卡介菌多糖核酸（BCG-PSN）对内毒素（LPS）诱发实验性乳腺炎影响的研究
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摘要
本研究首先以山羊为实验动物,利用LPS诱发山羊乳腺炎症,研究BCG-PSN对其乳腺防御系统的影响和保护作用;然后在LPS诱发的大鼠实验性乳腺炎模型上深入揭示BCG-PSN通过免疫调理作用,激活动物乳腺防御体系,保护乳腺的作用机理;并在体外初步研究了BCG-PSN对泌乳奶牛外周血嗜中性粒细胞(PMN)功能的影响.
结果如下:
1内毒素对山羊乳腺中炎症相关因子活性的影响
8只泌乳初期的健康睢宁白山羊,产后72 h分别用LPS(实验组)和灭菌生理盐水(对照组)经乳头管灌注左、右侧乳区.灌注前及灌注后1、2、3、4、5、6、7、8、9、24 h观察山羊全身及乳腺局部变化.灌注24 h后,处死动物,取乳腺组织,部分用Bouin氏液固定,部分-70℃保存.临床症状及病理切片观察均显示,山羊表现出典型的急性乳腺炎症状.检测乳腺组织中部分炎症相关因子的含量及基因表达水平,结果显示,与对照组相比,实验组N-乙酰-β-D-氨基葡萄糖苷酶(N-Acetyl-β-D-glucosaminidase,NAGase)、髓过氧化物酶(myeloperoxidase,MPO)、诱导型一氧化氮合成酶(inducible nitric oxide synthase,iNOs)活性及肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素-1β(interleukin-1β,IL-1β)及白细胞介素-6(interleukin-6,IL-6)的含量显著升高(P＜0.01);相同条件下对两种处理组织样中三种细胞因子mRNA表达水平进行PCR扩增,实验组能检测到明显的目的条带,而对照侧未见明显目的条带。提示LPS灌注引起的乳腺组织中炎性细胞因子及炎症相关酶的过度释放是造成山羊乳腺损伤的原因.
2卡介菌多糖核酸对实验性乳腺炎山羊乳腺组织的保护研究
泌乳初期健康睢宁白山羊6只,左乳区(实验组)经乳头管灌注卡介菌多糖核酸(polysaccharide nucleic acid of Bacillus Guerin,BCG-PSN)5 mL,右乳区(对照组)灌入等量生理盐水作为对照,连灌6天.第7天按50μg/kg体重分别向左、右乳区灌注LPS.灌注前及灌注后1、2、3、4、5、6、7、8、9,24 h观察山羊全身及乳腺局部变化。灌注24h后,处死动物,取乳腺组织,部分用Bouin氏液固定、部分-70℃保存.临床症状及病理切片观察均显示,山羊表现典型的急性乳腺炎症状.与对照组相比,乳腺灌注BCG-PSN能显著降低乳腺组织中部分炎症相关因子的含量及其基因表达水平.其中NAGase、MPO、iNOs活性显著降低(P＜0.05);TNF-α、IL-1β的含量及其mRNA表达水平均显著降低(P＜0.05),IL-6的含量显著降低(P＜0.05),其mRNA表达水平有所降低但差异不显著(P＞0.05).实验结果表明,灌注BCG-PSN可以抑制乳腺组织内TNF-α、IL-1β等炎性细胞因子及炎症相关酶的过度释放、减轻炎症因子对乳腺组织的损伤,对LPS诱发山羊乳腺炎有一定的保护作用.
3卡介菌多糖核酸对实验性乳腺炎大鼠乳腺组织的保护研究
为探讨BCG-PSN对LPS诱导实验性动物乳腺炎的保护机制,72只清洁级SD大鼠被随机分成实验组和对照组(n=36)。确定怀孕14 d起,隔日左后腿胫骨前肌肌内注射BCG-PSN(实验组)或灭菌生理盐水(对照组)0.33 ml/只,连续五次;产后72h经乳头管灌注LPS 10μg/侧到第四对乳腺(两侧)内.分别于灌注前(定义为0 h)及灌注后3、6、9、12和24 h(n=6)颈静脉放血处死动物,采集样品.组织病理学观察显示,BCG-PSN加快了LPS诱发炎症的组织修复进程,促进了炎症后期泌乳量的恢复。酶活性检测结果显示,NAGase、iNOs活性在乳腺组织中和血清中变化规律相反;组织中两种酶活性,实验组和对照组均分别在6 h、9 h达到最高,血清中NAGase活性实验组12 h、对照组9 h最低,iNO活性分别在6 h、3h最低.放射免疫检测结果显示,同对照组相比,BCG-PSN使乳腺组织中炎症相关细胞因子TNF-α、IL-1β及IL-6的峰值降低,出峰时间前提,而血清中这三种细胞因子均未表现出明显的变化.定量RT-PCR结果显示,BCG-PSN能降低乳腺组织中Toll样受体-4(toll-likereceptor-4,TLR-4)mRNA表达水平,实验组与对照组相比,第6、9、24 h差异显著,实验结果说明,BCG-PSN可以通过降低TLR-4的表达,抑制炎性细胞因子及酶的过度分泌,从而缓解LPS及相关因子对乳腺组织的损伤,达到保护乳腺的目的.
4卡介菌多糖核酸对实验性乳腺炎大鼠的免疫调节机理研究
为探讨BCG-PSN对LPS诱导的实验性乳腺炎大鼠免疫功能的调节机理,72只清洁级SD大鼠被随机分成实验组和对照组(n=36).确定怀孕14天起,隔日左后腿胫骨前肌肌内注射BCG-PSN(实验组)或灭菌生理盐水(对照组)0.33ml/只,连续五次;产后72h经乳头管灌注LPS 10μg/侧到第四对乳腺(两侧)内.分别于灌注前(定义为0 h)及灌注后3、6、9、12和24 h(n=6)颈静脉放血处死动物,采集样品。PMN标志酶MPO活性检测结果显示,乳腺组织中MPO活性实验组在第6 h达到高峰,而对照组一直到24 h仍维持较高水平,和对照组相比,BCG-PSN显著降低了12、24 hMPO的活性;血清中MPO活性12 h最低。灌注后,组织中白细胞介素-2(interleukin-2,IL-2)含量迅速升高,实验组和对照组均在24 h达到峰值,同灌注前相比差异显著;实验组在0和24 h显著高于对照组。流式细胞检测结果显示,BCG-PSN在一定程度上提高了0 h外周血中细胞毒性T淋巴细胞(CD8+)细胞数量;同0 h相比,对照组在24 h CD4+/CD3+显著下降,CD8+/CD3+显著升高,因而CD4+/CD8+显著下降;而实验组无明显变化。定量RT-PCR结果显示,IL-2和干扰素-γ(interferon-γ,INF-γ)mRNA表达,实验组和对照组表现出相同的变化规律,LPS灌注后上升,后有所恢复;白细胞介素-4(interleukin-4,IL-4)mRNA表达实验组和对照组表现出不同的变化规律,对照组,同0 h相比,第3、6 h显著下降,然后恢复到正常的水平,实验组第3 h显著高于0 h而后迅速下降,其中第9 h降低明显;BCG-PSN抑制了INF-γ/IL-4 mRNA表达相对比值的升高.实验结果表明,BCG-PSN在炎症初期加快了PMN向乳腺内迁徙,而在炎症后期促进了机体对PMN的清除;在乳腺灌注LPS后抑制了CD4+/CD8+比值的下降,INF-γ/IL-4 mRNA表达相对比值的升高,维持了T淋巴细胞各亚群数量与功能的平衡.提示BCG-PSN可以通过调节大鼠乳腺防御系统内的特异性及非特异性免疫因子,对乳腺产生保护.
5卡介菌多糖核酸对泌乳奶牛外周血PMN吞噬功能及活性氧释放的影响
为探讨BCG-PSN对泌乳奶牛外周血PMN吞噬功能及活性氧(reactive oxygenspecies,ROS)释放的影响,选取处于泌乳初期的健康奶牛,无菌采集颈静脉血,肝素抗凝.(1)不同浓度的BCG-PSN(终浓度分别为0、2、5、10、40、80μg/mL)与全血共孵育2 h,加入FITC标记的大肠杆菌悬液10μL,37℃20min后,放入冰水中终止吞噬反应;溶血素裂解红细胞,0.01mol/L、pH7.2 PBS洗涤两次,重悬后FL1通道检测PMN对大肠杆菌的吞噬率.(2)不同浓度的BCG-PSN(终浓度分别为0、2、5、10、40、80μg/mL)与全血共孵育2 h后,加入乙酸肉豆蔻佛波酯(phorbol myrisateacetate,PMA)刺激PMN,其中PMA刺激的终浓度为100ng/mL,同时每个浓度梯度设无PMA刺激对照(等量PBS代替PMA);37℃作用15min后加入双氢罗丹明123(dihydrorhodamine 123,DHR 123),终浓度为5μM,然后37℃孵育10min;溶血素裂解红细胞,0.01mol/L、pH7.2 PBS洗涤两次,多聚甲醛固定、重悬后流式细胞仪检测.实验结果显示,BCG-PSN可以降低PMA刺激引起的PMN的ROS的大量释放,且这种抑制呈剂量依赖性降低;而对PMN的吞噬功能没有明显的影响.结果说明BCG-PSN对PMN功能的影响不是通过直接影响其吞噬功能发挥作用;而降低炎症反应时PMN氧自由基的过度产生是BCG-PSN减轻机体炎症反应的原因之一.提示,BCG-PSN对奶牛乳腺炎的免疫生理调控有潜在的应用价值.
综上所述,BCG-PSN通过调节乳腺防御系统内的特异性与非特异性防御因素、TLR-4及相关炎性因子,减轻LPS诱导造成的乳腺组织损伤。本研究证实,BCG-PSN作为免疫生理调节剂在动物乳腺炎防控中有潜在的应用前景
In this study,effects of BCG-PSN on mammary defense and protective effects of BCG-PSN on mammary gland were first evaluated by experimental mastitis induced by LPS in goats.Then,the mechanism by which BCG-PSN activated natural defense system was discussed in rat model.On the base of these,changes of PMN function were observed after co-incubation with BCG-PSN.The results as follows:
1 Effect of LPS on Inflammation Factors in Mammary Tissue of Goats Relating with Mastitis
Eight healthy Suining white goats at early stages of lactation were infused with endotoxin or lipopolysaccharide(LPS)(50μg/bwt) in the left half of the mammary gland and physiological saline was infused in the control contralateral half.At intervals of 0,1,2, 3,4,5,6,7,8,9 and 24 h after infusion,mediators of inflammation were measured and the degree of neutrophil(PMN) infiltration and clinical variables were recorded.After 24 h,the animals were euthanized and mammary tissue was collected.A section was fixed for histopathologic evaluation and the remaining tissue was stored at -70℃.Clinical and histopathologic examination indicated that infusion of LPS induced acute mastitis in left half of the mammary gland.Infusion of LPS significantly increased the activity of N-Acetyl-β-D-glucosaminidase(NAGase),myeloperoxidase(MPO) and inducible nitric oxide synthase(iNOs) and the concentration of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6)(P＜0.01).There was a general increase in the levels of mRNA cytokine expression,too.The result showed that over release of inflammatory factors may cause damage to mammary gland.
2 Protection of BCG-PSN to Mammary Tissue of Goat Experimental Mastitis
Six healthy Suining white goats at early stages of lactation were intramammary infused with BCG-PSN(5mL) in the left quarters and physiological saline(5mL) in the control contralateral quarters.The administration of polysaccharide nucleic acid of Bacillus Guerin (BCG-PSN) was carried out for six consecutive days.On the seventh day,the mammary quarters(both right and left) of the six(6) goats were infused with LPS(50μg/bwt).At varying intervals of 0,1,2,3,4,5,6,7,8,9 and 24 h before and after infusion inflammation was recorded.After 24 h,the animals were euthanized and mammary tissue was collected from the same position.A section was fixed for histopathological evaluations and the remaining tissue was stored at -70℃.Clinical and histopathological examinations indicated that infusion of LPS induced acute mastitis in both quarters.The results showed that infusion of BCG-PSN significantly reduced activity of NAGase,MPO,iNOS and the concentration of TNF-α,IL-1β,and IL-6(P＜0.05).There was a general reduction in the levels of mRNA cytokine expression(P＜0.05).These findings suggest that BCG-PSN inhibits release of inflammatory factors that cause damage to mammary epithelial cells during mastitis infections in goats.
3 Protection of BCG-PSN to Mammary Tissue of Rat Experimental Mastitis
The aim of this study was to evaluate in rats,protection of BCG-PSN to mammary tissue of rat experimental mastitis.Seventy-two lactating SD rats were randomly divided into control and treatment group(n=36).BCG-PSN(treatment group,TG) or sterile pyrogen-free physiological saline(control group,CG) 0.33ml were injected into the left tibialis anterior muscle of rats 14 days after conception.The administration was repeated for five consecutive times every other day.Seventy-two hours after parturition,30 rats of each group were inoculated with 10μg Escherichia coli LPS dissolved in 100μL physiological saline into the left 4(L4) and right 4(R4) mammary glands and six as control. Just before the inoculation(control group defined as 0 h) and at 3,6,9,12 and 24 h after inoculation six rats at every time point were euthanatized and samples were collected.The histopathological observation indicated that treatment with BCG-PSN made a rapid renovation of mammary tissue compared with CG.Milk secretion elevated with an increasing of the luminal spaces with milk at the later stage of inflammation in TG.In mammary tissue,both NAGase and iNOs peaked at 6 h in TG and 9 h in CG,whereas serum NAGase reached nadir level at 12 h PI in TG and 9 h PI in CG,and serum iNOs reached nadir level at 6 h and 3 h PI respectively.Administration BCG-PSN reduced the peak level of TNF-α,IL-1βand IL-6 in mammary tissue compared with CG,whereas no significant changes were observed in serum after LPS challenge.RT-PCR analysis showed that BCG-PSN decreased the toll-like receptor-4(TLR-4) mRNA expression level from 3 h PI and significant reduction was observed at 6h,9 h and 24 h PI.These findings suggested that BCG-PSN has a general protective effect against LPS-induced local mammary injury by reducing TLR-4 mRNA expression level and further inhibiting the release of inflammatory factors that cause damage to mammary gland.
4 Immunoregulation of BCG-PSN to Rats of Experimental Mastiffs
The aim of this study was to evaluate in rats,immunoregulation of BCG-PSN to rats of experimental mastitis.Seventy-two lactating SD rats were randomly divided into control and treatment group(n=36).BCG-PSN(treatment group,TG) or sterile pyrogen-free physiological saline(control group,CG) 0.33ml were injected into the left tibialis anterior muscle of rats 14 days after conception.The administration was repeated for five consecutive times every other day.Seventy-two hours after parturition,30 rats of each group were inoculated with 10μg LPS dissolved in 100μL physiological saline into the left 4(L4) and right 4(R4) mammary glands and six as control.Just before the inoculation (control group defined as 0 h) and at 3,6,9,12 and 24 h after inoculation six rats at every time point were euthanatized and samples were collected.The results indicated that the concentrations of MPO in mammary tissue peaked at 6 h in TG,and in CG kept a high level until 24 h PI.Significant reduce of MPO was observed at 12 h and 24 h PI compared TG with CG.Serum MPO reached nadir at the same time(12 h after LPS challenge) both CG and TG.After LPS infusion,the concentrations of IL-2 increased dramatically and peaked at 24 h both CG and TG.BCG-PSN induced significant elevated of IL-2 at 0 h and 24 compared with control.Flow cytometfic analysis showed that,compared with control(0 h),the 24 h group exhibited a CD4+(T-helper) T cell decline,a CDS+(T-cytotoxic or T-suppressor) T cell increase,and decreased CD4/CD8 ratio in CG.No significant changes were observed in TG.The results of RT-PCR showed that in CG,the levels of IL-2,and INF-γmRNA expression increased,whereas IL-4 mRNA expression decreased after LPS challenged.As a consequence,the INF-γ/IL-4 mRNA radio was significant higher 3 h,6 h, and 9 h PI compared with normal value(0 h).BCG-PSN increased the mRNA expression both INF-γand IL-4 before infusion of LPS.After LPS challenged,significantly reduced Th1/Th2 cytokine radio was observed,because Th1 cytokine IFN-γwas suppressed and Th2 cytokine IL-4 was enhanced compared with CG.The study demonstrated that BCG-PSN may protect the mammary gland by improving the non-special and special immune factors of rats.
5 Effect of BCG-PSN on Phagocytosis and Generation of Reactive Oxygen Species of Lactating Cow Peripheral Blood PMN
The aim of this study was to evaluate in vitro,effect of BCG-PSN on phagocytosis and generation of reactive oxygen species(ROS) of lactating cow peripheral blood PMN. Peripheral blood of healthy lactation cow at early stages of lactation was collected from the jugular vein by venipuncture in evacuated tubes containing heparin as anticoagulant.(1) FITC-labeled E.coli 10μL was added to each sample after a 2 h co-incubation with different concentrations of BCG-PSN(final concentration 0、2、5、10、40、80μg/mL).After further 20 min incubation at 37℃,phagocytosis was stopped by dipping into ice water. Then erythrocytes were lysed with lysing solution and the leucocytes were washed two times with PBS(0.01mol/L,pH7.2).The cells were then resuspended in PBS and analyzed on a FACScan flow cytometer.FL1 green channel captured FITC fluorescence.(2) Phorbol myrisate acetate(PMA,final concentrationl00ng/mL) was used to stimulate PMN after a 2 h co-incubation with different concentrations of BCG-PSN(final concentration 0、2、5、10、40、80μg/mL).Control tests of every group were set up using PBS instead of PMA.All tubes were incubated at 37℃for 15 min and then working dihydrorhodamine 123(DHR 123,final concentration 5μM) solution was added.After further 10 min incubation at 37℃, erythrocytes were lysed with lysing solution.Then the leucocytes were washed two times with PBS(0.01mol/L,pH7.2) and stabilized by paraformaldehyde.The the cells were then resuspended in PBS and analyzed on a FACScan flow cytometer.The results showed that BCG-PSN could significant reduced the generation of reactive oxygen species of PMN and had no effect on the phagocytosis of PMN.This suggests that BCG-PSN protects the mammary gland from inflammatory injury by attenuating the release of ROS but not by directly phagocytosis.BCG-PSN may be a potential candidate to prevent bovine mastitis.
In conclusion,BCG-PSN may protect the mammary gland by modulating the secretion of non-special and special immune factors,down-regulating the expression of TLR-4 and inflammation mediator.The results suggest BCG-PSN can be used as a potential candidate to prevent mastitis.
结果如下:
1内毒素对山羊乳腺中炎症相关因子活性的影响
8只泌乳初期的健康睢宁白山羊,产后72 h分别用LPS(实验组)和灭菌生理盐水(对照组)经乳头管灌注左、右侧乳区.灌注前及灌注后1、2、3、4、5、6、7、8、9、24 h观察山羊全身及乳腺局部变化.灌注24 h后,处死动物,取乳腺组织,部分用Bouin氏液固定,部分-70℃保存.临床症状及病理切片观察均显示,山羊表现出典型的急性乳腺炎症状.检测乳腺组织中部分炎症相关因子的含量及基因表达水平,结果显示,与对照组相比,实验组N-乙酰-β-D-氨基葡萄糖苷酶(N-Acetyl-β-D-glucosaminidase,NAGase)、髓过氧化物酶(myeloperoxidase,MPO)、诱导型一氧化氮合成酶(inducible nitric oxide synthase,iNOs)活性及肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素-1β(interleukin-1β,IL-1β)及白细胞介素-6(interleukin-6,IL-6)的含量显著升高(P＜0.01);相同条件下对两种处理组织样中三种细胞因子mRNA表达水平进行PCR扩增,实验组能检测到明显的目的条带,而对照侧未见明显目的条带。提示LPS灌注引起的乳腺组织中炎性细胞因子及炎症相关酶的过度释放是造成山羊乳腺损伤的原因.
2卡介菌多糖核酸对实验性乳腺炎山羊乳腺组织的保护研究
泌乳初期健康睢宁白山羊6只,左乳区(实验组)经乳头管灌注卡介菌多糖核酸(polysaccharide nucleic acid of Bacillus Guerin,BCG-PSN)5 mL,右乳区(对照组)灌入等量生理盐水作为对照,连灌6天.第7天按50μg/kg体重分别向左、右乳区灌注LPS.灌注前及灌注后1、2、3、4、5、6、7、8、9,24 h观察山羊全身及乳腺局部变化。灌注24h后,处死动物,取乳腺组织,部分用Bouin氏液固定、部分-70℃保存.临床症状及病理切片观察均显示,山羊表现典型的急性乳腺炎症状.与对照组相比,乳腺灌注BCG-PSN能显著降低乳腺组织中部分炎症相关因子的含量及其基因表达水平.其中NAGase、MPO、iNOs活性显著降低(P＜0.05);TNF-α、IL-1β的含量及其mRNA表达水平均显著降低(P＜0.05),IL-6的含量显著降低(P＜0.05),其mRNA表达水平有所降低但差异不显著(P＞0.05).实验结果表明,灌注BCG-PSN可以抑制乳腺组织内TNF-α、IL-1β等炎性细胞因子及炎症相关酶的过度释放、减轻炎症因子对乳腺组织的损伤,对LPS诱发山羊乳腺炎有一定的保护作用.
3卡介菌多糖核酸对实验性乳腺炎大鼠乳腺组织的保护研究
为探讨BCG-PSN对LPS诱导实验性动物乳腺炎的保护机制,72只清洁级SD大鼠被随机分成实验组和对照组(n=36)。确定怀孕14 d起,隔日左后腿胫骨前肌肌内注射BCG-PSN(实验组)或灭菌生理盐水(对照组)0.33 ml/只,连续五次;产后72h经乳头管灌注LPS 10μg/侧到第四对乳腺(两侧)内.分别于灌注前(定义为0 h)及灌注后3、6、9、12和24 h(n=6)颈静脉放血处死动物,采集样品.组织病理学观察显示,BCG-PSN加快了LPS诱发炎症的组织修复进程,促进了炎症后期泌乳量的恢复。酶活性检测结果显示,NAGase、iNOs活性在乳腺组织中和血清中变化规律相反;组织中两种酶活性,实验组和对照组均分别在6 h、9 h达到最高,血清中NAGase活性实验组12 h、对照组9 h最低,iNO活性分别在6 h、3h最低.放射免疫检测结果显示,同对照组相比,BCG-PSN使乳腺组织中炎症相关细胞因子TNF-α、IL-1β及IL-6的峰值降低,出峰时间前提,而血清中这三种细胞因子均未表现出明显的变化.定量RT-PCR结果显示,BCG-PSN能降低乳腺组织中Toll样受体-4(toll-likereceptor-4,TLR-4)mRNA表达水平,实验组与对照组相比,第6、9、24 h差异显著,实验结果说明,BCG-PSN可以通过降低TLR-4的表达,抑制炎性细胞因子及酶的过度分泌,从而缓解LPS及相关因子对乳腺组织的损伤,达到保护乳腺的目的.
4卡介菌多糖核酸对实验性乳腺炎大鼠的免疫调节机理研究
为探讨BCG-PSN对LPS诱导的实验性乳腺炎大鼠免疫功能的调节机理,72只清洁级SD大鼠被随机分成实验组和对照组(n=36).确定怀孕14天起,隔日左后腿胫骨前肌肌内注射BCG-PSN(实验组)或灭菌生理盐水(对照组)0.33ml/只,连续五次;产后72h经乳头管灌注LPS 10μg/侧到第四对乳腺(两侧)内.分别于灌注前(定义为0 h)及灌注后3、6、9、12和24 h(n=6)颈静脉放血处死动物,采集样品。PMN标志酶MPO活性检测结果显示,乳腺组织中MPO活性实验组在第6 h达到高峰,而对照组一直到24 h仍维持较高水平,和对照组相比,BCG-PSN显著降低了12、24 hMPO的活性;血清中MPO活性12 h最低。灌注后,组织中白细胞介素-2(interleukin-2,IL-2)含量迅速升高,实验组和对照组均在24 h达到峰值,同灌注前相比差异显著;实验组在0和24 h显著高于对照组。流式细胞检测结果显示,BCG-PSN在一定程度上提高了0 h外周血中细胞毒性T淋巴细胞(CD8+)细胞数量;同0 h相比,对照组在24 h CD4+/CD3+显著下降,CD8+/CD3+显著升高,因而CD4+/CD8+显著下降;而实验组无明显变化。定量RT-PCR结果显示,IL-2和干扰素-γ(interferon-γ,INF-γ)mRNA表达,实验组和对照组表现出相同的变化规律,LPS灌注后上升,后有所恢复;白细胞介素-4(interleukin-4,IL-4)mRNA表达实验组和对照组表现出不同的变化规律,对照组,同0 h相比,第3、6 h显著下降,然后恢复到正常的水平,实验组第3 h显著高于0 h而后迅速下降,其中第9 h降低明显;BCG-PSN抑制了INF-γ/IL-4 mRNA表达相对比值的升高.实验结果表明,BCG-PSN在炎症初期加快了PMN向乳腺内迁徙,而在炎症后期促进了机体对PMN的清除;在乳腺灌注LPS后抑制了CD4+/CD8+比值的下降,INF-γ/IL-4 mRNA表达相对比值的升高,维持了T淋巴细胞各亚群数量与功能的平衡.提示BCG-PSN可以通过调节大鼠乳腺防御系统内的特异性及非特异性免疫因子,对乳腺产生保护.
5卡介菌多糖核酸对泌乳奶牛外周血PMN吞噬功能及活性氧释放的影响
为探讨BCG-PSN对泌乳奶牛外周血PMN吞噬功能及活性氧(reactive oxygenspecies,ROS)释放的影响,选取处于泌乳初期的健康奶牛,无菌采集颈静脉血,肝素抗凝.(1)不同浓度的BCG-PSN(终浓度分别为0、2、5、10、40、80μg/mL)与全血共孵育2 h,加入FITC标记的大肠杆菌悬液10μL,37℃20min后,放入冰水中终止吞噬反应;溶血素裂解红细胞,0.01mol/L、pH7.2 PBS洗涤两次,重悬后FL1通道检测PMN对大肠杆菌的吞噬率.(2)不同浓度的BCG-PSN(终浓度分别为0、2、5、10、40、80μg/mL)与全血共孵育2 h后,加入乙酸肉豆蔻佛波酯(phorbol myrisateacetate,PMA)刺激PMN,其中PMA刺激的终浓度为100ng/mL,同时每个浓度梯度设无PMA刺激对照(等量PBS代替PMA);37℃作用15min后加入双氢罗丹明123(dihydrorhodamine 123,DHR 123),终浓度为5μM,然后37℃孵育10min;溶血素裂解红细胞,0.01mol/L、pH7.2 PBS洗涤两次,多聚甲醛固定、重悬后流式细胞仪检测.实验结果显示,BCG-PSN可以降低PMA刺激引起的PMN的ROS的大量释放,且这种抑制呈剂量依赖性降低;而对PMN的吞噬功能没有明显的影响.结果说明BCG-PSN对PMN功能的影响不是通过直接影响其吞噬功能发挥作用;而降低炎症反应时PMN氧自由基的过度产生是BCG-PSN减轻机体炎症反应的原因之一.提示,BCG-PSN对奶牛乳腺炎的免疫生理调控有潜在的应用价值.
综上所述,BCG-PSN通过调节乳腺防御系统内的特异性与非特异性防御因素、TLR-4及相关炎性因子,减轻LPS诱导造成的乳腺组织损伤。本研究证实,BCG-PSN作为免疫生理调节剂在动物乳腺炎防控中有潜在的应用前景
In this study,effects of BCG-PSN on mammary defense and protective effects of BCG-PSN on mammary gland were first evaluated by experimental mastitis induced by LPS in goats.Then,the mechanism by which BCG-PSN activated natural defense system was discussed in rat model.On the base of these,changes of PMN function were observed after co-incubation with BCG-PSN.The results as follows:
1 Effect of LPS on Inflammation Factors in Mammary Tissue of Goats Relating with Mastitis
Eight healthy Suining white goats at early stages of lactation were infused with endotoxin or lipopolysaccharide(LPS)(50μg/bwt) in the left half of the mammary gland and physiological saline was infused in the control contralateral half.At intervals of 0,1,2, 3,4,5,6,7,8,9 and 24 h after infusion,mediators of inflammation were measured and the degree of neutrophil(PMN) infiltration and clinical variables were recorded.After 24 h,the animals were euthanized and mammary tissue was collected.A section was fixed for histopathologic evaluation and the remaining tissue was stored at -70℃.Clinical and histopathologic examination indicated that infusion of LPS induced acute mastitis in left half of the mammary gland.Infusion of LPS significantly increased the activity of N-Acetyl-β-D-glucosaminidase(NAGase),myeloperoxidase(MPO) and inducible nitric oxide synthase(iNOs) and the concentration of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6)(P＜0.01).There was a general increase in the levels of mRNA cytokine expression,too.The result showed that over release of inflammatory factors may cause damage to mammary gland.
2 Protection of BCG-PSN to Mammary Tissue of Goat Experimental Mastitis
Six healthy Suining white goats at early stages of lactation were intramammary infused with BCG-PSN(5mL) in the left quarters and physiological saline(5mL) in the control contralateral quarters.The administration of polysaccharide nucleic acid of Bacillus Guerin (BCG-PSN) was carried out for six consecutive days.On the seventh day,the mammary quarters(both right and left) of the six(6) goats were infused with LPS(50μg/bwt).At varying intervals of 0,1,2,3,4,5,6,7,8,9 and 24 h before and after infusion inflammation was recorded.After 24 h,the animals were euthanized and mammary tissue was collected from the same position.A section was fixed for histopathological evaluations and the remaining tissue was stored at -70℃.Clinical and histopathological examinations indicated that infusion of LPS induced acute mastitis in both quarters.The results showed that infusion of BCG-PSN significantly reduced activity of NAGase,MPO,iNOS and the concentration of TNF-α,IL-1β,and IL-6(P＜0.05).There was a general reduction in the levels of mRNA cytokine expression(P＜0.05).These findings suggest that BCG-PSN inhibits release of inflammatory factors that cause damage to mammary epithelial cells during mastitis infections in goats.
3 Protection of BCG-PSN to Mammary Tissue of Rat Experimental Mastitis
The aim of this study was to evaluate in rats,protection of BCG-PSN to mammary tissue of rat experimental mastitis.Seventy-two lactating SD rats were randomly divided into control and treatment group(n=36).BCG-PSN(treatment group,TG) or sterile pyrogen-free physiological saline(control group,CG) 0.33ml were injected into the left tibialis anterior muscle of rats 14 days after conception.The administration was repeated for five consecutive times every other day.Seventy-two hours after parturition,30 rats of each group were inoculated with 10μg Escherichia coli LPS dissolved in 100μL physiological saline into the left 4(L4) and right 4(R4) mammary glands and six as control. Just before the inoculation(control group defined as 0 h) and at 3,6,9,12 and 24 h after inoculation six rats at every time point were euthanatized and samples were collected.The histopathological observation indicated that treatment with BCG-PSN made a rapid renovation of mammary tissue compared with CG.Milk secretion elevated with an increasing of the luminal spaces with milk at the later stage of inflammation in TG.In mammary tissue,both NAGase and iNOs peaked at 6 h in TG and 9 h in CG,whereas serum NAGase reached nadir level at 12 h PI in TG and 9 h PI in CG,and serum iNOs reached nadir level at 6 h and 3 h PI respectively.Administration BCG-PSN reduced the peak level of TNF-α,IL-1βand IL-6 in mammary tissue compared with CG,whereas no significant changes were observed in serum after LPS challenge.RT-PCR analysis showed that BCG-PSN decreased the toll-like receptor-4(TLR-4) mRNA expression level from 3 h PI and significant reduction was observed at 6h,9 h and 24 h PI.These findings suggested that BCG-PSN has a general protective effect against LPS-induced local mammary injury by reducing TLR-4 mRNA expression level and further inhibiting the release of inflammatory factors that cause damage to mammary gland.
4 Immunoregulation of BCG-PSN to Rats of Experimental Mastiffs
The aim of this study was to evaluate in rats,immunoregulation of BCG-PSN to rats of experimental mastitis.Seventy-two lactating SD rats were randomly divided into control and treatment group(n=36).BCG-PSN(treatment group,TG) or sterile pyrogen-free physiological saline(control group,CG) 0.33ml were injected into the left tibialis anterior muscle of rats 14 days after conception.The administration was repeated for five consecutive times every other day.Seventy-two hours after parturition,30 rats of each group were inoculated with 10μg LPS dissolved in 100μL physiological saline into the left 4(L4) and right 4(R4) mammary glands and six as control.Just before the inoculation (control group defined as 0 h) and at 3,6,9,12 and 24 h after inoculation six rats at every time point were euthanatized and samples were collected.The results indicated that the concentrations of MPO in mammary tissue peaked at 6 h in TG,and in CG kept a high level until 24 h PI.Significant reduce of MPO was observed at 12 h and 24 h PI compared TG with CG.Serum MPO reached nadir at the same time(12 h after LPS challenge) both CG and TG.After LPS infusion,the concentrations of IL-2 increased dramatically and peaked at 24 h both CG and TG.BCG-PSN induced significant elevated of IL-2 at 0 h and 24 compared with control.Flow cytometfic analysis showed that,compared with control(0 h),the 24 h group exhibited a CD4+(T-helper) T cell decline,a CDS+(T-cytotoxic or T-suppressor) T cell increase,and decreased CD4/CD8 ratio in CG.No significant changes were observed in TG.The results of RT-PCR showed that in CG,the levels of IL-2,and INF-γmRNA expression increased,whereas IL-4 mRNA expression decreased after LPS challenged.As a consequence,the INF-γ/IL-4 mRNA radio was significant higher 3 h,6 h, and 9 h PI compared with normal value(0 h).BCG-PSN increased the mRNA expression both INF-γand IL-4 before infusion of LPS.After LPS challenged,significantly reduced Th1/Th2 cytokine radio was observed,because Th1 cytokine IFN-γwas suppressed and Th2 cytokine IL-4 was enhanced compared with CG.The study demonstrated that BCG-PSN may protect the mammary gland by improving the non-special and special immune factors of rats.
5 Effect of BCG-PSN on Phagocytosis and Generation of Reactive Oxygen Species of Lactating Cow Peripheral Blood PMN
The aim of this study was to evaluate in vitro,effect of BCG-PSN on phagocytosis and generation of reactive oxygen species(ROS) of lactating cow peripheral blood PMN. Peripheral blood of healthy lactation cow at early stages of lactation was collected from the jugular vein by venipuncture in evacuated tubes containing heparin as anticoagulant.(1) FITC-labeled E.coli 10μL was added to each sample after a 2 h co-incubation with different concentrations of BCG-PSN(final concentration 0、2、5、10、40、80μg/mL).After further 20 min incubation at 37℃,phagocytosis was stopped by dipping into ice water. Then erythrocytes were lysed with lysing solution and the leucocytes were washed two times with PBS(0.01mol/L,pH7.2).The cells were then resuspended in PBS and analyzed on a FACScan flow cytometer.FL1 green channel captured FITC fluorescence.(2) Phorbol myrisate acetate(PMA,final concentrationl00ng/mL) was used to stimulate PMN after a 2 h co-incubation with different concentrations of BCG-PSN(final concentration 0、2、5、10、40、80μg/mL).Control tests of every group were set up using PBS instead of PMA.All tubes were incubated at 37℃for 15 min and then working dihydrorhodamine 123(DHR 123,final concentration 5μM) solution was added.After further 10 min incubation at 37℃, erythrocytes were lysed with lysing solution.Then the leucocytes were washed two times with PBS(0.01mol/L,pH7.2) and stabilized by paraformaldehyde.The the cells were then resuspended in PBS and analyzed on a FACScan flow cytometer.The results showed that BCG-PSN could significant reduced the generation of reactive oxygen species of PMN and had no effect on the phagocytosis of PMN.This suggests that BCG-PSN protects the mammary gland from inflammatory injury by attenuating the release of ROS but not by directly phagocytosis.BCG-PSN may be a potential candidate to prevent bovine mastitis.
In conclusion,BCG-PSN may protect the mammary gland by modulating the secretion of non-special and special immune factors,down-regulating the expression of TLR-4 and inflammation mediator.The results suggest BCG-PSN can be used as a potential candidate to prevent mastitis.
引文
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