摘要
本试验将分离自乳腺炎病牛乳汁的金黄色葡萄球菌和无乳链球菌制成细菌悬液,通过乳头管将细菌悬液注入泌乳母鼠乳池内,诱发小鼠乳腺炎。在建立小鼠乳腺炎模型的基础上,通过细菌计数、组织学、组织化学、免疫组化染色技术及酶联免疫吸附试验(ELISA)等方法研究了乳腺炎模型中金黄色葡萄球菌和无乳链球菌混合感染诱发的乳腺免疫应答,初步探索了优得乐对乳腺炎的治疗效果,为研究开发天然药物防治奶牛乳腺炎提供了新的思路和方法。
研究结果显示:模型组母鼠乳腺内的细菌数在攻菌后24h达到峰值(7.66±0.13lgCFU/g乳腺组织),随后逐渐下降。模型组乳腺组织在攻菌后12h出现明显脂肪变性,并随感染时间延长有加重趋势,并在攻菌后24h形成标准乳腺炎模型,出现大量中性粒细胞浸润、充血、腺上皮细胞坏死等病理变化。模型组肥大细胞数和脱颗粒肥大细胞数在攻菌后的各时间点都极显著多于生理盐水组(P<0.01)。肥大细胞总数和脱颗粒肥大细胞数随感染时间延长呈增多趋势。模型组诱导型一氧化氮合酶和3-硝基酪氨酸阳性表达随感染时间延长逐渐增多,在攻菌后48h显著增多。模型组TNF-α和IFN-γ水平在攻菌后6h达到峰值,随后逐渐降低,在攻菌后36h降致最低点,随后升高,到攻菌后72h达到峰值,随后降低。模型组IL-4水平在攻菌后24h达到峰值,在攻菌后36h下降,随后升高,在攻菌后48h达到峰值,随后降低。
治疗组乳腺内细菌数在攻菌后12h~5d均显著低于模型组(P<0.05),治疗组中性粒细胞减少,充血不明显,病理变化减轻。治疗组脱颗粒肥大细胞数在攻菌后18h,24h,36h,48h,比模型组极显著减少(P<0.01),提示优得乐能够稳定肥大细胞膜抑制其脱颗粒减少炎性介质的释放。和模型组相比,治疗组诱导型一氧化氮合酶和3-硝基酪氨酸阳性表达显著减少,表明优得乐能够抑制一氧化氮的过渡产生,减轻乳腺组织炎症的发展。治疗组TNF-α水平在感染后48h,72h,5d极显著低于模型组(P<0.01);治疗组IFN-γ水平在感染后36h~5d极显著高于模型组(P<0.01);治疗组IL-4水平在感染后24h~5d极显著低于模型组(P<0.01);表明优得乐能够有效降低乳腺中TNF-α和IL-4的水平,升高IFN-γ的水平,通过对细胞因子的调节,达到治愈炎症的目的。
结论:优得乐能够明显抑制金黄色葡萄球菌和无乳链球菌在小鼠乳腺内的增殖;优得乐可明显减轻小鼠金黄色葡萄球菌和无乳链球菌混合感染小鼠乳腺炎的病理反应;优得乐能显著降低诱导型一氧化氮合酶和3-硝基酪氨酸在乳腺组织中的表达,通过调节TNF-α,IFN-γ和IL-4等细胞因子的水平来减轻乳腺局部的炎症;优得乐对小鼠实验性乳腺炎具有良好的治疗作用,为临床治疗奶牛乳腺炎新药的筛选提供了一条新的思路和途径。
A strain of Staphylococcus aureus and Group B Streptococcus were isolated from the milk of dairy cows suffering from clinical mastitis. Lactating mice were challenged by inoculation of Staphylococcus aureus and Group B Streptococcus suspension through the teat canal to develop mastitis model. The immune response of mammary glands triggered by Staphylococcus aureus and Group B Streptococcus infection and the effect of Youdele on mastitis were studied through CFU counts, histological, histochemical, immunohistochemical techniques and ELISA. The results of this study provided a new idea and way to study natural medicine to treat bovine mastitis.
The results show that a peak of colonization in mammary glands (7.66±0.13 lgCFU/g mammary gland tissues) was observed at 24h after challenge and the bacterial number decreased after 24h. The steatosis was investigated at 12h post-challenge and pathology of mammary glands became more serious with the development of mammary infection. Mouse mastitis model was developed at 24h after inoculation of bacteria. It was clearly shown that neutrophils heavily occupied the dilated alveoli. The interlobular blood vessels were characteristic of congestion and the epithelial cells of some alveoli displayed markedly necrotic feature. A significant increase (P<0.01) in the number of mast cells and degranulated mast cells was detected in mammary glands of the model mice compared to the control mice at the indicated timepoints. The number of mast cells and degranulated mast cells increased with the progress of infection. The positive staining intensity of both inducible NO synthase (iNOS) and 3-nitrotynosine (3-NT) increased with the progress of infection and had a significant difference compared to the control group at 48h post-challange. The contents of TNF-αand IFN-γin mammary glands of the model group reached the maxlmum at 6h post-challange and decreased at the mininum 36 h post-challange. Both of them increased at 48h post-challange and reached the maxlmum at 72 h post-challange and degraded at the last time. The content of IL-4 creased the maxlmum at 24h, and degraded the mininum at 36h post-challange. It reached the maxlmum at 48h post-challange second time and increased at the last time.
A significant decrease (P<0.05) in the number of bacteria was detected in mammary glands of the treated group mice compared to the model group mice at 12 h~5d post-challenge. The inflammation of mammary glands in treated group appeared to be alleviated. The neutrophil infiltration and congestion of some lobular vessels dramatically reduced in thetreated group. A significant decrease (P<0.01) in the number of degranulated mast cells was detected in mammary gland from the treated group mice compared to the model group mice at 18h,24h,36h,48h, post-challenge. It suggested that Youdele could inhibit the degranulation of mast cells, reduce inflmmatory mediators and block excessive inflammation. Compared to the model group mice, the positive staining intensity of iNOS and 3-NT of the treated group decreased. The mammary immunity of the treated group was enhanced due to the decrease of the level of NO. The contents of TNF-αin mammary gland from the treated group were lower than that in model group at 48h,72h,5d ( P<0.01). The contents of IFN-γin mammary gland from the treating group was significantly higher than that in the model group at 36h~5d post-challenge (P<0.01). The IL-4 levels of treat group were significantly lower than those in the mastitis model group at 24h~5d post-challenge (P<0.01).It is show that Youdele could treat the inflammation through degrade the TNF-α, IL-4 levels and heighten the contents of IFN-γ.
Conclusion: Youdele could inhibit bacterial proliferation in mammary glands of model mice. Youdele could improve mammary immunity and reduce mammary inflammation through modulating the secretions of TNF-α, IFN-γ, and IL-4 in mice mastitis model and inhibiting the number of degranulated mast cells. It could also alleviate pathological response and inflammatory symptom of mastitis caused by Staphylococcus aureus and Group B Streptococcus apparently. Youdele could reduce the expression of the iNOS and 3-NT in the mammary gland. Thus, it plays a protective role on experimental mouse mastitis caused by S. aureus and GBS. This data provide a new strategy for the therapy of bovine mastitis.
引文
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