甘草甜素对人工诱导小鼠乳腺炎的免疫保护效应研究
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摘要
奶牛乳腺炎至今不仅对奶牛业造成严重的经济损失，而且由于治疗过程中抗生素的广泛应用，给人类的健康带来严重的、现实的和潜在的危害。为了进一步认识奶牛乳腺炎发生的免疫病理机制和寻找更理想的防治方法提供基础研究数据，本试验对保定地区5个奶牛场临床型奶牛乳腺炎的病原进行了分离鉴定；并用分离到的金黄色葡萄球菌建立了小鼠实验性乳腺炎模型，观察和分析了乳腺炎模型的局部及整体的临床表现和免疫病理变化；探讨了甘草甜素对小鼠实验性乳腺炎，乳腺局部和整体病理机制及免疫功能的影响。结果表明：将43份临床型乳腺炎奶样进行细菌分离鉴定，生化结果表明共分离到10种91株细菌，以金黄色葡萄球菌(21.98％)、链球菌(19.78％)、大肠杆菌(19.78％)感染为主。小鼠实验性乳腺炎模型，以细菌菌落数(Colony-Forming Units，CFU)为接菌单位，将雌孕鼠分为正常对照组、生理盐水组及1.0×10~2CFU／50μL、4.0×10~2CFU／50μL、7.0×10~2CFU／50μL、1.0×10~3CFU／50μL、1.0×10~4CFU／50μL不同浓度金黄色葡萄球菌悬液组，产后8～10d经乳头管注入到小鼠的第4对(腹部)乳腺内，24h观察炎症反应。结果7.0×10~2CFU／50μL金葡菌组乳腺上皮脱落，腺泡腔内大量炎性细胞浸润，以嗜中性白细胞为主，充血，腺泡内空泡减少，腺泡分泌量减少，间隔增宽，炎症明显。而随着金黄色葡萄球菌用量的加大，乳腺组织的炎症程度加剧。间质宽度、TNF-α及IFN-γ含量与对照组相比极显著升高(P＜0.01)，金葡菌在乳腺组织内大量繁殖，CFU急剧增加。小鼠体温升高、临床表现等全身症状以及病理变化真实反映了急性乳腺炎自然发病过程，因此选择7.0×10~2CFU／50μL金葡菌继续下面的试验。甘草甜素对小鼠实验性乳腺炎的影响，将受孕雌鼠随机分成正常对照组、阳性对照组和试验组。正常对照组于产后8～10d经乳头管注入50μL灭菌生理盐水；阳性对照组和试验组小鼠分别于产后8～10d经乳头管注入50μL7.0×10~2CFU细菌悬液人工发病。分别于接菌-12h、0h、12h、36h时，正常对照组和阳性对照组腹腔注射灭菌生理盐水0.2mL，试验组分成3个剂量组，将甘草甜素分别配制成2.2 mg／mL、4.4 mg／mL、8.8 mg／mL三个剂量，分别腹腔注射甘草甜素溶液0.2mL。分别于接菌后6h、18h、42h、66h脱颈致死。取乳腺组织固定，进行组织病理学观察及间质宽度的测定，甲苯胺蓝染色观察乳腺肥大细胞的变化，取乳腺匀浆液，用酶联免疫吸附试验(ELISA)法检测TNF-α及IFN-γ含量变化。结果甘草甜素各组小鼠精神状态良好、体温平稳，能够抑制金葡菌在乳腺组织内繁殖，显著降低CFU(P＜0.01)，因而减少了对乳腺组织的刺激，病理变化减轻，间质宽度缩小，充血减轻。甘草甜素不同剂量组肥大细胞数在感染6～42h与生理盐水组、阳性对照组相比无统计学差异(P＞0.05)，且组间无差异性(P＞0.05)，但甘草甜素组脱颗粒肥大细胞少于阳性对照组，数据表明甘草甜素能够很好地抑制肥大细胞脱颗粒。ELISA试验结果显示甘草甜素显著降低乳腺内TNF-α和IFN-γ的浓度，且呈剂量依赖性，但高于正常对照组。甘草甜素调节乳腺内TNF-α和IFN-γ水平在一定范围内，即参与机体免疫反应又控制组织的过度炎症。结论：保定地区5个奶牛场临床型乳腺炎其病原体以金黄色葡萄球菌、链球菌、大肠杆菌感染为主；用金黄色葡萄球菌建立的小鼠实验性乳腺炎模型其局部等症状和病理机制与自然感染的乳腺炎炎症病理过程类同，可以用做乳腺炎的免疫病理学和筛选有效药物使用；甘草甜素对小鼠实验性乳腺炎有一定的保护和免疫调节作用。
Bovine mastitis not only caused severe economic loss in dairy herds, but also brought serious and potential damage for humans healthy because antibiotics was widely used during therapy. In order to further know immunopathology and look for more ideal method to provide basic data.This study investigated the pathogens from five clinical mastitis farms in Baoding area;the mice experimental mastitis model induced by Staphylococcus aureus was established, local and body symptoms,immunopathology were observed;the effect of GL on the pathological mechanism and immune function was discussed when mice experimental mastitis.The pathogens of forty three milk samples from clinical dairy mastitis were isolated and indentified by biochemical method. It showed that there were ninety-one strains,ten species,most of them were Staphylococcus aureus (21.98%),Streptococcus (19.78%)and Escherichia coli (19.78%) .The pregnant BALB/C female mice were randomly divided into nomal control group,sterile physiological saline solution (PSS) group and 1.0×10~2CFU/50μL,4.0×10~2CFU/50μL,7.0×10~2CFU/50μL, 1.0×10~3CFU/ 50μL,1.0×10~4CFU/50μL of Staphylococcus aureus groups.Either PSS or Staphylococcus aureus 50μL was inoculated into the fourth abdominal mammary gland via the teatduct 8～10d after parturition, inflammation reaction was observed on 24 hours later. Histopathologic examination of mammary gland revealed that polymorphonuclear neutrophils(PMN) and exfoliated epithelial cells in 7.0×10~2CFU/50μL Staphylococcus aureus group were found in alveoli Cases , vacuole and secretion of alveoli Cases were decreased, the interval width increased, inflammation of the mammary gland was significant. The interstitial width, the concentrations of TNF-α,IFN-γin mammary gland increased significantly (P＜0.01) compared with those of nomal control group, Staphylococcus aureus was reproduced in mammary gland and CFU was rapidly increased.The spontaneous diseased process of acute mastitis was factually reflected by body symptoms and pathological changes. Based on above results, the experimental mastitis model by 7.0×10~2CFU/50μL Staphylococcus aureus via teat duct in mice were established successfully. The pregnant BALB/C female mice were randomly divided into nomal control group,positive control group and experimental groups, and inoculated into the fourth abdominal mammary gland via the teatduct with 50μL 7.0×10~2CFU Staphylococcus aureus 8～10d after parturition. Then the mice administrated orally on-12,0,12,36 hours after intraperitoneal injection with different dosage of Glycyrrhizin (2.2mg/mL,4.4 mg/mL,8.8 mg/mL)or sterile physiological saline solution 0.2mL.The mice were sacrificed by cervical dislocation 6,18,42,66 hours later.The mammary lysate was collected. The contents of TNF-αand IFN-γwere assayed through ELISA. The mammary glands were fixed for histopathologic evaluations, the interval width. The number and distribution change of Mast Cell in mammary gland were observed by improved toluidine dye method.Good psychosis, balanced temperature and CFU of Glycyrrhizin groups decreased remarkably compared with those of positive control group (P＜0.01) .Histopathological findings showed that tissue scathe,pathological changes,interstitial width were mitigated. In comparison with those of PSS and PC groups, there were no significant difference among different dosages of GL groups (P＞0.05 ). The data indicated that GL could inhibit degranulating. ELISA results showed that TNF-αand IFN-γconcentration were significantly reduced by GL and depended on dosages, but were higher than that of normal control group.GL modulated the range of TNF-αand IFN-γin a normal level, not only concerned with immunoreaction but also controled severe inflammation. Conclusion: The incidence of Staphylococcus aureus, Streptococcus uberis and Escherichia coli isolated from five clinical mastitis farms in Baoding area were high. The body symptoms and pathological mechanism of the mice experimental mastitis induced by Staphylococcus aureus were same as pathology in normal bovine mastitis, the model could be used for immunopathologic and drug selection. The GL had protective and immunoregulatable effect on the mice experimental mastitis.
Bovine mastitis not only caused severe economic loss in dairy herds, but also brought serious and potential damage for humans healthy because antibiotics was widely used during therapy. In order to further know immunopathology and look for more ideal method to provide basic data.This study investigated the pathogens from five clinical mastitis farms in Baoding area;the mice experimental mastitis model induced by Staphylococcus aureus was established, local and body symptoms,immunopathology were observed;the effect of GL on the pathological mechanism and immune function was discussed when mice experimental mastitis.The pathogens of forty three milk samples from clinical dairy mastitis were isolated and indentified by biochemical method. It showed that there were ninety-one strains,ten species,most of them were Staphylococcus aureus (21.98%),Streptococcus (19.78%)and Escherichia coli (19.78%) .The pregnant BALB/C female mice were randomly divided into nomal control group,sterile physiological saline solution (PSS) group and 1.0×10~2CFU/50μL,4.0×10~2CFU/50μL,7.0×10~2CFU/50μL, 1.0×10~3CFU/ 50μL,1.0×10~4CFU/50μL of Staphylococcus aureus groups.Either PSS or Staphylococcus aureus 50μL was inoculated into the fourth abdominal mammary gland via the teatduct 8～10d after parturition, inflammation reaction was observed on 24 hours later. Histopathologic examination of mammary gland revealed that polymorphonuclear neutrophils(PMN) and exfoliated epithelial cells in 7.0×10~2CFU/50μL Staphylococcus aureus group were found in alveoli Cases , vacuole and secretion of alveoli Cases were decreased, the interval width increased, inflammation of the mammary gland was significant. The interstitial width, the concentrations of TNF-α,IFN-γin mammary gland increased significantly (P＜0.01) compared with those of nomal control group, Staphylococcus aureus was reproduced in mammary gland and CFU was rapidly increased.The spontaneous diseased process of acute mastitis was factually reflected by body symptoms and pathological changes. Based on above results, the experimental mastitis model by 7.0×10~2CFU/50μL Staphylococcus aureus via teat duct in mice were established successfully. The pregnant BALB/C female mice were randomly divided into nomal control group,positive control group and experimental groups, and inoculated into the fourth abdominal mammary gland via the teatduct with 50μL 7.0×10~2CFU Staphylococcus aureus 8～10d after parturition. Then the mice administrated orally on-12,0,12,36 hours after intraperitoneal injection with different dosage of Glycyrrhizin (2.2mg/mL,4.4 mg/mL,8.8 mg/mL)or sterile physiological saline solution 0.2mL.The mice were sacrificed by cervical dislocation 6,18,42,66 hours later.The mammary lysate was collected. The contents of TNF-αand IFN-γwere assayed through ELISA. The mammary glands were fixed for histopathologic evaluations, the interval width. The number and distribution change of Mast Cell in mammary gland were observed by improved toluidine dye method.Good psychosis, balanced temperature and CFU of Glycyrrhizin groups decreased remarkably compared with those of positive control group (P＜0.01) .Histopathological findings showed that tissue scathe,pathological changes,interstitial width were mitigated. In comparison with those of PSS and PC groups, there were no significant difference among different dosages of GL groups (P＞0.05 ). The data indicated that GL could inhibit degranulating. ELISA results showed that TNF-αand IFN-γconcentration were significantly reduced by GL and depended on dosages, but were higher than that of normal control group.GL modulated the range of TNF-αand IFN-γin a normal level, not only concerned with immunoreaction but also controled severe inflammation. Conclusion: The incidence of Staphylococcus aureus, Streptococcus uberis and Escherichia coli isolated from five clinical mastitis farms in Baoding area were high. The body symptoms and pathological mechanism of the mice experimental mastitis induced by Staphylococcus aureus were same as pathology in normal bovine mastitis, the model could be used for immunopathologic and drug selection. The GL had protective and immunoregulatable effect on the mice experimental mastitis.
引文
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