卡维地洛预先干预联合胸腺肽α1对早期脓毒症大鼠免疫功能的影响
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摘要
目的探讨卡维地洛预先干预联合胸腺肽α1对早期脓毒症大鼠免疫功能的影响。方法将50只SD大鼠随机平均分为5组:脓毒症组(S组)、卡维地洛预先干预组(CS组)、胸腺肽α1组(ST组)、卡维地洛预先干预+胸腺肽α1组(CST组)、正常对照组(N组),除N组外各组大鼠尾静脉注射脂多糖LPS(20mg/kg)制成脓毒症模型,N组大鼠注射等容量的生理盐水,CS组和CST组于注射LPS前4周给予卡维地洛按10mg·kg~(-1)·d~(-1)灌胃,1次/d,ST组和CST组注射LPS后立即给予胸腺肽α1(50μg/100g)皮下注射,24h后检测并比较各组大鼠CD3~+、CD4~+及CD8~+T淋巴细胞亚群、mHLA-DR%、TNF-α、IL-6、IL~(-1)0的差异。结果 (1)与N组比较,S组、CS组、ST组、CST组大鼠CD3~+、CD4~+、CD8~+T淋巴细胞百分比、mHLA-DR%下降,TNF-α、IL-6、IL~(-1)0浓度显著升高,差异均有统计学意义(P<0.05);(2)与S组比较,CS组大鼠CD3~+、CD4~+、CD8~+T淋巴细胞百分比及mHLA-DR%升高,TNF-α、IL-6、IL~(-1)0浓度降低,但无统计学差异(P>0.05);ST组、CST组和N组大鼠CD3~+、CD4~+T淋巴细胞百分比、mHLA-DR%,N组CD8~+T淋巴细胞百分比显著升高,ST组、CST组和N组大鼠TNF-α、IL~(-1)0,CST组和N组IL-6浓度显著降低,差异均有统计学意义(P<0.05);(3)与CS组比较,ST组、CST组和N组CD3~+、CD4~+T淋巴细胞百分比,CST组和N组mHLA-DR%,N组CD8~+T淋巴细胞百分比显著升高,ST组、CST组和N组TNF-α和IL~(-1)0以及N组IL-6浓度降低,差异均有统计学意义(P<0.05);(4)与ST组比较,CST组和N组CD3~+、CD4~+T淋巴细胞百分比及mHLA-DR%,N组CD8~+T淋巴细胞百分比升高,CST组和N组TNF-α、IL~(-1)0,N组IL-6浓度降低,差异均有统计学意义(P<0.05)。结论仅用卡维地洛预先干预对早期脓毒症大鼠免疫功能影响较小,但卡维地洛与胸腺肽α1联合可增强胸腺肽α1对脓毒症大鼠的免疫调节功能。
Objective To research the effect of carvedilol-advance intervention combined with thymosin alpha 1 on immune function in early septic rats. Methods Fifty SD rats were randomly divided into five groups equally: sepsis group(group S), carvedilol-advance intervention group(group CS), thymosin alpha 1 group(group ST), carvediloladvance intervention and thymosin alpha 1 group(group CST), and normal control group(group N). All the rats except for group N were injected lipopolysaccharide(LPS, 20 mg/kg) into caudal vein to induce sepsis. The rats in group N were injected the equal volume saline. For the group CS and CST, the carvedilol had been orally administered 10 mg/kg once a day for 4 weeks prior to the injection of LPS. For the group ST and CST, thymosin alpha 1(50μg/100 g) was injected through subcutaneous tissue immediately after LPS injection. The CD3~+, CD4~+, CD8~+T lymphocyte subsets, monocyte human leukocyte antigen-DR(mHLA-DR), tumor necrosis factor(TNF)-α, interleukin(IL)-6 and IL-10 in each group were detected and compared after 24 hours. Results Compared with group N, the percentage of CD3~+, CD4~+, CD8~+T lymphocyte subsets, mHLA-DR% decreased and concentration of TNF-α, IL-6 and IL-10 increased significantly in group S, CS, ST and CST, all with statistically significant difference(P<0.05). Compared with group S, the percentage of CD3~+, CD4~+, CD8~+T lymphocyte subsets and mHLA-DR% in group CS increased, and the concentration of TNF-α, IL-6 and IL-10 decreased. But the result didn't show statistically significant difference(P>0.05). The percentage of CD3~+, CD4~+ lymphocyte subsets and mHLA-DR% in group ST and CST, and CD8~+ lymphocyte subsets in group N increased, the concentration of TNF-α and IL-10 in group ST, CST and N,IL-6 in group CST and N decreased significantly, all with statistically significant difference(P<0.05). Compared with group CS, the percentage of CD3~+, CD4~+ lymphocyte subsets in group ST, CST and N, mHLA-DR% in group CST and N, the percentage of CD8~+lymphocyte subsets in group N increased, while the concentration of TNF-α and IL-10 in group ST, CST and N, the concentration of IL-6 in group N decreased, all with statistically significant difference(P<0.05). Compared with group ST, the percentage of CD3~+, CD4~+ lymphocyte subsets and mHLA-DR% in group CST and N, the percentage of CD8~+lymphocyte subsets in group N increased, while the concentration of TNF-α and IL-10 in group CST and N, IL-6 in group N decreased, all with statistically significant difference(P<0.05). Conclusion Carvedilol-advance intervention has little effect on the immune function of early septic rats, but when combined with thymosin-α1, it enhance the improvement effect of thymosin-α1 upon the immune function in early sepsis rats.
Objective To research the effect of carvedilol-advance intervention combined with thymosin alpha 1 on immune function in early septic rats. Methods Fifty SD rats were randomly divided into five groups equally: sepsis group(group S), carvedilol-advance intervention group(group CS), thymosin alpha 1 group(group ST), carvediloladvance intervention and thymosin alpha 1 group(group CST), and normal control group(group N). All the rats except for group N were injected lipopolysaccharide(LPS, 20 mg/kg) into caudal vein to induce sepsis. The rats in group N were injected the equal volume saline. For the group CS and CST, the carvedilol had been orally administered 10 mg/kg once a day for 4 weeks prior to the injection of LPS. For the group ST and CST, thymosin alpha 1(50μg/100 g) was injected through subcutaneous tissue immediately after LPS injection. The CD3~+, CD4~+, CD8~+T lymphocyte subsets, monocyte human leukocyte antigen-DR(mHLA-DR), tumor necrosis factor(TNF)-α, interleukin(IL)-6 and IL-10 in each group were detected and compared after 24 hours. Results Compared with group N, the percentage of CD3~+, CD4~+, CD8~+T lymphocyte subsets, mHLA-DR% decreased and concentration of TNF-α, IL-6 and IL-10 increased significantly in group S, CS, ST and CST, all with statistically significant difference(P<0.05). Compared with group S, the percentage of CD3~+, CD4~+, CD8~+T lymphocyte subsets and mHLA-DR% in group CS increased, and the concentration of TNF-α, IL-6 and IL-10 decreased. But the result didn't show statistically significant difference(P>0.05). The percentage of CD3~+, CD4~+ lymphocyte subsets and mHLA-DR% in group ST and CST, and CD8~+ lymphocyte subsets in group N increased, the concentration of TNF-α and IL-10 in group ST, CST and N,IL-6 in group CST and N decreased significantly, all with statistically significant difference(P<0.05). Compared with group CS, the percentage of CD3~+, CD4~+ lymphocyte subsets in group ST, CST and N, mHLA-DR% in group CST and N, the percentage of CD8~+lymphocyte subsets in group N increased, while the concentration of TNF-α and IL-10 in group ST, CST and N, the concentration of IL-6 in group N decreased, all with statistically significant difference(P<0.05). Compared with group ST, the percentage of CD3~+, CD4~+ lymphocyte subsets and mHLA-DR% in group CST and N, the percentage of CD8~+lymphocyte subsets in group N increased, while the concentration of TNF-α and IL-10 in group CST and N, IL-6 in group N decreased, all with statistically significant difference(P<0.05). Conclusion Carvedilol-advance intervention has little effect on the immune function of early septic rats, but when combined with thymosin-α1, it enhance the improvement effect of thymosin-α1 upon the immune function in early sepsis rats.
引文
1 Fleischmann C,Scherag A,Adhikafi NK,et al.Assessment of global incidence and mortality of hospital-treated Sepsis.Current Estimates and Limitations[J].Am J Respir Crit Care Med,2016,193(3):259-272
2 Dellinger RP,Levy MM,Rhodes A,et al.Surviving sepsis campaign:international guidelines for management severe sepsis and septic shock,2012[J].Intensive Care Medicine,2013,39(2):165-228
3师灵灵,韩艳秋,任慧娟,等.脓毒症的病理生理机制研究进展[J].中华医院感染学杂志,2016,26(8):1914-1916
4 Miksa M,Wu R,Zhou M,et al.Sympathetic excitotoxicity in sepsis:pro-inflammatory priming of macrophages by norepinephrine[J].Front Biosci,2005,10:2217-2229
5 Wang H,Yu M,Ochani M,et al.Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation[J].Nature,2003,421(6921):384-388
6 Vizi ES,Elenkov IJ.Nonsynaptic noradrenaline release in neuroimmune responses[J].Acta Biol Hung,2002,53(1-2):229-244
7 Yang S,Koo DJ,Zhou M,et al.Gut-derived norepinephrine plays a critical role in producing hepatocellular dysfunction during early sepsis[J].Am J Physiol Gastrointest Liver Physiol,2000,279(6):G1274-1281
8曹新营,王志军,杨文琦,等.卡维地洛对CHF病人细胞免疫功能及临床疗效的影响[J].中西医结合心脑血管病杂志,2017,15(16):2010-2012
9俞杨,田金徽,杨克虎,等.胸腺肽α1治疗脓毒症的系统评价[J].中国危重病急救医学,2009,21(1):21-24
10黎丽芬,蔡常洁,唐朝霞,等.胸腺肽α1对脓毒症大鼠模型的Th17和Treg淋巴细胞功能性极化的效应研究[J].中华重症医学电子杂志,2018,4(1):42-50
11徐叔云,卞如濂,陈修.药理实验方法学[M].3版.北京:人民卫生出版社,2001:202-204
12 Pinsky MR.Dysregulation of the immune response in severe sepsis[J].Am J Med Sci,2004,328(4):220-229
13 Wilson J.Early propranolol treatment induces lung hemeoxygenase-1,attenuates metabolic dysfunction,and improves survival following experimental sepsis[J].Crit Care,2013,17(5):R195
14张廉君.β受体阻滞剂在脓毒性休克中的应用研究进展[J].西南军医,2015,17(5):546-548
15 Macchia A,Romero M,Comignani PD,et al.Previous prescription ofβ-blockers is associated with reduced mortality among patients hospitalized in intensive care units for sepsis[J].Crit Care Med,2012,40(10):2768-2772
16 Christensen S,Johansen MB,Tonnesen E,et al.Preadmissionβ-blocker use and 30-day mortality among patients in intensive care:a cohort study[J].Crit Care,2011,15(2):R87
17 Jeschke MG,Finnerty CC,Kulp GA,et al.Combination of recombinant human growth hormone and propranolol decrease hypermetabolism and inflammation in severely burned children[J].Pediatr Crit Care Med,2008,9(2):209-216
18 Huston JM.The vagus nerve and the inflammatory reflex:wandering on a new treatment paradigm for systemic inflammation and sepsis[J].Surg Infect,2012,13(4):187-193
19 Stanojevie S,Dimitrijevie M,Kustrimovic NA,et al.Adrenal hormone deprivation affects maerophage catecholamine metabolism andβ2-adrenoceptor density,but not propranolol stimulation of tumour necrosis factor-alpha production[J].Exp Physiol,2013,98(3):665-678
20陈军喜,孙坚,管细红,等.早期脓毒症大鼠心脏变化特点及卡维地洛预先干预作用的实验研究[J].安徽医科大学学报,2015,50(10):1430-1433
21 Sáenz JJ,Izura JJ,Manrique A,et al.Early prognosis in severe sepsis via analyzing the monocyte immunophenotype[J].Intensive Care Med,2001,27:970-977
22 D?cke WD,H?flich C,Davis KA,et al.Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression:a multicenter standardized study[J].Clin Chem,2005,51(12):2341-2347
23 Wu JF,Ma J,Chen J,et al.Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis[J].Crit Care,2011,15:R220
24 Xiao W,Mindrinos MN,Seok J,et al.A genomic storm in criticallyinjured humans[J].J Exp Med,2011,208(13):2581-2590
25刘军.对全身性感染免疫与炎症关系的思考[J].中华急诊医学杂志,2017,26(11):1230-1235
26颜景旺,邓勇,樊海宁.脓毒症中细胞因子的研究进展[J].中国现代医药杂志,2010,12(4):125-126
27 Osuchowski MF,Welch K,Siddiqui J,et al.Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARScontinuum in sepsis and predict mortality[J].J Immunol,2006,177(3):1967-1974
28 Yumin L,Hao C,Xun L,et al.A new immunomodulatory therapy for severe sepsis:Ulinastatin Plus Thymosinα1[J].J Intensive Care Med,2009,24:47-53
29 Liu F,Wang HM,Wang T,et al.The efficacy of thymosinα1as immunomodulatory treatment for sepsis:a systematic review of randomized controlled trials[J].BMC Infectious Diseases,2016,16:488
2 Dellinger RP,Levy MM,Rhodes A,et al.Surviving sepsis campaign:international guidelines for management severe sepsis and septic shock,2012[J].Intensive Care Medicine,2013,39(2):165-228
3师灵灵,韩艳秋,任慧娟,等.脓毒症的病理生理机制研究进展[J].中华医院感染学杂志,2016,26(8):1914-1916
4 Miksa M,Wu R,Zhou M,et al.Sympathetic excitotoxicity in sepsis:pro-inflammatory priming of macrophages by norepinephrine[J].Front Biosci,2005,10:2217-2229
5 Wang H,Yu M,Ochani M,et al.Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation[J].Nature,2003,421(6921):384-388
6 Vizi ES,Elenkov IJ.Nonsynaptic noradrenaline release in neuroimmune responses[J].Acta Biol Hung,2002,53(1-2):229-244
7 Yang S,Koo DJ,Zhou M,et al.Gut-derived norepinephrine plays a critical role in producing hepatocellular dysfunction during early sepsis[J].Am J Physiol Gastrointest Liver Physiol,2000,279(6):G1274-1281
8曹新营,王志军,杨文琦,等.卡维地洛对CHF病人细胞免疫功能及临床疗效的影响[J].中西医结合心脑血管病杂志,2017,15(16):2010-2012
9俞杨,田金徽,杨克虎,等.胸腺肽α1治疗脓毒症的系统评价[J].中国危重病急救医学,2009,21(1):21-24
10黎丽芬,蔡常洁,唐朝霞,等.胸腺肽α1对脓毒症大鼠模型的Th17和Treg淋巴细胞功能性极化的效应研究[J].中华重症医学电子杂志,2018,4(1):42-50
11徐叔云,卞如濂,陈修.药理实验方法学[M].3版.北京:人民卫生出版社,2001:202-204
12 Pinsky MR.Dysregulation of the immune response in severe sepsis[J].Am J Med Sci,2004,328(4):220-229
13 Wilson J.Early propranolol treatment induces lung hemeoxygenase-1,attenuates metabolic dysfunction,and improves survival following experimental sepsis[J].Crit Care,2013,17(5):R195
14张廉君.β受体阻滞剂在脓毒性休克中的应用研究进展[J].西南军医,2015,17(5):546-548
15 Macchia A,Romero M,Comignani PD,et al.Previous prescription ofβ-blockers is associated with reduced mortality among patients hospitalized in intensive care units for sepsis[J].Crit Care Med,2012,40(10):2768-2772
16 Christensen S,Johansen MB,Tonnesen E,et al.Preadmissionβ-blocker use and 30-day mortality among patients in intensive care:a cohort study[J].Crit Care,2011,15(2):R87
17 Jeschke MG,Finnerty CC,Kulp GA,et al.Combination of recombinant human growth hormone and propranolol decrease hypermetabolism and inflammation in severely burned children[J].Pediatr Crit Care Med,2008,9(2):209-216
18 Huston JM.The vagus nerve and the inflammatory reflex:wandering on a new treatment paradigm for systemic inflammation and sepsis[J].Surg Infect,2012,13(4):187-193
19 Stanojevie S,Dimitrijevie M,Kustrimovic NA,et al.Adrenal hormone deprivation affects maerophage catecholamine metabolism andβ2-adrenoceptor density,but not propranolol stimulation of tumour necrosis factor-alpha production[J].Exp Physiol,2013,98(3):665-678
20陈军喜,孙坚,管细红,等.早期脓毒症大鼠心脏变化特点及卡维地洛预先干预作用的实验研究[J].安徽医科大学学报,2015,50(10):1430-1433
21 Sáenz JJ,Izura JJ,Manrique A,et al.Early prognosis in severe sepsis via analyzing the monocyte immunophenotype[J].Intensive Care Med,2001,27:970-977
22 D?cke WD,H?flich C,Davis KA,et al.Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression:a multicenter standardized study[J].Clin Chem,2005,51(12):2341-2347
23 Wu JF,Ma J,Chen J,et al.Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis[J].Crit Care,2011,15:R220
24 Xiao W,Mindrinos MN,Seok J,et al.A genomic storm in criticallyinjured humans[J].J Exp Med,2011,208(13):2581-2590
25刘军.对全身性感染免疫与炎症关系的思考[J].中华急诊医学杂志,2017,26(11):1230-1235
26颜景旺,邓勇,樊海宁.脓毒症中细胞因子的研究进展[J].中国现代医药杂志,2010,12(4):125-126
27 Osuchowski MF,Welch K,Siddiqui J,et al.Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARScontinuum in sepsis and predict mortality[J].J Immunol,2006,177(3):1967-1974
28 Yumin L,Hao C,Xun L,et al.A new immunomodulatory therapy for severe sepsis:Ulinastatin Plus Thymosinα1[J].J Intensive Care Med,2009,24:47-53
29 Liu F,Wang HM,Wang T,et al.The efficacy of thymosinα1as immunomodulatory treatment for sepsis:a systematic review of randomized controlled trials[J].BMC Infectious Diseases,2016,16:488