan JG,Tyne AS,Pang A,et al.A rifapentine-containing inhaled triple antibiotic formulation for rapid treatment of tubercular infection[J].Pharm Res,2014,31(5):1239-1253
14 Lauzardo M,Ashkin D.Optimizing the dose of rifapentine to treat tuberculosis.It's elementary[J].Am J Respir Crit Care Med,2015,191(3):251-252
15 Shi D,Li D,Wang Q,et al.Silencing SOCS1 in dendritic cells promote survival of mice with systemic Candida albicans infection via inducing Th1-cell differentiation[J].Immunol Lett,2018,197(2):53-62
16 De Carvalho PGC,Custódio LA,Conchoncosta I,et al.Concanavalin-A induces IL-17 production during the course of Candida albicans infection[J].FEMS Immunol Med Microbiol,2012,64(2):273-279
17 Noben-Trauth N,Hu-Li J,Paul WE.IL-4 secreted from individual naive CD4+T cells acts in an autocrine manner to induce Th2 differentiation[J].Eur J Immunol,2015,32(5):1428-1433
18 Kong X,Leng D,Liang G,et al.Paeoniflorin augments systemic Candida albicans infection through inhibiting Th1 and Th17 cell expression in a mouse model[J].Int Immunopharmacol,2018,60(1):76-83
19 Nakagawa M,Coleman HN,Wang X,et al.IL-12 Secretion by Langerhans Cells Stimulated with Candida Skin Test Reagent is Mediated by Dectin-1 in Some Healthy Individuals[J].Cytokine,2014,65(2):202-209
20 Whibley N,Maccallum DM,Vickers MA,et al.Expansion of Foxp3+T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge[J].Eur J Immunol,2014,44(4):1069-1083
2 Mane A,Vidhate P,Kusro C,et al.Molecular mechanisms associated with Fluconazole resistance in clinical Candida albicans isolates from India[J].Mycoses,2016,59(2):93-100
3 Rahemi D,Babaee N,Kazemi S,et al.An in vitro study of the effect of cinnamaldehyde on the growth of Candida albicans compared to nystatin and fluconazole[J].Fuel,2015,70(3):289-295
4 Getahun H,Matteelli A,Abubakar I,et al.Management of latent Mycobacterium tuberculosis infection:WHO guidelines for low tuberculosis burden countries[J].Eur Respir J,2015,46(6):1563-1576
5王莉,茅伟安,曹永兵,等.28种药物联合氟康唑对白念珠菌体外抑菌作用的初步研究[J].中国真菌学杂志,2013,8(6):329-333
6王玉连,张璐璐,秦玉璘,等.利福喷丁对氟康唑体外抗耐药白念珠菌的增效作用[J].中国真菌学杂志,2016,11(3):156-159
7 Voigt J,Hünniger K,Bouzani M,et al.Human natural killer cells acting asphagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity[J].JInfect Dis,2014,209(4):616-626
8 Jaechen S,Youngjoo J,Seonmin P,et al.Mechanism underlying renal failure caused by pathogenic Candida albicans infection[J].Biomed Rep,2015,3(2):179-182
9 Katragkou A,Alexander EL,Eoh H,et al.Effects of fluconazole on the metabolomic profile of Candida albicans[J].J Antimicrob Chemother,2016,71(3):635-640
10 Dovigo LN,Pavarina AC,Mima EG,et al.Fungicidal effect of photodynamic therapy against fluconazole-resistant Candida albicans and Candida glabrata[J].Mycoses,2015,54(2):123-130
11 Bulik CC,Sobel JD,Nailor MD.Susceptibility profile of vaginal isolates of Candida albicans prior to and following fluconazole introduction-impact of two decades[J].Mycoses,2015,54(1):34-38
12 Jindani A,Harrison TS,Nunn AJ,et al.High-dose rifapentine with moxifloxacin for pulmonary tuberculosis[J].N Engl J Med,2014,371(17):1599-1608
13 Chan JG,Tyne AS,Pang A,et al.A rifapentine-containing inhaled triple antibiotic formulation for rapid treatment of tubercular infection[J].Pharm Res,2014,31(5):1239-1253
14 Lauzardo M,Ashkin D.Optimizing the dose of rifapentine to treat tuberculosis.It's elementary[J].Am J Respir Crit Care Med,2015,191(3):251-252
15 Shi D,Li D,Wang Q,et al.Silencing SOCS1 in dendritic cells promote survival of mice with systemic Candida albicans infection via inducing Th1-cell differentiation[J].Immunol Lett,2018,197(2):53-62
16 De Carvalho PGC,Custódio LA,Conchoncosta I,et al.Concanavalin-A induces IL-17 production during the course of Candida albicans infection[J].FEMS Immunol Med Microbiol,2012,64(2):273-279
17 Noben-Trauth N,Hu-Li J,Paul WE.IL-4 secreted from individual naive CD4+T cells acts in an autocrine manner to induce Th2 differentiation[J].Eur J Immunol,2015,32(5):1428-1433
18 Kong X,Leng D,Liang G,et al.Paeoniflorin augments systemic Candida albicans infection through inhibiting Th1 and Th17 cell expression in a mouse model[J].Int Immunopharmacol,2018,60(1):76-83
19 Nakagawa M,Coleman HN,Wang X,et al.IL-12 Secretion by Langerhans Cells Stimulated with Candida Skin Test Reagent is Mediated by Dectin-1 in Some Healthy Individuals[J].Cytokine,2014,65(2):202-209
20 Whibley N,Maccallum DM,Vickers MA,et al.Expansion of Foxp3+T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge[J].Eur J Immunol,2014,44(4):1069-1083