咖啡酸抗LPS诱导的奶牛乳腺上皮细胞炎性损伤作用及其分子机制
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摘要
“金蒲”灌注剂是本实验室研制的一种治疗奶牛乳房炎的纯中药制剂,咖啡酸是该方剂中的一种主要活性成分,本文通过研究咖啡酸抗脂多糖(LPS)诱导的奶牛乳腺上皮细胞(bMEC)的炎性损伤作用及其分子机制,为该方剂的临床应用提供理论依据和技术支持。
本研究通过MTT法检测LPS对bMEC细胞活力的影响,并筛选了LPS诱导bMEC损伤模型条件；利用扫描、透射电镜观察bMEC超微结构变化和流式细胞术检测bMEC的凋亡情况对损伤模型进行了评价；通过深度测序技术分析LPS诱导的bMEC基因表达谱变化,筛选差异基因并对其进行多重分析,预测了LPS诱导的bMEC损伤分子机制；利用Western Blot及RT-PCR技术对相关炎症信号通路中关键蛋白和炎性因子的表达进行了验证；并探讨了咖啡酸抗LPS诱导的bMEC结构损伤的分子机制。相关研究结果如下：
不同浓度的LPS(10、50、100、200μg/mL)作用bMEC不同时间(3、6、12、18h)后,结果显示,LPS能够显著地降低bMEC的细胞活力,这种作用具有明显的时间、剂量依赖性。选择50μg/mL的LPS作用bMEC12h作为损伤模型条件。扫描电镜观察显示：模型组细胞界限不清,细胞明显固缩,细胞表面微绒毛排列紊乱或缺失,细胞出现不同程度塌陷；透射电镜观察显示：模型组细胞游离面微绒毛肿胀或断裂,细胞核空化,内质网极度扩张,线粒体结构模糊,细胞质基质结构疏松；流式细胞术检测结果显示：模型组细胞的细胞凋亡率明显升高,尤其是早期细胞凋亡率。说明LPS能够破坏bMEC的细胞形态结构。
咖啡酸(10、25、50μg/mL)显著地降低了LPS诱导的bMEC细胞活力下降,明显减弱了LPS诱导的细胞形态结构损伤,显著降低了LPS诱导的细胞凋亡率,咖啡酸的功效具有明显剂量依赖性。
基因转录组深度测序分析结果显示,模型组与对照组细胞共有1435个差异基因,其中上调基因1301个,下调基因134个。GO分析得出,差异基因主要富集于与细胞应激应答、信号转导、物质代谢、生长分化等生物进程,说明LPS对bMEC的生理功能产生了较大的影响。KEGG Pathway分析发现,多个差异基因富集于NF-κB、MAPKs信号转导通路中,因此初步阐明LPS通过激活bMEC的NF-κB、MAPKs信号通路,诱导大量的炎性介质释放,导致了bMEC的炎性损伤。
咖啡酸(10、25、50μg/mL)通过减少IκBa的降解和降低p65的磷酸化水平,抑制了bMEC的NF-κB的活性；通过降低p38、JNK、ERK1/2的磷酸化水平,抑制了细胞MAPKs信号通路的转导,从而减少了LPS诱导的bMEC的IL-8、IL-1β、IL-6和TNF-a的表达,减弱了LPS诱导的bMEC炎性损伤作用。
Jin-Pu-Guan-Zhu-Ji developed in our laboratory is a kind of Traditional Chinese Veterinary Medicine used for treating bovine mastitis, while caffeic acid acts as an important active ingredient. In order to provide theoretical and technological support for the clinical application of the herb formulation, the protective effect of caffeic acid against lipopolysaccharide (LPS)-induced inflammation injury of bovine mammary epithelial cells (bMEC) and the possible molecular mechanisms were studied in this dissertation.
The effect of LPS on cell viability of bMEC was tested by MTT, then the LPS-injured bMEC modle was preliminarily established. The injury modle of bMEC caused by LPS was evaluated by scanning electron microscopy (SEM), transmission electron microscope (TEM) and flow cytometry (FCM). Changes of gene expression profile of bMEC induced by LPS were analyzed by deep sequencing technology. Through the multiple analysis of differential expression genes, we predicted the molecular mechanism of LPS-induced injury to bMEC. The levels of several key proteins and the expression of inflammatory cytokines were verified by the Western blot and RT-PCR, which related to the prediction of inflammatory signaling pathways. LPS caused inflammation injury of bMEC could be weakened by caffeic acid, then the molecular mechanisms of anti-inflammation injury of bmec induced by LPS were explored. The test results are as follows:
Bovine mammary epithelial cells were treated with various concentrations (10,50,100, and200μg/mL) of LPS for3,6,12, and18h, the results showed that LPS significantly inhibited cell viability in a time-and dose-dependent manner. Cells were stimulated with a selected treatment,50μg/mL of LPS for12h, as the model conditions of inflammation injury of bMEC induced by LPS for further research. In model group, morphological changes including fuzzy cell boundary, cellular atrophy, disorderly or missing microvilli and different degrees of cell collapse were observed by SEM. Subcellular structure changes including swelling or rupture of microvilli, nuclear cavitation, extreme expansion of endoplasmic reticulum, hazy mitochondrial structures, loose cytoplasmic matrix structure were studied by means of TEM. The data of FCM showed that cell apoptosis was significantly increased after cells were stimulated with LPS, especially the early apoptosis rate. The above data revealed that LPS could destroy the cell morphology structures of bMEC, thus affecting the physiological function of bMEC.
Caffeic acid could significantly reduce the decline of cell vitality induced by LPS, and obviously weaken the damage of cell morphological structure and subcellular structure induced by LPS. The effects of caffeic acid were in a dose-dependent manner.
The molecular mechanisms of LPS-induced inflammtion injury of bMEC was analyzed by sequencing depth on transcriptome profiling.1435genes were sifted to be diffrently expressed, including1301up-regulated genes and134down-regulated genes. GO analysis revealed that the differential expression genes were mainly related to growth and differentiation, stress responses, signal transduction, material metabolism processes of bMEC, these results indicated that variations in physiologic functions. KEGG Pathway analysis obtained that several differential expression genes mainly related to nuclear transcription factor kappa B (NF-κB) signaling pathway and mitogen-activated protein kinases (MAPKs) signaling pathway. So the NF-κB signaling pathway and MAPKs signaling pathway of bMEC could be activated by LPS, then a large number of inflammatory mediators were released, which resulted in the inflammation injury of bMEC.
The degradation of IκBα and phosphorylation of p65induced by LPS were partially inhibited by caffeic acid in a dose-dependent manner, which indicated a weakening activity of NF-κB. The LPS-induced phosphorylation of p38and JNK were partially inhibited by caffeic acid in a dose-dependent manner, the phosphorylation of ERK1/2was completely inhibited by all concentrations of caffeic acid, which indicated a weakening activity of MAPKs. The expression of IL-8, IL-1β, IL-6and TNF-α could be effectively inhibited by caffeic acid, which mainly regulated by NF-κB and MAPKs signaling pathway, thus significantly weakened LPS-induced inflammatory injury of bMEC.
本研究通过MTT法检测LPS对bMEC细胞活力的影响,并筛选了LPS诱导bMEC损伤模型条件；利用扫描、透射电镜观察bMEC超微结构变化和流式细胞术检测bMEC的凋亡情况对损伤模型进行了评价；通过深度测序技术分析LPS诱导的bMEC基因表达谱变化,筛选差异基因并对其进行多重分析,预测了LPS诱导的bMEC损伤分子机制；利用Western Blot及RT-PCR技术对相关炎症信号通路中关键蛋白和炎性因子的表达进行了验证；并探讨了咖啡酸抗LPS诱导的bMEC结构损伤的分子机制。相关研究结果如下：
不同浓度的LPS(10、50、100、200μg/mL)作用bMEC不同时间(3、6、12、18h)后,结果显示,LPS能够显著地降低bMEC的细胞活力,这种作用具有明显的时间、剂量依赖性。选择50μg/mL的LPS作用bMEC12h作为损伤模型条件。扫描电镜观察显示：模型组细胞界限不清,细胞明显固缩,细胞表面微绒毛排列紊乱或缺失,细胞出现不同程度塌陷；透射电镜观察显示：模型组细胞游离面微绒毛肿胀或断裂,细胞核空化,内质网极度扩张,线粒体结构模糊,细胞质基质结构疏松；流式细胞术检测结果显示：模型组细胞的细胞凋亡率明显升高,尤其是早期细胞凋亡率。说明LPS能够破坏bMEC的细胞形态结构。
咖啡酸(10、25、50μg/mL)显著地降低了LPS诱导的bMEC细胞活力下降,明显减弱了LPS诱导的细胞形态结构损伤,显著降低了LPS诱导的细胞凋亡率,咖啡酸的功效具有明显剂量依赖性。
基因转录组深度测序分析结果显示,模型组与对照组细胞共有1435个差异基因,其中上调基因1301个,下调基因134个。GO分析得出,差异基因主要富集于与细胞应激应答、信号转导、物质代谢、生长分化等生物进程,说明LPS对bMEC的生理功能产生了较大的影响。KEGG Pathway分析发现,多个差异基因富集于NF-κB、MAPKs信号转导通路中,因此初步阐明LPS通过激活bMEC的NF-κB、MAPKs信号通路,诱导大量的炎性介质释放,导致了bMEC的炎性损伤。
咖啡酸(10、25、50μg/mL)通过减少IκBa的降解和降低p65的磷酸化水平,抑制了bMEC的NF-κB的活性；通过降低p38、JNK、ERK1/2的磷酸化水平,抑制了细胞MAPKs信号通路的转导,从而减少了LPS诱导的bMEC的IL-8、IL-1β、IL-6和TNF-a的表达,减弱了LPS诱导的bMEC炎性损伤作用。
Jin-Pu-Guan-Zhu-Ji developed in our laboratory is a kind of Traditional Chinese Veterinary Medicine used for treating bovine mastitis, while caffeic acid acts as an important active ingredient. In order to provide theoretical and technological support for the clinical application of the herb formulation, the protective effect of caffeic acid against lipopolysaccharide (LPS)-induced inflammation injury of bovine mammary epithelial cells (bMEC) and the possible molecular mechanisms were studied in this dissertation.
The effect of LPS on cell viability of bMEC was tested by MTT, then the LPS-injured bMEC modle was preliminarily established. The injury modle of bMEC caused by LPS was evaluated by scanning electron microscopy (SEM), transmission electron microscope (TEM) and flow cytometry (FCM). Changes of gene expression profile of bMEC induced by LPS were analyzed by deep sequencing technology. Through the multiple analysis of differential expression genes, we predicted the molecular mechanism of LPS-induced injury to bMEC. The levels of several key proteins and the expression of inflammatory cytokines were verified by the Western blot and RT-PCR, which related to the prediction of inflammatory signaling pathways. LPS caused inflammation injury of bMEC could be weakened by caffeic acid, then the molecular mechanisms of anti-inflammation injury of bmec induced by LPS were explored. The test results are as follows:
Bovine mammary epithelial cells were treated with various concentrations (10,50,100, and200μg/mL) of LPS for3,6,12, and18h, the results showed that LPS significantly inhibited cell viability in a time-and dose-dependent manner. Cells were stimulated with a selected treatment,50μg/mL of LPS for12h, as the model conditions of inflammation injury of bMEC induced by LPS for further research. In model group, morphological changes including fuzzy cell boundary, cellular atrophy, disorderly or missing microvilli and different degrees of cell collapse were observed by SEM. Subcellular structure changes including swelling or rupture of microvilli, nuclear cavitation, extreme expansion of endoplasmic reticulum, hazy mitochondrial structures, loose cytoplasmic matrix structure were studied by means of TEM. The data of FCM showed that cell apoptosis was significantly increased after cells were stimulated with LPS, especially the early apoptosis rate. The above data revealed that LPS could destroy the cell morphology structures of bMEC, thus affecting the physiological function of bMEC.
Caffeic acid could significantly reduce the decline of cell vitality induced by LPS, and obviously weaken the damage of cell morphological structure and subcellular structure induced by LPS. The effects of caffeic acid were in a dose-dependent manner.
The molecular mechanisms of LPS-induced inflammtion injury of bMEC was analyzed by sequencing depth on transcriptome profiling.1435genes were sifted to be diffrently expressed, including1301up-regulated genes and134down-regulated genes. GO analysis revealed that the differential expression genes were mainly related to growth and differentiation, stress responses, signal transduction, material metabolism processes of bMEC, these results indicated that variations in physiologic functions. KEGG Pathway analysis obtained that several differential expression genes mainly related to nuclear transcription factor kappa B (NF-κB) signaling pathway and mitogen-activated protein kinases (MAPKs) signaling pathway. So the NF-κB signaling pathway and MAPKs signaling pathway of bMEC could be activated by LPS, then a large number of inflammatory mediators were released, which resulted in the inflammation injury of bMEC.
The degradation of IκBα and phosphorylation of p65induced by LPS were partially inhibited by caffeic acid in a dose-dependent manner, which indicated a weakening activity of NF-κB. The LPS-induced phosphorylation of p38and JNK were partially inhibited by caffeic acid in a dose-dependent manner, the phosphorylation of ERK1/2was completely inhibited by all concentrations of caffeic acid, which indicated a weakening activity of MAPKs. The expression of IL-8, IL-1β, IL-6and TNF-α could be effectively inhibited by caffeic acid, which mainly regulated by NF-κB and MAPKs signaling pathway, thus significantly weakened LPS-induced inflammatory injury of bMEC.
引文
[1]Barbano D. M., Ma Y., Santos M V. Influence of raw milk quality on fluid milk shelf life[J]. J Dairy Sci,2006,89 Suppl 1:E15-E19.
[2]Kemp M. H., Nolan A. M., Cripps P. J.et al. Animal-based measurements of the severity of mastitis in dairy cows[J]. Vet Rec,2008,163 (6):175-179.
[3]Oliver S. P., Influence of inflammation on mammary gland metabolism and milk composition[M],1994.
[4]Huijps K., Lam T. J., Hogeveen H. Costs of mastitis:facts and perception[J]. J Dairy Res, 2008,75(1):113-120.
[5]Hortet P., Seegers H. Loss in milk yield and related composition changes resulting from clinical mastitis in dairy cows[J]. Prev Vet Med,1998,37 (1-4):1-20.
[6]Akers R. M., Nickerson S. C. Mastitis and its impact on structure and function in the ruminant mammary gland[J]. J Mammary Gland Biol Neoplasia,2011,16 (4):275-289.
[7]Hogeveen H., Huijps K., Lam T. J. Economic aspects of mastitis:new developments[J]. N Z Vet J,2011,59(1):16-23.
[8]Lam T. J., van den Borne B. H., Jansen J.et al. Improving bovine udder health:a national mastitis control program in the Netherlands[J]. J Dairy Sci,2013,96 (2):1301-1311.
[9]Nielsen Christel. Economic Impact of Mastitis in Dairy Cow [D]:Swedish University of Agricultural Sciences,2009.
[10]Zhao X., Lacasse P. Mammary tissue damage during bovine mastitis:causes and control[J]. J Anim Sci,2008,86 (13 Suppl):57-65.
[11]Wilson D. J., Gonzalez R. N., Das H. H. Bovine mastitis pathogens in New York and Pennsylvania:prevalence and effects on somatic cell count and milk production[J]. J Dairy Sci,1997,80 (10):2592-2598.
[12]段玉.奶牛乳腺炎危害性分析[J].中国畜禽种业,2007,8：76-78.
[13]金尔光,曾新华,周木清,等.奶牛乳房炎研究概况[J].养殖与饲料,2008,6：69-70.
[14]蒋春茂,周新民,周广生,等.奶牛乳房炎研究进展[J].中国畜牧兽医,2004,31(05)：36-38.
[15]Jansen J., Renes R. J., Lam T. J. Evaluation of two communication strategies to improve udder health management[J]. J Dairy Sci,2010,93 (2):604-612.
[16]Reyher K. K., Haine D., Dohoo I. R.et al. Examining the effect of intramammary infections with minor mastitis pathogens on the acquisition of new intramammary infections with major mastitis pathogens--a systematic review and meta-analysis[J]. J Dairy Sci,2012,95 (11):6483-6502.
[17]Zecconi A., Binda E., Borromeo V.et al. Relationship between some Staphylococcus aureus pathogenic factors and growth rates and somatic cell counts[J]. J Dairy Res,2005,72 (2): 203-208.
[18]王桂琴,吴聪明,宋丽华,等.奶牛乳房炎大肠杆菌的血清型及耐药性调查研究[J].中国兽医杂志,2006,42(12)：19-20.
[19]Wellenberg G. J., van der Poel W. H., Van Oirschot J. T. Viral infections and bovine mastitis:a review[J]. Vet Microbiol,2002,88 (1):27-45.
[20]Herlekar D. A., Shashikant C. S., Gurjar A. A.et al. Presence of viral and bacterial organisms in milk and their association with somatic cell counts[J]. J Dairy Sci,2013,96 (10):6336-6346.
[21]Jagielski T., Lassa H., Ahrholdt J.et al. Genotyping of bovine Prototheca mastitis isolates from Poland[J]. Vet Microbiol,2011,149 (1-2):283-287.
[22]Walia H. S.. Abraham T. K., Shaikh H. Fungal mastitis. Case report[J]. Acta Chir Scand. 1987,153 (2):133-135.
[23 ]周接水.I Prototheca zopfii引起的牛乳房炎[J].畜禽业,1999,9：57-58.
[24]Costa E. O., Melville P. A., Ribeiro A. R.et al. Epidemiologic study of environmental sources in a Prototheca zopfii outbreak of bovine mastitis[J]. Mycopathologia,1997,137 (1):33-36.
[25]Jensen H. E., Aalbaek B., Bloch B.et al. Bovine mammary protothecosis due to Prototheca zopfii[J]. Med Mycol,1998,36 (2):89-95.
[26]Fu P., Sun Z., Zhang Y.et al. Development of a direct competitive ELISA for the detection of Mycoplasma bovis infection based on a monoclonal antibody of P48 protein[J]. BMC Vet Res.2014,10(1):42.
[27]Wawegama N. K., Browning G. F., Kanci A.et al. Development of a recombinant protein-based enzyme-linked immunosorbent assay for diagnosis of Mycoplasma bovis infection in cattle[J]. Clin Vaccine Immunol,2014,21 (2):196-202.
[28]HertI J. A., Schukken Y. H., Welcome F. L.et al. Pathogen-specific effects on milk yield in repeated clinical mastitis episodes in Holstein dairy cows[J]. J Dairy Sci,2014,97 (3): 1465-1480.
[29]Park H. R., Hong M. K., Hwang S. Y.et al. Characterisation of Pseudomonas aeruginosa related to bovine mastitis[J]. Acta Vet Hung,2014,62 (1):1-12.
[30]Schukken Y., Chuff M., Moroni P.et al. The "other" gram-negative bacteria in mastitis: Klebsiella, serratia, and more[J]. Vet Clin North Am Food Anim Pract,2012,28 (2): 239-256.
[31]Quesnell R. R., Klaessig S., Watts J. L.et al. Bovine intramammary Escherichia coli challenge infections in late gestation demonstrate a dominant antiinflammatory immunological response[J]. J Dairy Sci,2012,95 (1):117-126.
[32]Bradley A. J., Green M. J. Aetiology of clinical mastitis in six Somerset dairy herds[J]. Vet Rec,2001,148 (22):683-686.
[33]Bradley A. J., Green M. J. Adaptation of Escherichia coli to the bovine mammary gland[J]. J Clin Microbiol,2001,39 (5):1845-1849.
[34]Boehmer J. L. Proteomic Analyses of Host and Pathogen Responses during Bovine Mastitis[J]. J Mammary Gland Biol Neoplasia,2011,16 (4):323-338.
[35]马翀.关于奶牛乳房炎几个问题的探究[D]：中国农业大学,2007.
[36]Green M. J., Green L. E., Medley G. F.et al. Influence of dry period bacterial intramammary infection on clinical mastitis in dairy cows[J]. J Dairy Sci,2002,85 (10):2589-2599.
[37]Dogan B., Klaessig S., Rishniw M.et al. Adherent and invasive Escherichia coli are associated with persistent bovine mastitis[J]. Vet Microbiol,2006,116 (4):270-282.
[38]Shpigel N. Y., Elazar S., Rosenshine I. Mammary pathogenic Escherichia coli[J]. Curr Opin Microbiol,2008,11 (1):60-65.
[39]Almeida R. A., Dogan B., Klaessing S.et al. Intracellular fate of strains of Escherichia coli isolated from dairy cows with acute or chronic mastitis[J]. Vet Res Commun,2011,35 (2): 89-101.
[40]Makovec J. A., Ruegg P. L. Results of milk samples submitted for microbiological examination in Wisconsin from 1994 to 2001 [J]. J Dairy Sci,2003,86 (11):3466-3472.
[41]Grohn Y. T., Wilson D. J., Gonzalez R. N.et al. Effect of pathogen-specific clinical mastitis on milk yield in dairy cows[J]. J Dairy Sci,2004,87 (10):3358-3374.
[42]Cha E., Bar D., Hertl J. A.et al. The cost and management of different types of clinical mastitis in dairy cows estimated by dynamic programming[J]. J Dairy Sci,2011,94 (9): 4476-4487.
[43]Seegers H., Fourichon C., Beaudeau F. Production effects related to mastitis and mastitis economics in dairy cattle herds[J]. Vet Res,2003,34 (5):475-491.
[44]Hazlett M. J., Little P. B., Maxie M. G.et al. Fatal mastitis of dairy cows:a retrospective study[J]. Can J Comp Med,1984,48 (2):125-129.
[45]Paduch J. H., Mohr E., Kromker V. The association between bedding material and the bacterial counts of Staphylococcus aureus, Streptococcus uberis and coliform bacteria on teat skin and in teat canals in lactating dairy cattle[J]. J Dairy Res,2013,80 (2):159-164.
[46]Rainard P., Riollet C. Innate immunity of the bovine mammary gland[J]. Vet Res,2006,37 (3):369-400.
[47]Bradley A. J., Breen J. E., Payne B.et al. A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant[J]. J Dairy Sci,2011,94 (2):692-704.
[48]Bradley A. J., Green M. J. The importance of the nonlactating period in the epidemiology of intramammary infection and strategies for prevention[J]. Vet Clin North Am Food Anim Pract,2004,20 (3):547-568.
[49]Green M. J., Bradley A. J., Medley G. F.et al. Cow, farm, and management factors during the dry period that determine the rate of clinical mastitis after calving[J]. J Dairy Sci,2007, 90 (8):3764-3776.
[50]Green M. J., Bradley A. J., Medley G. V.et al. Cow, farm, and herd management factors in the dry period associated with raised somatic cell counts in early lactation[J]. J Dairy Sci, 2008,91 (4):1403-1415.
[51]Barkema H. W., Schukken Y. H., Lam T. J.et al. Incidence of clinical mastitis in dairy herds grouped in three categories by bulk milk somatic cell counts[J]. J Dairy Sci,1998,81 (2): 411-419.
[52]Pieper J., Hoedemaker M., Kromker V. [Significance of the dry period for the development and prevention of new infections of the bovine mammary gland][J]. Tierarztl Prax Ausg G Grosstiere Nutztiere,2013,41 (5):315-324,325.
[53]Dietert R. R., Piepenbrink M. S. The managed immune system:protecting the womb to delay the tomb[J]. Hum Exp Toxicol.2008,27 (2):129-134.
[54]Comalli M. P., Eberhart R. J., Griel LC Jret al. Changes in the microscopic anatomy of the bovine teat canal during mammary involution[J]. Am J Vet Res.1984,45 (11):2236-2242.
[55]Oldham E. R., Eberhart R. J., Lange A. L.et al. Changes in the bovine teat canal during the nonlactating period and early lactation, as measured by teat canal impressions[J]. Am J Vet Res,1991,52 (12):2075-2079.
[56]Jonsson N. N., Fortes M. R., Piper E. K.et al. Comparison of metabolic, hematological, and peripheral blood leukocyte cytokine profiles of dairy cows and heifers during the peri parturient period[J]. J Dairy Sci,2013,96 (4):2283-2292.
[57]Moves K. M., Drackley J. K., Morin D. E.et al. Predisposition of cows to mastitis in non-infected mammary glands:effects of dietary-induced negative energy balance during mid-lactation on immune-related genes[J]. Funct Integr Genomics,2011,11 (1):151-156.
[58]Zarrin M., Wellnitz O., van Dorland H. A.et al. Induced hyperketonemia affects the mammary immune response during lipopolysaccharide challenge in dairy cows[J]. J Dairy Sci,2014,97(1):330-339.
[59]Suriyasathaporn W., Heuer C., Noordhuizen-Stassen E. N.et al. Hyperketonemia and the impairment of udder defense:a review[J]. Vet Res,2000,31 (4):397-412.
[60]Kelm S. C., Freeman A. E. Direct and correlated responses to selection for milk yield: results and conclusions of regional project NC-2, "improvement of dairy cattle through breeding, with emphasis on selection". NC-2 Technical Committee[J]. J Dairy Sci,2000,83 (12):2721-2732.
[61]Shook G. E. Major advances in determining appropriate selection goals[J]. J Dairy Sci,2006, 89(4):1349-1361.
[62]Lovis L., Frutschi Mascher V., Gern L.et al. [Cattle farmers' perception of the nuisances caused by insects and ticks to cattle in the Canton Jura][J]. Schweiz Arch Tierheilkd,2008, 150 (9):457-465.
[63]Porcherie A., Cunha P., Trotereau A.et al. Repertoire of Escherichia coli agonists sensed by innate immunity receptors of the bovine udder and mammary epithelial cells[J]. Vet Res, 2012,43(1):14.
[64]Paulrud C. O., Basic concepts of the bovine teat canal[M],2005:215-245.
[65]Paduch J. H., Mohr E., Kromker V. The association between teat end hyperkeratosis and teat canal microbial load in lactating dairy cattle[J]. Vet Microbiol,2012,158 (3-4):353-359.
[66]Neijenhuis F., Barkema H. W., Hogeveen H.et al. Relationship between teat-end callosity and occurrence of clinical mastitis[J]. J Dairy Sci,2001,84 (12):2664-2672.
[67]Zecconi A., Hamann J., Bronzo V.et al. Relationship between teat tissue immune defences and intramammary infections[J]. Adv Exp Med Biol,2000,480:287-293.
[68]Rinaldi M., Li R. W., Bannerman D. D.et al. A sentinel function for teat tissues in dairy cows:dominant innate immune response elements define early response to E. coli mastitis[J]. Funct Integr Genomics,2010,10 (1):21-38.
[69]Du Preez J. H. Teat canal infections[J]. Kieler Milchw. Forsch,1985 (37):267-273.
[70]Pryor S. M. Bovine mastitis and ecology of Streptococcus uberis[D]:University of Waikato, New Zealand,2008.
[71]Heeschen W. H., IDF and mastitis-a general review. In:Hillerton, J. E. (Ed.), Mastitis Research into Practice. Proc[M]. Christchurch, New Zealand,2010.
[72]Pantoja J. C., Hulland C., Ruegg P. L. Dynamics of somatic cell counts and intramammary infections across the dry period[J]. Prev Vet Med,2009,90 (1-2):43-54.
[73]Archer S. C., Mc Coy F., Wapenaar W.et al. Association between somatic cell count after first parturition and cumulative milk yield in dairy cows[J]. Vet Rec,2013,173 (13):316.
[74]Sordillo L. M., Streicher K. L. Mammary gland immunity and mastitis susceptibility[J]. J Mammary Gland Biol Neoplasia,2002,7 (2):135-146.
[75]Sordillo L. M., Shafer-Weaver K., DeRosa D. Immunobiology of the mammary gland[J]. J Dairy Sci,1997,80(8):1851-1865.
[76]Paape M. J., Shafer-Weaver K., Capuco A. V.et al. Immune surveillance of mammary tissue by phagocytic cells[J]. Adv Exp Med Biol,2000,480:259-277.
[77]MJ Paape, A Contreras. Historical perspective on the evolution of the milk somatic cell count[J]. Flem Vet Suppl,1997:66-93.
[78]Mehrzad J., Desrosiers C., Lauzon K.et al. Proteases involved in mammary tissue damage during endotoxin-induced mastitis in dairy cows[J]. J Dairy Sci,2005,88 (1):211-222.
[79]Paape M. J., Shafer-Weaver K., Capuco A. V.et al. Immune surveillance of mammary tissue by phagocytic cells[J]. Adv Exp Med Biol,2000,480:259-277.
[80]Paape M. J., Bannerman D. D., Zhao X.et al. The bovine neutrophil:Structure and function in blood and milk[J]. Vet Res,2003,34 (5):597-627.
[81]Lakritz J., Tyler J. W., Marsh A. E.et al. Tilmicosin reduces lipopolysaccharide-stimulated bovine alveolar macrophage prostaglandin E(2) production via a mechanism involving phospholipases[J]. Vet Ther,2002,3(1):7-21.
[82]Paape M., Mehrzad J., Zhao X.et al. Defense of the bovine mammary gland by polymorphonuclear neutrophil leukocytes[J]. J Mammary Gland Biol Neoplasia,2002,7 (2): 109-121.
[83]Riollet C., Rainard P., Poutrel B. Cells and cytokines in inflammatory secretions of bovine mammary gland[J]. Adv Exp Med Biol,2000,480:247-258.
[84]Mullan N. A., Carter E. A., Nguyen K. A. Phagocytic and bactericidal properties of bovine macrophages from non-lactating mammary glands[J]. Res Vet Sci,1985,38 (2):160-166.
[85]Ledbetter T. K., Paape M. J., Douglass L. W. Cytotoxic effects of peroxynitrite, polymorphonuclear neutrophils, free-radical scavengers, inhibitors of myeloperoxidase, and inhibitors of nitric oxide synthase on bovine mammary secretory epithelial cells[J]. Am J Vet Res,2001,62 (3):286-293.
[86]Burvenich C., Monfardini E., Mehrzad J.et al. Role of neutrophil polymorphonuclear leukocytes during bovine coliform mastitis:physiology or pathology?[J]. Verh K Acad Geneeskd Belg,2004,66 (2):97-150,150-153.
[87]Burk D. R., Senechal-Willis P., Lopez L. C.et al. Suppression of lipopolysaccharide-induced inflammatory responses in RAW 264.7 murine macrophages by aqueous extract of Clinopodium vulgare L. (Lamiaceae)[J]. J Ethnopharmacol,2009,126 (3):397-405.
[88]崔立莉.奶牛乳腺上皮细胞体外培养体系的建立及其应用[D]：新疆农业大学,2006.
[89]Farrera C., Fadeel B. Macrophage clearance of neutrophil extracellular traps is a silent process[J]. J Immunol,2013,191 (5):2647-2656.
[90]Mehrzad J., Duchateau L., Burvenich C. Viability of milk neutrophils and severity of bovine coliform mastitis[J]. J Dairy Sci,2004,87 (12):4150-4162.
[91]Taylor B. C., Keefe R. G., Dellinger J. D.et al. T cell populations and cytokine expression in milk derived from normal and bacteria-infected bovine mammary glands[J]. Cell Immunol, 1997,182(1):68-76.
[92]Riollet C., Rainard P., Poutrel B. Cell subpopulations and cytokine expression in cow milk in response to chronic Staphylococcus aureus infection[J]. J Dairy Sci,2001,84 (5): 1077-1084.
[93]Asai K., Kai K., Rikiishi H.et al. Variation in CD4+ T and CD8+ T lymphocyte subpopulations in bovine mammary gland secretions during lactating and non-lactating periods[J]. Vet Immunol Immunopathol,1998,65 (1):51-61.
[94]Wong P., Pamer E. G. CD8 T cell responses to infectious pathogens[J]. Annu Rev Immunol, 2003,21:29-70.
[95]Bharathan M., Mullarky I. K. Targeting mucosal immunity in the battle to develop a mastitis vaccine[J]. J Mammary Gland Biol Neoplasia,2011,16 (4):409-419.
[96]Park Y. H., Joo Y. S., Park J. Y.et al. Characterization of lymphocyte subpopulations and major histocompatibility complex haplotypes of mastitis-resistant and susceptible cows[J]. J Vet Sci,2004,5(1):29-39.
[97]Soltys J., Quinn M. T. Selective recruitment of T-cell subsets to the udder during staphylococcal and streptococcal mastitis:analysis of lymphocyte subsets and adhesion molecule expression[J]. Infect Immun,1999,67 (12):6293-6302.
[98]Bougarn S., Cunha P., Gilbert F. B.et al. Staphylococcal-associated molecular patterns enhance expression of immune defense genes induced by IL-17 in mammary epithelial cells[J]. Cytokine,2011,56 (3):749-759.
[99]Pappu R., Rutz S., Ouyang W. Regulation of epithelial immunity by IL-17 family cytokines[J]. Trends Immunol,2012,33 (7):343-349.
[100]He Y., Chu Q., Ma P.et al. Association of bovine CD4 and STAT5b single nucleotide polymorphisms with somatic cell scores and milk production traits in Chinese Holsteins[J]. J Dairy Res,2011:1-8.
[101]Shafer-Weaver K. A., Pighetti G. M., Sordillo L. M. Diminished mammary gland lymphocyte functions parallel shifts in trafficking patterns during the postpartum period[J]. Proc Soc Exp Biol Med,1996,212 (3):271-280.
[102]Banos G., Wall E., Coffey M. P.et al. Identification of immune traits correlated with dairy cow health, reproduction and productivity [J]. PLoS One,2013,8 (6):e65766.
[103]Wu Y. L., Ding Y. P., Tanaka Y.et al. gammadelta T cells and their potential for immunotherapy[J]. Int J Biol Sci,2014,10 (2):119-135.
[104]汤新逸,王胜军.IL-17～+γδT细胞[J].细胞与分子免疫学杂志,2011,27(07)：817-819.
[105]敬晓棋.乳腺炎细胞因子及T淋巴细胞亚群研究[D]：西北农林科技大学,2013.
[106]Moretta A. Natural killer cells and dendritic cells:rendezvous in abused tissues[J]. Nat Rev Immunol,2002,2(12):957-964.
[107]Robertson M. J. Role of chemokines in the biology of natural killer cells[J]. J Leukoc Biol, 2002,71 (2):173-183.
[108]Maghazachi A. A. Role of chemokines in the biology of natural killer cells[J]. Curr Top Microbiol Immunol,2010,341:37-58.
[109]Cooper M. A., Fehniger T. A., Caligiuri M. A. The biology of human natural killer-cell subsets[J]. Trends Immunol,2001,22 (11):633-640.
[110]Ueno H., Klechevsky E., Morita R.et al. Dendritic cell subsets in health and disease[J]. Immunol Rev,2007,219:118-142.
[111]Gilbert F. B., Cunha P., Jensen K.et al. Differential response of bovine mammary epithelial cells to Staphylococcus aureus or Escherichia coli agonists of the innate immune system[J]. Vet Res,2013,44(1):40.
[112]Strandberg Y., Gray C., Vuocolo T.et al. Lipopolysaccharide and lipoteichoic acid induce different innate immune responses in bovine mammary epithelial cells[J]. Cytokine,2005, 31(1):72-86.
[113]Giinther J., Koczan D., Yang W.et al. Assessment of the immune capacity of mammary epithelial cells:comparison with mammary tissue after challenge with Escherichia coli[J]. Vet Res,2009,40 (4)
[114]Goldammer T., Zerbe H., Molenaar A.et al. Mastitis increases mammary mRNA abundance of beta-defensin 5, toll-like-receptor 2 (TLR2), and TLR4 but not TLR9 in cattle[J]. Clin Diagn Lab Immunol,2004,11 (1):174-185.
[115]Yang W., Zerbe H., Petzl W.et al. Bovine TLR2 and TLR4 properly transduce signals from Staphylococcus aureus and E. coli, but S. aureus fails to both activate NF-kappaB in mammary epithelial cells and to quickly induce TNFalpha and interleukin-8 (CXCL8) expression in the udder[J]. Mol Immunol,2008,45 (5):1385-1397.
[116]Porcherie A., Cunha P., Trotereau A.et al. Repertoire of Escherichia coli agonists sensed by innate immunity receptors of the bovine udder and mammary epithelial cells[J]. Vet Res, 2012,43:14.
[117]Genini S., Badaoui B., Sclep G.et al. Strengthening insights into host responses to mastitis infection in ruminants by combining heterogeneous microarray data sources[J]. BMC Genomics,2011.12(1):225.
[118]Griesbeck-Zilch B., Osman M., Kuhn Ch.et al. Analysis of key molecules of the innate immune system in mammary epithelial cells isolated from marker-assisted and conventionally selected cattle[J]. J Dairy Sci,2009,92 (9):4621-4633.
[119]Burvenich C., Van Merris V., Mehrzad J.et al. Severity of E. coli mastitis is mainly determined by cow factors[J]. Vet Res,2003,34 (5):521-564.
[120]王新,张秀英.中药治疗奶牛乳房炎的研究现状与展望[J].中国兽药杂志,2004,38 (02):43-46.
[121]Bradley A. J., Leach K. A., Breen J. E.et al. Survey of the incidence and aetiology of mastitis on dairy farms in England and Wales[J]. Vet Rec,2007,160 (8):253-257.
[122]Kalmus P., Aasmae B., Karssin A.et al. Udder pathogens and their resistance to antimicrobial agents in dairy cows in Estonia[J]. Acta Vet Scand,2011,53:4.
[123]Lee J. W., Paape M. J., Elsasser T. H.et al. Elevated milk soluble CD14 in bovine mammary glands challenged with Escherichia coli lipopolysaccharide[J]. J Dairy Sci,2003,86 (7): 2382-2389.
[124]Paape M. J., Lilius E. M., Wiitanen P. A.et al. Intramammary defense against infections induced by Escherichia coli in cows[J]. Am J Vet Res,1996,57 (4):477-482.
[125]Gonen E., Vallon-Eberhard A., Elazar S.et al. Toll-like receptor 4 is needed to restrict the invasion of Escherichia coli P4 into mammary gland epithelial cells in a murine model of acute mastitis[J]. Cell Microbiol,2007,9 (12):2826-2838.
[126]Shimazu R., Akashi S., Ogata H.et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4[J]. J Exp Med,1999,189 (11):1777-1782.
[127]Miyake K. Endotoxin recognition molecules, Toll-like receptor 4-MD-2[J]. Semin Immunol, 2004,16(1):11-16.
[128]Risco A., Del Fresno C., Mambol A.et al. p38gamma and p38delta kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation[J]. Proc Natl Acad Sci U S A,2012,109 (28):11200-11205.
[129]Hines D. J., Choi H. B., Hines R. M.et al. Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides[J]. PLoS One,2013,8(3)
[130]Li Q., Verma I. M. NF-kappaB regulation in the immune system[J]. Nat Rev Immunol,2002, 2 (10):725-734.
[131]Calzado M. A., Bacher S., Schmitz M. L. NF-kappaB inhibitors for the treatment of inflammatory diseases and cancer[J]. Curr Med Chem,2007,14 (3):367-376.
[132]Petzl W., Zerbe H., Gunther J.et al. Escherichia coli, but not Staphylococcus aureus triggers an early increased expression of factors contributing to the innate immune defense in the udder of the cow[J]. Vet Res,2008,39 (2):18.
[133]Bougarn S., Cunha P., Harmache A.et al. Muramyl dipeptide synergizes with Staphylococcus aureus lipoteichoic acid to recruit neutrophils in the mammary gland and to stimulate mammary epithelial cells[J]. Clin Vaccine Immunol,2010,17 (11):1797-1809.
[134]Schmitz S., Pfaffl M. W., Meyer H. H.et al. Short-term changes of mRNA expression of various inflammatory factors and milk proteins in mammary tissue during LPS-induced mastitis[J]. Domest Anim Endocrinol,2004,26 (2):111-126.
[135]Wellnitz O., Baumert A., Saudenowa M.et al. Immune response of bovine milk somatic cells to endotoxin in healthy quarters with normal and very low cell counts[J]. J Dairy Res, 2010,77 (4):452-459.
[136]Morimoto K., Kanda N., Shinde S.et al. Effect of enterotoxigenic Escherichia coli vaccine on innate immune function of bovine mammary gland infused with lipopolysaccharide[J]. J Dairy Sci,2012,95 (9):5067-5074.
[137]Wellnitz O., Kerr D. E. Cryopreserved bovine mammary cells to model epithelial response to infection[J]. Vet Immunol Immunopathol,2004,101 (3-4):191-202.
[138]Hoeben D., Burvenich C., Trevisi E.et al. Role of endotoxin and TNF-alpha in the pathogenesis of experimentally induced coliform mastitis in periparturient cows[J]. J Dairy Res,2000,67 (4):503-514.
[139]Wellnitz O., Bruckmaier R. M. The innate immune response of the bovine mammary gland to bacterial infection[J]. Vet J,2012,192 (2):148-152.
[140]Ibeagha-Awemu E. M., Lee J. W., Ibeagha A. E.et al. Bacterial lipopolysaccharide induces increased expression of toll-like receptor (TLR) 4 and downstream TLR signaling molecules in bovine mammary epithelial cells[J]. Vet Res,2008,39 (2):11.
[141]陈莎莎,丁月云,金融,等.乳铁蛋白的抑菌作用及其机制[J].中国乳品工业,2007,35(05)：53-55.
[142]Unnewehr H., Rittirsch D., Sarma J. V.et al. Changes and regulation of the C5a receptor on neutrophils during septic shock in humans[J]. J Immunol,2013,190 (8):4215-4225.
[143]Jani P. K., Kajdacsi E., Megyeri M.et al. MASP-1 induces a unique cytokine pattern in endothelial cells:a novel link between complement system and neutrophil granulocytes[J]. PLoS One,2014,9 (1):e87104.
[144]庞继达.奶牛乳腺免疫调节的相关因素[J].中国奶牛,2010,4：44-46.
[145]Osman K. M., Hassan H. M., Ibrahim I. M.et al. The impact of staphylococcal mastitis on the level of milk IL-6, lysozyme and nitric oxide[J]. Comp Immunol Microbiol Infect Dis, 2010,33(1):85-93.
[146]李鑫,谭志坚,凌欣华,等.溶菌酶在饲料中的应用[J].畜牧与兽医,2013,45(11)：104-107.
[147]Liu X., Wang Y., Guo W.et al. Zinc-finger nickase-mediated insertion of the lysostaphin gene into the beta-casein locus in cloned cows[J]. Nat Commun,2013,4:2565.
[148]Liu X., Wang Y., Tian Y.et al. Generation of mastitis resistance in cows by targeting human lysozyme gene to beta-casein locus using zinc-finger nucleases[J]. Proc Biol Sci.2014.281 (1780):20133368.
[149]Alluwaimi A. M. The cytokines of bovine mammary gland:prospects for diagnosis and therapy[J]. Res Vet Sci,2004,77(3):211-222.
[150]Bannerman D. D., Paape M. J., Lee J. W.et al. Escherichia coli and Staphylococcus aureus elicit differential innate immune responses following intramammary infection[J]. Clin Diagn Lab Immunol,2004,11 (3):463-472.
[151]Stein B. N., Gamble J. R., Pitson S. M.et al. Activation of endothelial extracellular signal-regulated kinase is essential for neutrophil transmigration:potential involvement of a soluble neutrophil factor in endothelial activation[J]. J Immunol.2003,171 (11): 6097-6104.
[152]Yuan S. Y., Shen Q., Rigor R. R.et al. Neutrophil transmigration, focal adhesion kinase and endothelial barrier function[J]. Microvasc Res,2012,83 (1):82-88.
[153]Hordijk P. L. Endothelial signalling events during leukocyte transmigration[J]. FEBS J, 2006,273 (19):4408-4415.
[154]Nishimura T. Expression of potential lymphocyte trafficking mediator molecules in the mammary gland[J]. Vet Res,2003,34 (1):3-10.
[155]Oliver S. P., Murinda S. E. Antimicrobial resistance of mastitis pathogens[J]. Vet Clin North Am Food Anim Pract,2012,28 (2):165-185.
[156]Oliver S. P., Murinda S. E., Jayarao B. M. Impact of antibiotic use in adult dairy cows on antimicrobial resistance of veterinary and human pathogens:a comprehensive review[J]. Foodborne Pathog Dis,2011,8 (3):337-355.
[157]Erskine R. J., Wagner S., DeGraves F. J. Mastitis therapy and pharmacology [J]. Vet Clin North Am Food Anim Pract,2003,19(1):109-138.
[158]Kerro Dego O., Oliver S. P., Almeida R. A. Host-pathogen gene expression profiles during infection of primary bovine mammary epithelial cells with Escherichia coli strains associated with acute or persistent bovine mastitis[J]. Vet Microbiol,2012,155 (2-4): 291-297.
[159]van Schaik G., Lotem M., Schukken Y. H. Trends in somatic cell counts, bacterial counts, and antibiotic residue violations in New York State during 1999-2000[J]. J Dairy Sci,2002, 85 (4):782-789.
[160]Hogan J. S., Smith K. L., Hoblet K. H.et al. Field survey of clinical mastitis in low somatic cell count herds[J]. J Dairy Sci,1989,72 (6):1547-1556.
[161]DeGraves F. J., Anderson K. L. Ibuprofen treatment of endotoxin-induced mastitis in cows[J]. Am J Vet Res,1993,54 (7):1128-1132.
[162]Lohuis J. A., van Werven T., Brand A.et al. Pharmacodynamics and pharmacokinetics of carprofen, a non-steroidal anti-inflammatory drug, in healthy cows and cows with Escherichia coli endotoxin-induced mastitis[J]. J Vet Pharmacol Ther,1991,14 (3): 219-229.
[163]Vangroenweghe F., Duchateau L., Boutet P.et al. Effect of carprofen treatment following experimentally induced Escherichia coli mastitis in primiparous cows[J]. J Dairy Sci,2005, 88 (7):2361-2376.
[164]刘延鑫,孙宇,刘学芳,等.中草药防治奶牛乳房炎的研究进展[J].中国畜牧兽医,2011,38(11)：177-180.
[165]谢慧胜,陆钢,王红军,等.奶牛增乳保健剂增乳散的研究[J].中国兽医杂志,1993,19(06)：42-44.
[166]秦俊文,张强,王萍,等.“乳炎平”防治奶牛乳房炎试验[J].中国兽医杂志,1997,23(11)：19-20.
[167]王忠仁,冯志丹,何艳芬,等.自拟“麻连甘草汤”治疗奶牛乳痈[J].中兽医医药杂志,1996,5：40.
[168]刘纯传,陈初茂,霍杏桃,等.乳炎清治疗奶牛临床型乳房炎疗效观察[J].中国兽医科技,1997,27(02)：38-40.
[169]贺永建,林义明.桃红散防治奶牛乳房炎效果试验[J].四川畜牧兽医学院学报,1999,13(02)：66-71.
[170]甘志华,李启良,蒋武成,等.复方丹参液治疗奶牛隐性乳房炎试验[J].湖南农学院学报,1995,21(01)：84-88.
[171]鲁希英.中药制剂治疗奶牛隐性乳房炎的研究[J].中兽医医药杂志,1999,1：15-16.
[172]张文玫,胡平,郭泽领.绿草素对奶牛乳房炎治疗的临床观察[J].中国兽药杂志,2000,34(03)：58-59.
[173]张彬,薛明,崔颖,等.新兽药消炎醌对乳牛乳腺炎临床治疗试验[J].中国兽医科技,2000,30(08)：28-29.
[174]郎景民,布日额,张婷,等.奶牛乳房炎生物制剂研究进展[J].内蒙古民族大学学报(自然科学版),2009,24(05)：545-548.
[175]孟庆娟,李志明,冯士彬,等.中药复方灌注剂对奶牛乳房炎的防治效果及免疫增强 作用[J].中国畜牧兽医,2011,28(07)：219-223.
[176]张淼涛,王秋芳,效梅,等.复方中草药对隐性乳房炎乳牛细胞免疫功能的影响[J].中国兽医科技,2001,31(01)：24-25.
[177]高冠喜,董宙.中药质量标准化与中药现代化发展的探讨[J].中国医药导报,2010,7(02)：76-77.
[178]方圣鼎,陈仁通,韦璧瑜.中药现代化的思考[J].中草药,2007,38(05)：641-646.
[179]张立煌,李杰.中药现代化的现状及发展趋势[J].浙江大学学报(医学版),2011,40(04)：349-353.
[180]蒋文跃.寻找物质基础非当前中药现代化关键[J].中草药,2003,34(01)：1-3.
[181]朱大元.中药活性成分研究是中药现代化的重要组成部分[J].化学进展,2009,21(01)：24-29.
[182]屠鹏飞.姜勇.中药创新药物的发现与研发[J].中国天然药物.2007.5(02)：81-86.
[183]况荣华,周林,傅颖珺.中药以LPS-TLR4为作用靶点的抗炎机制的研究进展[J].南昌大学学报(医学版).2011,51(10)：89-92.
[184]Shin K. M., Kim I. T., Park Y. M.et al. Anti-inflammatory effect of caffeic acid methyl ester and its mode of action through the inhibition of prostaglandin E2, nitric oxide and tumor necrosis factor-alpha production[J]. Biochem Pharmacol,2004,68 (12):2327-2336.
[185]Jung J. E., Kim H. S., Lee C. S.et al. Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells[J]. Carcinogenesis,2007,28 (8):1780-1787.
[186]Bufalo M. C., Ferreira I.. Costa G.et al. Propolis and its constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-kappaB and MAPK activation in macrophages[J]. J Ethnopharmacol,2013
[187]Riollet C., Rainard P., Poutrel B. Differential induction of complement fragment C5a and inflammatory cytokines during intramammary infections with Escherichia coli and Staphylococcus aureus[J]. Clin Diagn Lab Immunol,2000,7 (2):161-167.
[188]Vangroenweghe F., Rainard P., Paape M.et al. Increase of Escherichia coli inoculum doses induces faster innate immune response in primiparous cows[J]. J Dairy Sci,2004,87 (12): 4132-4144.
[189]王亨.牛乳腺上皮细胞培养及乳房炎致病菌与细胞相互作用的研究[D]：中国农业大学,2007.
[190]李忠秋.牛乳腺上皮细胞研究进展[J].黑龙江农业科学,2008,5：130-133.
[191]陈建晖,高学军,李庆章.奶牛乳腺上皮细胞体外培养技术研究进展[J].东北农业大学学报,2009,40(07)：132-135.
[192]Flint D. J., Tonner E., Knight C. H.et al. Control of mammary involution by insulin-like growth factor binding proteins:role of prolactin[J]. Livestock Production Science,2001,70 (1-2):115-120.
[193]Lamote I., Meyer E., Massart-Leen A. M.et al. Sex steroids and growth factors in the regulation of mammary gland proliferation, differentiation, and involution[J]. Steroids, 2004,69 (3):145-159.
[194]Woodward T. L., Xie J., Fendrick J. L.et al. Proliferation of mouse mammary epithelial cells in vitro:interactions among epidermal growth factor, insulin-like growth factor I, ovarian hormones, and extracellular matrix proteins[J]. Endocrinology,2000,141 (10):3578-3586.
[195]Burvenich C., Bannerman D. D., Lippolis J. D.et al. Cumulative physiological events influence the inflammatory response of the bovine udder to Escherichia coli infections during the transition period[J]. J Dairy Sci,2007,90 Suppl 1:E39-E54.
[196]Akers R. M., Thompson W. Effect of induced leucocyte migration on mammary cell morphology and milk component biosynthesis[J]. J Dairy Sci,1987,70 (8):1685-1695.
[197]Zhao X., Lacasse P. Mammary tissue damage during bovine mastitis:causes and control[J]. J Anim Sci,2008,86 (13 Suppl):57-65.
[198]Semba R. D. Mastitis and transmission of human immunodeficiency virus through breast milk[J]. Ann N Y Acad Sci,2000,918:156-162.
[199]Willumsen J. F., Filteau S. M., Coutsoudis A.et al. Subclinical mastitis as a risk factor for mother-infant HIV transmission[J]. Adv Exp Med Biol,2000,478:211-223.
[200]Moussaoui F., Michelutti I., Le Roux Y.et al. Mechanisms involved in milk endogenous proteolysis induced by a lipopolysaccharide experimental mastitis[J]. J Dairy Sci,2002,85 (10):2562-2570.
[201]Capuco A. V., Paape M. J., Nickerson S. C. In vitro study of polymorphonuclear leukocyte damage to mammary tissues of lactating cows[J]. Am J Vet Res,1986,47 (3):663-668.
[202]凌云,燕鲍燕,张永林,等.兴安蒲公英的化学成分研究[J].海军总医院学报,1999,12(04)：233-235.
[203]赵守训,杭秉倩.蒲公英的化学成分和药理作用[J].中国野生植物资源,2001,20(03)：1-3.
[204]杨九凌,祝晓玲,李成文,等.咖啡酸及其衍生物咖啡酸苯乙酯药理作用研究进展[J].中国药学杂志,2013,48(08)：577-582.
[205]Lyczak J. B., Cannon C. L., Pier G. B. Lung infections associated with cystic fibrosis[J]. Clin Microbiol Rev,2002,15 (2):194-222.
[206]Dosogne H., Vangroenweghe F., Barrio B.et al. Decreased number and bactericidal activity against Staphylococcus aureus of the resident cells in milk of dairy cows during early lactation[J]. J Dairy Res,2001,68 (4):539-549.
[207]Rainard P., Riollet C., Poutrel B.et al. Phagocytosis and killing of Staphylococcus aureus by bovine neutrophils after priming by tumor necrosis factor-alpha and the des-arginine derivative of C5a[J]. Am J Vet Res,2000,61 (8):951-959.
[208]Capuco A. V., Paape M. J., Nickerson S. C. In vitro study of polymorphonuclear leukocyte damage to mammary tissues of lactating cows[J]. Am J Vet Res,1986,47 (3):663-668.
[209]Lahouassa H., Moussay E., Rainard P.et al. Differential cytokine and chemokine responses of bovine mammary epithelial cells to Staphylococcus aureus and Escherichia coli[J]. Cytokine,2007,38 (1):12-21.
[210]Buitenhuis B., Rontved C. M., Edwards S. M.et al. In depth analysis of genes and pathways of the mammary gland involved in the pathogenesis of bovine Escherichia coli-mastitis[J]. BMC Genomics,2011,12:130.
[211]Elazar S., Gonen E., Livneh-Kol A.et al. Essential role of neutrophils but not mammary alveolar macrophages in a murine model of acute Escherichia coli mastitis[J]. Vet Res, 2010,41 (4):53.
[212]Kumar H., Kawai T., Akira S. Pathogen recognition by the innate immune system[J]. Int Rev Immunol,2011,30 (1):16-34.
[213]Hines D. J., Choi H. B., Hines R. M.et al. Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides[J]. PLoS One,2013,8(3):e60388.
[214]宋舟,张立艳,董海兵,等.JAK-STAT信号通路研究进展[J].中国畜牧兽医,2012,39(06)：128-132.
[215]Kacimi R., Giffard R. G., Yenari M. A. Endotoxin-activated microglia injure brain derived endothelial cells via NF-kappaB, JAK-STAT and JNK stress kinase pathways[J]. J Inflamm (Lond),2011,8:7.
[216]Platanias L. C. Map kinase signaling pathways and hematologic malignancies[J]. Blood, 2003,101 (12):4667-4679.
[217]Guha M., Mackman N. LPS induction of gene expression in human monocytes[J]. Cell Signal,2001,13 (2):85-94.
[218]Cho S. Y., Park S. J., Kwon M. J.et al. Quercetin suppresses proinflammatory cytokines production through MAP kinases andNF-kappaB pathway in lipopolysaccharide-stimulated macrophage[J]. Mol Cell Biochem,2003,243 (1-2):153-160.
[219]Vanden Berghe W., Plaisance S., Boone E.et al. p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor[J]. J Biol Chem,1998,273 (6): 3285-3290.
[220]Parthasarathy G., Philipp M. T. The MEK/ERK pathway is the primary conduit for Borrelia burgdorferi-induced inflammation and P53-mediated apoptosis in oligodendrocytes[J]. Apoptosis,2014,19(1):76-89.
[221]Xu X., Yin P., Wan C.et al. Punicalagin Inhibits Inflammation in LPS-Induced RAW264.7 Macrophages via the Suppression of TLR4-Mediated MAPKs and NF-kappaB Activation[J]. Inflammation,2014
[222]Sung M. H., Li N., Lao Q.et al. Switching of the relative dominance between feedback mechanisms in lipopolysaccharide-induced NF-kappaB signaling[J]. Sci Signal,2014,7 (308):a6.
[223]Liu H. T., He J. L., Li W. M.et al. Geniposide inhibits interleukin-6 and interleukin-8 production in lipopolysaccharide-induced human umbilical vein endothelial cells by blocking p38 and ERK1/2 signaling pathways[J]. Inflamm Res,2010,59 (6):451-461.
[224]Ryu M., Kim E. H., Chun M.et al. Astragali Radix elicits anti-inflammation via activation of MKP-1, concomitant with attenuation of p38 and Erk[J]. J Ethnopharmacol,2008,115 (2): 184-193.
[225]Dudhgaonkar S., Thyagarajan A., Sliva D. Suppression of the inflammatory response by triterpenes isolated from the mushroom Ganoderma lucidum[J]. Int Immunopharmacol, 2009,9(11):1272-1280.
[226]黄田英,李庆章,侯晓明.乳腺中JAK-STAT信号通路的研究进展[J].中国乳品工业,2010,38(02)：41-44.
[227]Philp J. A., Burdon T. G., Watson C. J. Differential activation of STATs 3 and 5 during mammary gland development[J]. FEBS Lett,1996,396 (1):77-80.
[228]Desrivieres S., Kunz C., Barash I.et al. The biological functions of the versatile transcription factors STAT3 and STAT5 and new strategies for their targeted inhibition[J]. J Mammary Gland Biol Neoplasia,2006,11(1):75-87.
[229]Khaled W. T., Read E. K., Nicholson S. E.et al. The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development[J]. Development,2007,134 (15): 2739-2750.
[230]Santos S. J., Haslam S. Z., Conrad S. E. Signal transducer and activator of transcription 5a mediates mammary ductal branching and proliferation in the nulliparous mouse[J]. Endocrinology,2010,151 (6):2876-2885.
[231]王文正,赵素梅,高士争.Leptin介导的JAK/STAT信号通路对脂类代谢调节的研究进展[J].中国细胞生物学学报,2011,33(05)：584-589.
[232]Shillingford J. M., Hennighausen L. Experimental mouse genetics-- answering fundamental questions about mammary gland biology[J]. Trends Endocrinol Metab,2001,12 (9): 402-408.
[233]Brym P., Kaminski S., Rusc A. New SSCP polymorphism within bovine STAT5A gene and its associations with milk performance traits in Black-and-White and Jersey cattle[J]. J Appl Genet,2004,45 (4):445-452.
[234]Liu X. F., Li M., Li Q. Z.et al. Stat5a increases lactation of dairy cow mammary gland epithelial cells cultured in vitro[J]. In Vitro Cell Dev Biol Anim,2012,48 (9):554-561.
[235]Ghosh S., Hayden M. S. New regulators of NF-kappaB in inflammation[J]. Nat Rev Immunol,2008,8(11):837-848.
[236]Lenardo M. J., Baltimore D. NF-kappa B:a pleiotropic mediator of inducible and tissue-specific gene control[J]. Cell,1989,58 (2):227-229.
[237]Li J., Peet G. W., Balzarano D.et al. Novel NEMO/IkappaB kinase and NF-kappa B target genes at the pre-B to immature B cell transition[J]. J Biol Chem,2001,276 (21): 18579-18590.
[238]Li X., Massa P. E., Hanidu A.et al. IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program[J]. J Biol Chem, 2002,277 (47):45129-45140.
[239]Hoffmann A., Baltimore D. Circuitry of nuclear factor kappaB signaling[J]. Immunol Rev, 2006,210:171-186.
[240]Croy C. H., Bergqvist S., Huxford T.et al. Biophysical characterization of the free IkappaBalpha ankyrin repeat domain in solution[J]. Protein Sci,2004,13 (7):1767-1777.
[241]Zhong H., SuYang H., Erdjument-Bromage H.et al. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism[J]. Cell,1997,89 (3):413-424.
[242]Scott M. L., Fujita T., Liou H. C.et al. The p65 subunit of NF-kappa B regulates I kappa B by two distinct mechanisms[J]. Genes Dev.1993,7 (7A):1266-1276.
[243]Ito C. Y.. Kazantsev A. G.. Baldwin A. S. Three NF-kappa B sites in the I kappa B-alpha promoter are required for induction of gene expression by TNF alpha[J]. Nucleic Acids Res, 1994,22 (18):3787-3792.
[244]Chiao P. J., Miyamoto S., Verma I. M. Autoregulation of I kappa B alpha activity[J]. Proc Natl Acad Sci U S A,1994,91 (1):28-32.
[245]Arenzana-Seisdedos F., Thompson J., Rodriguez M S.et al. Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B[J]. Mol Cell Biol.1995,15 (5):2689-2696.
[246]Arenzana-Seisdedos F., Turpin P., Rodriguez M.et al. Nuclear localization of I kappa B alpha promotes active transport of NF-kappa B from the nucleus to the cytoplasm[J]. J Cell Sci,1997,110 (Pt 3):369-378.
[247]Tam W. F., Lee L. H., Davis L.et al. Cytoplasmic sequestration of rel proteins by IkappaBalpha requires CRM1-dependent nuclear export[J]. Mol Cell Biol,2000,20 (6): 2269-2284.
[248]Hoffmann A., Levchenko A., Scott M. L.et al. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation[J]. Science,2002,298 (5596):1241-1245.
[249]Cheng J. D., Ryseck R. P., Attar R. M.et al. Functional redundancy of the nuclear factor kappa B inhibitors I kappa B alpha and I kappa B beta[J]. J Exp Med,1998,188 (6): 1055-1062.
[250]Lee S. H., Hannink M. Characterization of the nuclear import and export functions of Ikappa B(epsilon)[J]. J Biol Chem,2002,277 (26):23358-23366.
[251]Tergaonkar V., Correa R. G., Ikawa M.et al. Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity[J]. Nat Cell Biol,2005,7 (9):921-923.
[252]Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity:update on Toll-like receptors[J]. Nat Immunol,2010,11 (5):373-384.
[253]Beaudoin T., LaFayette S., Roussel L.et al. The level of p38alpha mitogen-activated protein kinase activation in airway epithelial cells determines the onset of innate immune responses to planktonic and biofilm Pseudomonas aeruginosa[J]. J Infect Dis,2013,207 (10): 1544-1555.
[254]Cario E., Rosenberg I. M., Brandwein S. L.et al. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors[J]. J Immunol,2000,164 (2):966-972.
[255]Guma M., Stepniak D., Shaked H.et al. Constitutive intestinal NF-kappaB does not trigger destructive inflammation unless accompanied by MAPK activation[J]. J Exp Med,2011, 208(9):1889-1900.
[256]Martel G., Rousseau S. TPL2 signalling:from Toll-like receptors-mediated ERK1/ERK2 activation to Cystic Fibrosis Lung disease[J]. Int J Biochem Cell Biol,2014 (In press).
[257]Kang N. J., Lee K. W., Shin B. J.et al. Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity and UVB-induced COX-2 expression[J]. Carcinogenesis,2009,30 (2):321-330.
[258]Lee Y., Shin D. H., Kim J. H.et al. Caffeic acid phenethyl ester-mediated Nrf2 activation and IkappaB kinase inhibition are involved in NFkappaB inhibitory effect:structural analysis for NFkappaB inhibition[J]. Eur J Pharmacol,2010,643 (1):21-28.
[259]Liu W., Ouyang X., Yang J.et al. AP-1 activated by toll-like receptors regulates expression of IL-23 p19[J]. J Biol Chem,2009,284 (36):24006-24016.
[260]Jung W. K., Choi I., Lee D. Y.et al. Caffeic acid phenethyl ester protects mice from lethal endotoxin shock and inhibits lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW 264.7 macrophages via the p38/ERK and NF-kappaB pathways[J]. Int J Biochem Cell Biol,2008,40 (11):2572-2582.
[261]Ha S. K., Moon E., Kim S. Y. Chrysin suppresses LPS-stimulated proinflammatory responses by blocking NF-kappaB and JNK activations in microglia cells[J]. Neurosci Lett, 2010,485 (3):143-147.
[262]Giinther J., Petzl W., Zerbe H.et al. Lipopolysaccharide priming enhances expression of effectors of immune defence while decreasing expression of pro-inflammatory cytokines in mammary epithelia cells from cows[J]. BMC Genomics,2012,13:17.
[263]Shuster D. E., Kehrli ME Jr, Rainard P.et al. Complement fragment C5a and inflammatory cytokines in neutrophil recruitment during intramammary infection with Escherichia coli[J]. Infect Immun,1997,65 (8):3286-3292.
[264]Scheibel M., Klein B., Merkle H.et al. IkBβ is an essential co-activator for LPS-induced IL-1β transcription in vivo[J]. J Exp Med,2010,207 (12):2621-2630.
[265]Wang L. C., Chu K. H., Liang Y. C.et al. Caffeic acid phenethyl ester inhibits nuclear factor-kappaB and protein kinase B signalling pathways and induces caspase-3 expression in primary human CD4+ T cells[J]. Clin Exp Immunol,2010,160 (2):223-232.
[266]Puangpraphant S., Berhow M. A., Vermillion K.et al. Dicaffeoylquinic acids in Yerba mate (Ilex paraguariensis St. Hilaire) inhibit NF-kappaB nucleus translocation in macrophages and induce apoptosis by activating caspases-8 and -3 in human colon cancer cells[J]. Mol Nutr Food Res,2011,55(10):1509-1522.
[267]杨九凌,祝晓玲,李成文,等.咖啡酸及其衍生物咖啡酸苯乙酯药理作用研究进展[J].中国药学杂志,2013,48(08)：577-582.
[2]Kemp M. H., Nolan A. M., Cripps P. J.et al. Animal-based measurements of the severity of mastitis in dairy cows[J]. Vet Rec,2008,163 (6):175-179.
[3]Oliver S. P., Influence of inflammation on mammary gland metabolism and milk composition[M],1994.
[4]Huijps K., Lam T. J., Hogeveen H. Costs of mastitis:facts and perception[J]. J Dairy Res, 2008,75(1):113-120.
[5]Hortet P., Seegers H. Loss in milk yield and related composition changes resulting from clinical mastitis in dairy cows[J]. Prev Vet Med,1998,37 (1-4):1-20.
[6]Akers R. M., Nickerson S. C. Mastitis and its impact on structure and function in the ruminant mammary gland[J]. J Mammary Gland Biol Neoplasia,2011,16 (4):275-289.
[7]Hogeveen H., Huijps K., Lam T. J. Economic aspects of mastitis:new developments[J]. N Z Vet J,2011,59(1):16-23.
[8]Lam T. J., van den Borne B. H., Jansen J.et al. Improving bovine udder health:a national mastitis control program in the Netherlands[J]. J Dairy Sci,2013,96 (2):1301-1311.
[9]Nielsen Christel. Economic Impact of Mastitis in Dairy Cow [D]:Swedish University of Agricultural Sciences,2009.
[10]Zhao X., Lacasse P. Mammary tissue damage during bovine mastitis:causes and control[J]. J Anim Sci,2008,86 (13 Suppl):57-65.
[11]Wilson D. J., Gonzalez R. N., Das H. H. Bovine mastitis pathogens in New York and Pennsylvania:prevalence and effects on somatic cell count and milk production[J]. J Dairy Sci,1997,80 (10):2592-2598.
[12]段玉.奶牛乳腺炎危害性分析[J].中国畜禽种业,2007,8：76-78.
[13]金尔光,曾新华,周木清,等.奶牛乳房炎研究概况[J].养殖与饲料,2008,6：69-70.
[14]蒋春茂,周新民,周广生,等.奶牛乳房炎研究进展[J].中国畜牧兽医,2004,31(05)：36-38.
[15]Jansen J., Renes R. J., Lam T. J. Evaluation of two communication strategies to improve udder health management[J]. J Dairy Sci,2010,93 (2):604-612.
[16]Reyher K. K., Haine D., Dohoo I. R.et al. Examining the effect of intramammary infections with minor mastitis pathogens on the acquisition of new intramammary infections with major mastitis pathogens--a systematic review and meta-analysis[J]. J Dairy Sci,2012,95 (11):6483-6502.
[17]Zecconi A., Binda E., Borromeo V.et al. Relationship between some Staphylococcus aureus pathogenic factors and growth rates and somatic cell counts[J]. J Dairy Res,2005,72 (2): 203-208.
[18]王桂琴,吴聪明,宋丽华,等.奶牛乳房炎大肠杆菌的血清型及耐药性调查研究[J].中国兽医杂志,2006,42(12)：19-20.
[19]Wellenberg G. J., van der Poel W. H., Van Oirschot J. T. Viral infections and bovine mastitis:a review[J]. Vet Microbiol,2002,88 (1):27-45.
[20]Herlekar D. A., Shashikant C. S., Gurjar A. A.et al. Presence of viral and bacterial organisms in milk and their association with somatic cell counts[J]. J Dairy Sci,2013,96 (10):6336-6346.
[21]Jagielski T., Lassa H., Ahrholdt J.et al. Genotyping of bovine Prototheca mastitis isolates from Poland[J]. Vet Microbiol,2011,149 (1-2):283-287.
[22]Walia H. S.. Abraham T. K., Shaikh H. Fungal mastitis. Case report[J]. Acta Chir Scand. 1987,153 (2):133-135.
[23 ]周接水.I Prototheca zopfii引起的牛乳房炎[J].畜禽业,1999,9：57-58.
[24]Costa E. O., Melville P. A., Ribeiro A. R.et al. Epidemiologic study of environmental sources in a Prototheca zopfii outbreak of bovine mastitis[J]. Mycopathologia,1997,137 (1):33-36.
[25]Jensen H. E., Aalbaek B., Bloch B.et al. Bovine mammary protothecosis due to Prototheca zopfii[J]. Med Mycol,1998,36 (2):89-95.
[26]Fu P., Sun Z., Zhang Y.et al. Development of a direct competitive ELISA for the detection of Mycoplasma bovis infection based on a monoclonal antibody of P48 protein[J]. BMC Vet Res.2014,10(1):42.
[27]Wawegama N. K., Browning G. F., Kanci A.et al. Development of a recombinant protein-based enzyme-linked immunosorbent assay for diagnosis of Mycoplasma bovis infection in cattle[J]. Clin Vaccine Immunol,2014,21 (2):196-202.
[28]HertI J. A., Schukken Y. H., Welcome F. L.et al. Pathogen-specific effects on milk yield in repeated clinical mastitis episodes in Holstein dairy cows[J]. J Dairy Sci,2014,97 (3): 1465-1480.
[29]Park H. R., Hong M. K., Hwang S. Y.et al. Characterisation of Pseudomonas aeruginosa related to bovine mastitis[J]. Acta Vet Hung,2014,62 (1):1-12.
[30]Schukken Y., Chuff M., Moroni P.et al. The "other" gram-negative bacteria in mastitis: Klebsiella, serratia, and more[J]. Vet Clin North Am Food Anim Pract,2012,28 (2): 239-256.
[31]Quesnell R. R., Klaessig S., Watts J. L.et al. Bovine intramammary Escherichia coli challenge infections in late gestation demonstrate a dominant antiinflammatory immunological response[J]. J Dairy Sci,2012,95 (1):117-126.
[32]Bradley A. J., Green M. J. Aetiology of clinical mastitis in six Somerset dairy herds[J]. Vet Rec,2001,148 (22):683-686.
[33]Bradley A. J., Green M. J. Adaptation of Escherichia coli to the bovine mammary gland[J]. J Clin Microbiol,2001,39 (5):1845-1849.
[34]Boehmer J. L. Proteomic Analyses of Host and Pathogen Responses during Bovine Mastitis[J]. J Mammary Gland Biol Neoplasia,2011,16 (4):323-338.
[35]马翀.关于奶牛乳房炎几个问题的探究[D]：中国农业大学,2007.
[36]Green M. J., Green L. E., Medley G. F.et al. Influence of dry period bacterial intramammary infection on clinical mastitis in dairy cows[J]. J Dairy Sci,2002,85 (10):2589-2599.
[37]Dogan B., Klaessig S., Rishniw M.et al. Adherent and invasive Escherichia coli are associated with persistent bovine mastitis[J]. Vet Microbiol,2006,116 (4):270-282.
[38]Shpigel N. Y., Elazar S., Rosenshine I. Mammary pathogenic Escherichia coli[J]. Curr Opin Microbiol,2008,11 (1):60-65.
[39]Almeida R. A., Dogan B., Klaessing S.et al. Intracellular fate of strains of Escherichia coli isolated from dairy cows with acute or chronic mastitis[J]. Vet Res Commun,2011,35 (2): 89-101.
[40]Makovec J. A., Ruegg P. L. Results of milk samples submitted for microbiological examination in Wisconsin from 1994 to 2001 [J]. J Dairy Sci,2003,86 (11):3466-3472.
[41]Grohn Y. T., Wilson D. J., Gonzalez R. N.et al. Effect of pathogen-specific clinical mastitis on milk yield in dairy cows[J]. J Dairy Sci,2004,87 (10):3358-3374.
[42]Cha E., Bar D., Hertl J. A.et al. The cost and management of different types of clinical mastitis in dairy cows estimated by dynamic programming[J]. J Dairy Sci,2011,94 (9): 4476-4487.
[43]Seegers H., Fourichon C., Beaudeau F. Production effects related to mastitis and mastitis economics in dairy cattle herds[J]. Vet Res,2003,34 (5):475-491.
[44]Hazlett M. J., Little P. B., Maxie M. G.et al. Fatal mastitis of dairy cows:a retrospective study[J]. Can J Comp Med,1984,48 (2):125-129.
[45]Paduch J. H., Mohr E., Kromker V. The association between bedding material and the bacterial counts of Staphylococcus aureus, Streptococcus uberis and coliform bacteria on teat skin and in teat canals in lactating dairy cattle[J]. J Dairy Res,2013,80 (2):159-164.
[46]Rainard P., Riollet C. Innate immunity of the bovine mammary gland[J]. Vet Res,2006,37 (3):369-400.
[47]Bradley A. J., Breen J. E., Payne B.et al. A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant[J]. J Dairy Sci,2011,94 (2):692-704.
[48]Bradley A. J., Green M. J. The importance of the nonlactating period in the epidemiology of intramammary infection and strategies for prevention[J]. Vet Clin North Am Food Anim Pract,2004,20 (3):547-568.
[49]Green M. J., Bradley A. J., Medley G. F.et al. Cow, farm, and management factors during the dry period that determine the rate of clinical mastitis after calving[J]. J Dairy Sci,2007, 90 (8):3764-3776.
[50]Green M. J., Bradley A. J., Medley G. V.et al. Cow, farm, and herd management factors in the dry period associated with raised somatic cell counts in early lactation[J]. J Dairy Sci, 2008,91 (4):1403-1415.
[51]Barkema H. W., Schukken Y. H., Lam T. J.et al. Incidence of clinical mastitis in dairy herds grouped in three categories by bulk milk somatic cell counts[J]. J Dairy Sci,1998,81 (2): 411-419.
[52]Pieper J., Hoedemaker M., Kromker V. [Significance of the dry period for the development and prevention of new infections of the bovine mammary gland][J]. Tierarztl Prax Ausg G Grosstiere Nutztiere,2013,41 (5):315-324,325.
[53]Dietert R. R., Piepenbrink M. S. The managed immune system:protecting the womb to delay the tomb[J]. Hum Exp Toxicol.2008,27 (2):129-134.
[54]Comalli M. P., Eberhart R. J., Griel LC Jret al. Changes in the microscopic anatomy of the bovine teat canal during mammary involution[J]. Am J Vet Res.1984,45 (11):2236-2242.
[55]Oldham E. R., Eberhart R. J., Lange A. L.et al. Changes in the bovine teat canal during the nonlactating period and early lactation, as measured by teat canal impressions[J]. Am J Vet Res,1991,52 (12):2075-2079.
[56]Jonsson N. N., Fortes M. R., Piper E. K.et al. Comparison of metabolic, hematological, and peripheral blood leukocyte cytokine profiles of dairy cows and heifers during the peri parturient period[J]. J Dairy Sci,2013,96 (4):2283-2292.
[57]Moves K. M., Drackley J. K., Morin D. E.et al. Predisposition of cows to mastitis in non-infected mammary glands:effects of dietary-induced negative energy balance during mid-lactation on immune-related genes[J]. Funct Integr Genomics,2011,11 (1):151-156.
[58]Zarrin M., Wellnitz O., van Dorland H. A.et al. Induced hyperketonemia affects the mammary immune response during lipopolysaccharide challenge in dairy cows[J]. J Dairy Sci,2014,97(1):330-339.
[59]Suriyasathaporn W., Heuer C., Noordhuizen-Stassen E. N.et al. Hyperketonemia and the impairment of udder defense:a review[J]. Vet Res,2000,31 (4):397-412.
[60]Kelm S. C., Freeman A. E. Direct and correlated responses to selection for milk yield: results and conclusions of regional project NC-2, "improvement of dairy cattle through breeding, with emphasis on selection". NC-2 Technical Committee[J]. J Dairy Sci,2000,83 (12):2721-2732.
[61]Shook G. E. Major advances in determining appropriate selection goals[J]. J Dairy Sci,2006, 89(4):1349-1361.
[62]Lovis L., Frutschi Mascher V., Gern L.et al. [Cattle farmers' perception of the nuisances caused by insects and ticks to cattle in the Canton Jura][J]. Schweiz Arch Tierheilkd,2008, 150 (9):457-465.
[63]Porcherie A., Cunha P., Trotereau A.et al. Repertoire of Escherichia coli agonists sensed by innate immunity receptors of the bovine udder and mammary epithelial cells[J]. Vet Res, 2012,43(1):14.
[64]Paulrud C. O., Basic concepts of the bovine teat canal[M],2005:215-245.
[65]Paduch J. H., Mohr E., Kromker V. The association between teat end hyperkeratosis and teat canal microbial load in lactating dairy cattle[J]. Vet Microbiol,2012,158 (3-4):353-359.
[66]Neijenhuis F., Barkema H. W., Hogeveen H.et al. Relationship between teat-end callosity and occurrence of clinical mastitis[J]. J Dairy Sci,2001,84 (12):2664-2672.
[67]Zecconi A., Hamann J., Bronzo V.et al. Relationship between teat tissue immune defences and intramammary infections[J]. Adv Exp Med Biol,2000,480:287-293.
[68]Rinaldi M., Li R. W., Bannerman D. D.et al. A sentinel function for teat tissues in dairy cows:dominant innate immune response elements define early response to E. coli mastitis[J]. Funct Integr Genomics,2010,10 (1):21-38.
[69]Du Preez J. H. Teat canal infections[J]. Kieler Milchw. Forsch,1985 (37):267-273.
[70]Pryor S. M. Bovine mastitis and ecology of Streptococcus uberis[D]:University of Waikato, New Zealand,2008.
[71]Heeschen W. H., IDF and mastitis-a general review. In:Hillerton, J. E. (Ed.), Mastitis Research into Practice. Proc[M]. Christchurch, New Zealand,2010.
[72]Pantoja J. C., Hulland C., Ruegg P. L. Dynamics of somatic cell counts and intramammary infections across the dry period[J]. Prev Vet Med,2009,90 (1-2):43-54.
[73]Archer S. C., Mc Coy F., Wapenaar W.et al. Association between somatic cell count after first parturition and cumulative milk yield in dairy cows[J]. Vet Rec,2013,173 (13):316.
[74]Sordillo L. M., Streicher K. L. Mammary gland immunity and mastitis susceptibility[J]. J Mammary Gland Biol Neoplasia,2002,7 (2):135-146.
[75]Sordillo L. M., Shafer-Weaver K., DeRosa D. Immunobiology of the mammary gland[J]. J Dairy Sci,1997,80(8):1851-1865.
[76]Paape M. J., Shafer-Weaver K., Capuco A. V.et al. Immune surveillance of mammary tissue by phagocytic cells[J]. Adv Exp Med Biol,2000,480:259-277.
[77]MJ Paape, A Contreras. Historical perspective on the evolution of the milk somatic cell count[J]. Flem Vet Suppl,1997:66-93.
[78]Mehrzad J., Desrosiers C., Lauzon K.et al. Proteases involved in mammary tissue damage during endotoxin-induced mastitis in dairy cows[J]. J Dairy Sci,2005,88 (1):211-222.
[79]Paape M. J., Shafer-Weaver K., Capuco A. V.et al. Immune surveillance of mammary tissue by phagocytic cells[J]. Adv Exp Med Biol,2000,480:259-277.
[80]Paape M. J., Bannerman D. D., Zhao X.et al. The bovine neutrophil:Structure and function in blood and milk[J]. Vet Res,2003,34 (5):597-627.
[81]Lakritz J., Tyler J. W., Marsh A. E.et al. Tilmicosin reduces lipopolysaccharide-stimulated bovine alveolar macrophage prostaglandin E(2) production via a mechanism involving phospholipases[J]. Vet Ther,2002,3(1):7-21.
[82]Paape M., Mehrzad J., Zhao X.et al. Defense of the bovine mammary gland by polymorphonuclear neutrophil leukocytes[J]. J Mammary Gland Biol Neoplasia,2002,7 (2): 109-121.
[83]Riollet C., Rainard P., Poutrel B. Cells and cytokines in inflammatory secretions of bovine mammary gland[J]. Adv Exp Med Biol,2000,480:247-258.
[84]Mullan N. A., Carter E. A., Nguyen K. A. Phagocytic and bactericidal properties of bovine macrophages from non-lactating mammary glands[J]. Res Vet Sci,1985,38 (2):160-166.
[85]Ledbetter T. K., Paape M. J., Douglass L. W. Cytotoxic effects of peroxynitrite, polymorphonuclear neutrophils, free-radical scavengers, inhibitors of myeloperoxidase, and inhibitors of nitric oxide synthase on bovine mammary secretory epithelial cells[J]. Am J Vet Res,2001,62 (3):286-293.
[86]Burvenich C., Monfardini E., Mehrzad J.et al. Role of neutrophil polymorphonuclear leukocytes during bovine coliform mastitis:physiology or pathology?[J]. Verh K Acad Geneeskd Belg,2004,66 (2):97-150,150-153.
[87]Burk D. R., Senechal-Willis P., Lopez L. C.et al. Suppression of lipopolysaccharide-induced inflammatory responses in RAW 264.7 murine macrophages by aqueous extract of Clinopodium vulgare L. (Lamiaceae)[J]. J Ethnopharmacol,2009,126 (3):397-405.
[88]崔立莉.奶牛乳腺上皮细胞体外培养体系的建立及其应用[D]：新疆农业大学,2006.
[89]Farrera C., Fadeel B. Macrophage clearance of neutrophil extracellular traps is a silent process[J]. J Immunol,2013,191 (5):2647-2656.
[90]Mehrzad J., Duchateau L., Burvenich C. Viability of milk neutrophils and severity of bovine coliform mastitis[J]. J Dairy Sci,2004,87 (12):4150-4162.
[91]Taylor B. C., Keefe R. G., Dellinger J. D.et al. T cell populations and cytokine expression in milk derived from normal and bacteria-infected bovine mammary glands[J]. Cell Immunol, 1997,182(1):68-76.
[92]Riollet C., Rainard P., Poutrel B. Cell subpopulations and cytokine expression in cow milk in response to chronic Staphylococcus aureus infection[J]. J Dairy Sci,2001,84 (5): 1077-1084.
[93]Asai K., Kai K., Rikiishi H.et al. Variation in CD4+ T and CD8+ T lymphocyte subpopulations in bovine mammary gland secretions during lactating and non-lactating periods[J]. Vet Immunol Immunopathol,1998,65 (1):51-61.
[94]Wong P., Pamer E. G. CD8 T cell responses to infectious pathogens[J]. Annu Rev Immunol, 2003,21:29-70.
[95]Bharathan M., Mullarky I. K. Targeting mucosal immunity in the battle to develop a mastitis vaccine[J]. J Mammary Gland Biol Neoplasia,2011,16 (4):409-419.
[96]Park Y. H., Joo Y. S., Park J. Y.et al. Characterization of lymphocyte subpopulations and major histocompatibility complex haplotypes of mastitis-resistant and susceptible cows[J]. J Vet Sci,2004,5(1):29-39.
[97]Soltys J., Quinn M. T. Selective recruitment of T-cell subsets to the udder during staphylococcal and streptococcal mastitis:analysis of lymphocyte subsets and adhesion molecule expression[J]. Infect Immun,1999,67 (12):6293-6302.
[98]Bougarn S., Cunha P., Gilbert F. B.et al. Staphylococcal-associated molecular patterns enhance expression of immune defense genes induced by IL-17 in mammary epithelial cells[J]. Cytokine,2011,56 (3):749-759.
[99]Pappu R., Rutz S., Ouyang W. Regulation of epithelial immunity by IL-17 family cytokines[J]. Trends Immunol,2012,33 (7):343-349.
[100]He Y., Chu Q., Ma P.et al. Association of bovine CD4 and STAT5b single nucleotide polymorphisms with somatic cell scores and milk production traits in Chinese Holsteins[J]. J Dairy Res,2011:1-8.
[101]Shafer-Weaver K. A., Pighetti G. M., Sordillo L. M. Diminished mammary gland lymphocyte functions parallel shifts in trafficking patterns during the postpartum period[J]. Proc Soc Exp Biol Med,1996,212 (3):271-280.
[102]Banos G., Wall E., Coffey M. P.et al. Identification of immune traits correlated with dairy cow health, reproduction and productivity [J]. PLoS One,2013,8 (6):e65766.
[103]Wu Y. L., Ding Y. P., Tanaka Y.et al. gammadelta T cells and their potential for immunotherapy[J]. Int J Biol Sci,2014,10 (2):119-135.
[104]汤新逸,王胜军.IL-17～+γδT细胞[J].细胞与分子免疫学杂志,2011,27(07)：817-819.
[105]敬晓棋.乳腺炎细胞因子及T淋巴细胞亚群研究[D]：西北农林科技大学,2013.
[106]Moretta A. Natural killer cells and dendritic cells:rendezvous in abused tissues[J]. Nat Rev Immunol,2002,2(12):957-964.
[107]Robertson M. J. Role of chemokines in the biology of natural killer cells[J]. J Leukoc Biol, 2002,71 (2):173-183.
[108]Maghazachi A. A. Role of chemokines in the biology of natural killer cells[J]. Curr Top Microbiol Immunol,2010,341:37-58.
[109]Cooper M. A., Fehniger T. A., Caligiuri M. A. The biology of human natural killer-cell subsets[J]. Trends Immunol,2001,22 (11):633-640.
[110]Ueno H., Klechevsky E., Morita R.et al. Dendritic cell subsets in health and disease[J]. Immunol Rev,2007,219:118-142.
[111]Gilbert F. B., Cunha P., Jensen K.et al. Differential response of bovine mammary epithelial cells to Staphylococcus aureus or Escherichia coli agonists of the innate immune system[J]. Vet Res,2013,44(1):40.
[112]Strandberg Y., Gray C., Vuocolo T.et al. Lipopolysaccharide and lipoteichoic acid induce different innate immune responses in bovine mammary epithelial cells[J]. Cytokine,2005, 31(1):72-86.
[113]Giinther J., Koczan D., Yang W.et al. Assessment of the immune capacity of mammary epithelial cells:comparison with mammary tissue after challenge with Escherichia coli[J]. Vet Res,2009,40 (4)
[114]Goldammer T., Zerbe H., Molenaar A.et al. Mastitis increases mammary mRNA abundance of beta-defensin 5, toll-like-receptor 2 (TLR2), and TLR4 but not TLR9 in cattle[J]. Clin Diagn Lab Immunol,2004,11 (1):174-185.
[115]Yang W., Zerbe H., Petzl W.et al. Bovine TLR2 and TLR4 properly transduce signals from Staphylococcus aureus and E. coli, but S. aureus fails to both activate NF-kappaB in mammary epithelial cells and to quickly induce TNFalpha and interleukin-8 (CXCL8) expression in the udder[J]. Mol Immunol,2008,45 (5):1385-1397.
[116]Porcherie A., Cunha P., Trotereau A.et al. Repertoire of Escherichia coli agonists sensed by innate immunity receptors of the bovine udder and mammary epithelial cells[J]. Vet Res, 2012,43:14.
[117]Genini S., Badaoui B., Sclep G.et al. Strengthening insights into host responses to mastitis infection in ruminants by combining heterogeneous microarray data sources[J]. BMC Genomics,2011.12(1):225.
[118]Griesbeck-Zilch B., Osman M., Kuhn Ch.et al. Analysis of key molecules of the innate immune system in mammary epithelial cells isolated from marker-assisted and conventionally selected cattle[J]. J Dairy Sci,2009,92 (9):4621-4633.
[119]Burvenich C., Van Merris V., Mehrzad J.et al. Severity of E. coli mastitis is mainly determined by cow factors[J]. Vet Res,2003,34 (5):521-564.
[120]王新,张秀英.中药治疗奶牛乳房炎的研究现状与展望[J].中国兽药杂志,2004,38 (02):43-46.
[121]Bradley A. J., Leach K. A., Breen J. E.et al. Survey of the incidence and aetiology of mastitis on dairy farms in England and Wales[J]. Vet Rec,2007,160 (8):253-257.
[122]Kalmus P., Aasmae B., Karssin A.et al. Udder pathogens and their resistance to antimicrobial agents in dairy cows in Estonia[J]. Acta Vet Scand,2011,53:4.
[123]Lee J. W., Paape M. J., Elsasser T. H.et al. Elevated milk soluble CD14 in bovine mammary glands challenged with Escherichia coli lipopolysaccharide[J]. J Dairy Sci,2003,86 (7): 2382-2389.
[124]Paape M. J., Lilius E. M., Wiitanen P. A.et al. Intramammary defense against infections induced by Escherichia coli in cows[J]. Am J Vet Res,1996,57 (4):477-482.
[125]Gonen E., Vallon-Eberhard A., Elazar S.et al. Toll-like receptor 4 is needed to restrict the invasion of Escherichia coli P4 into mammary gland epithelial cells in a murine model of acute mastitis[J]. Cell Microbiol,2007,9 (12):2826-2838.
[126]Shimazu R., Akashi S., Ogata H.et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4[J]. J Exp Med,1999,189 (11):1777-1782.
[127]Miyake K. Endotoxin recognition molecules, Toll-like receptor 4-MD-2[J]. Semin Immunol, 2004,16(1):11-16.
[128]Risco A., Del Fresno C., Mambol A.et al. p38gamma and p38delta kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation[J]. Proc Natl Acad Sci U S A,2012,109 (28):11200-11205.
[129]Hines D. J., Choi H. B., Hines R. M.et al. Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides[J]. PLoS One,2013,8(3)
[130]Li Q., Verma I. M. NF-kappaB regulation in the immune system[J]. Nat Rev Immunol,2002, 2 (10):725-734.
[131]Calzado M. A., Bacher S., Schmitz M. L. NF-kappaB inhibitors for the treatment of inflammatory diseases and cancer[J]. Curr Med Chem,2007,14 (3):367-376.
[132]Petzl W., Zerbe H., Gunther J.et al. Escherichia coli, but not Staphylococcus aureus triggers an early increased expression of factors contributing to the innate immune defense in the udder of the cow[J]. Vet Res,2008,39 (2):18.
[133]Bougarn S., Cunha P., Harmache A.et al. Muramyl dipeptide synergizes with Staphylococcus aureus lipoteichoic acid to recruit neutrophils in the mammary gland and to stimulate mammary epithelial cells[J]. Clin Vaccine Immunol,2010,17 (11):1797-1809.
[134]Schmitz S., Pfaffl M. W., Meyer H. H.et al. Short-term changes of mRNA expression of various inflammatory factors and milk proteins in mammary tissue during LPS-induced mastitis[J]. Domest Anim Endocrinol,2004,26 (2):111-126.
[135]Wellnitz O., Baumert A., Saudenowa M.et al. Immune response of bovine milk somatic cells to endotoxin in healthy quarters with normal and very low cell counts[J]. J Dairy Res, 2010,77 (4):452-459.
[136]Morimoto K., Kanda N., Shinde S.et al. Effect of enterotoxigenic Escherichia coli vaccine on innate immune function of bovine mammary gland infused with lipopolysaccharide[J]. J Dairy Sci,2012,95 (9):5067-5074.
[137]Wellnitz O., Kerr D. E. Cryopreserved bovine mammary cells to model epithelial response to infection[J]. Vet Immunol Immunopathol,2004,101 (3-4):191-202.
[138]Hoeben D., Burvenich C., Trevisi E.et al. Role of endotoxin and TNF-alpha in the pathogenesis of experimentally induced coliform mastitis in periparturient cows[J]. J Dairy Res,2000,67 (4):503-514.
[139]Wellnitz O., Bruckmaier R. M. The innate immune response of the bovine mammary gland to bacterial infection[J]. Vet J,2012,192 (2):148-152.
[140]Ibeagha-Awemu E. M., Lee J. W., Ibeagha A. E.et al. Bacterial lipopolysaccharide induces increased expression of toll-like receptor (TLR) 4 and downstream TLR signaling molecules in bovine mammary epithelial cells[J]. Vet Res,2008,39 (2):11.
[141]陈莎莎,丁月云,金融,等.乳铁蛋白的抑菌作用及其机制[J].中国乳品工业,2007,35(05)：53-55.
[142]Unnewehr H., Rittirsch D., Sarma J. V.et al. Changes and regulation of the C5a receptor on neutrophils during septic shock in humans[J]. J Immunol,2013,190 (8):4215-4225.
[143]Jani P. K., Kajdacsi E., Megyeri M.et al. MASP-1 induces a unique cytokine pattern in endothelial cells:a novel link between complement system and neutrophil granulocytes[J]. PLoS One,2014,9 (1):e87104.
[144]庞继达.奶牛乳腺免疫调节的相关因素[J].中国奶牛,2010,4：44-46.
[145]Osman K. M., Hassan H. M., Ibrahim I. M.et al. The impact of staphylococcal mastitis on the level of milk IL-6, lysozyme and nitric oxide[J]. Comp Immunol Microbiol Infect Dis, 2010,33(1):85-93.
[146]李鑫,谭志坚,凌欣华,等.溶菌酶在饲料中的应用[J].畜牧与兽医,2013,45(11)：104-107.
[147]Liu X., Wang Y., Guo W.et al. Zinc-finger nickase-mediated insertion of the lysostaphin gene into the beta-casein locus in cloned cows[J]. Nat Commun,2013,4:2565.
[148]Liu X., Wang Y., Tian Y.et al. Generation of mastitis resistance in cows by targeting human lysozyme gene to beta-casein locus using zinc-finger nucleases[J]. Proc Biol Sci.2014.281 (1780):20133368.
[149]Alluwaimi A. M. The cytokines of bovine mammary gland:prospects for diagnosis and therapy[J]. Res Vet Sci,2004,77(3):211-222.
[150]Bannerman D. D., Paape M. J., Lee J. W.et al. Escherichia coli and Staphylococcus aureus elicit differential innate immune responses following intramammary infection[J]. Clin Diagn Lab Immunol,2004,11 (3):463-472.
[151]Stein B. N., Gamble J. R., Pitson S. M.et al. Activation of endothelial extracellular signal-regulated kinase is essential for neutrophil transmigration:potential involvement of a soluble neutrophil factor in endothelial activation[J]. J Immunol.2003,171 (11): 6097-6104.
[152]Yuan S. Y., Shen Q., Rigor R. R.et al. Neutrophil transmigration, focal adhesion kinase and endothelial barrier function[J]. Microvasc Res,2012,83 (1):82-88.
[153]Hordijk P. L. Endothelial signalling events during leukocyte transmigration[J]. FEBS J, 2006,273 (19):4408-4415.
[154]Nishimura T. Expression of potential lymphocyte trafficking mediator molecules in the mammary gland[J]. Vet Res,2003,34 (1):3-10.
[155]Oliver S. P., Murinda S. E. Antimicrobial resistance of mastitis pathogens[J]. Vet Clin North Am Food Anim Pract,2012,28 (2):165-185.
[156]Oliver S. P., Murinda S. E., Jayarao B. M. Impact of antibiotic use in adult dairy cows on antimicrobial resistance of veterinary and human pathogens:a comprehensive review[J]. Foodborne Pathog Dis,2011,8 (3):337-355.
[157]Erskine R. J., Wagner S., DeGraves F. J. Mastitis therapy and pharmacology [J]. Vet Clin North Am Food Anim Pract,2003,19(1):109-138.
[158]Kerro Dego O., Oliver S. P., Almeida R. A. Host-pathogen gene expression profiles during infection of primary bovine mammary epithelial cells with Escherichia coli strains associated with acute or persistent bovine mastitis[J]. Vet Microbiol,2012,155 (2-4): 291-297.
[159]van Schaik G., Lotem M., Schukken Y. H. Trends in somatic cell counts, bacterial counts, and antibiotic residue violations in New York State during 1999-2000[J]. J Dairy Sci,2002, 85 (4):782-789.
[160]Hogan J. S., Smith K. L., Hoblet K. H.et al. Field survey of clinical mastitis in low somatic cell count herds[J]. J Dairy Sci,1989,72 (6):1547-1556.
[161]DeGraves F. J., Anderson K. L. Ibuprofen treatment of endotoxin-induced mastitis in cows[J]. Am J Vet Res,1993,54 (7):1128-1132.
[162]Lohuis J. A., van Werven T., Brand A.et al. Pharmacodynamics and pharmacokinetics of carprofen, a non-steroidal anti-inflammatory drug, in healthy cows and cows with Escherichia coli endotoxin-induced mastitis[J]. J Vet Pharmacol Ther,1991,14 (3): 219-229.
[163]Vangroenweghe F., Duchateau L., Boutet P.et al. Effect of carprofen treatment following experimentally induced Escherichia coli mastitis in primiparous cows[J]. J Dairy Sci,2005, 88 (7):2361-2376.
[164]刘延鑫,孙宇,刘学芳,等.中草药防治奶牛乳房炎的研究进展[J].中国畜牧兽医,2011,38(11)：177-180.
[165]谢慧胜,陆钢,王红军,等.奶牛增乳保健剂增乳散的研究[J].中国兽医杂志,1993,19(06)：42-44.
[166]秦俊文,张强,王萍,等.“乳炎平”防治奶牛乳房炎试验[J].中国兽医杂志,1997,23(11)：19-20.
[167]王忠仁,冯志丹,何艳芬,等.自拟“麻连甘草汤”治疗奶牛乳痈[J].中兽医医药杂志,1996,5：40.
[168]刘纯传,陈初茂,霍杏桃,等.乳炎清治疗奶牛临床型乳房炎疗效观察[J].中国兽医科技,1997,27(02)：38-40.
[169]贺永建,林义明.桃红散防治奶牛乳房炎效果试验[J].四川畜牧兽医学院学报,1999,13(02)：66-71.
[170]甘志华,李启良,蒋武成,等.复方丹参液治疗奶牛隐性乳房炎试验[J].湖南农学院学报,1995,21(01)：84-88.
[171]鲁希英.中药制剂治疗奶牛隐性乳房炎的研究[J].中兽医医药杂志,1999,1：15-16.
[172]张文玫,胡平,郭泽领.绿草素对奶牛乳房炎治疗的临床观察[J].中国兽药杂志,2000,34(03)：58-59.
[173]张彬,薛明,崔颖,等.新兽药消炎醌对乳牛乳腺炎临床治疗试验[J].中国兽医科技,2000,30(08)：28-29.
[174]郎景民,布日额,张婷,等.奶牛乳房炎生物制剂研究进展[J].内蒙古民族大学学报(自然科学版),2009,24(05)：545-548.
[175]孟庆娟,李志明,冯士彬,等.中药复方灌注剂对奶牛乳房炎的防治效果及免疫增强 作用[J].中国畜牧兽医,2011,28(07)：219-223.
[176]张淼涛,王秋芳,效梅,等.复方中草药对隐性乳房炎乳牛细胞免疫功能的影响[J].中国兽医科技,2001,31(01)：24-25.
[177]高冠喜,董宙.中药质量标准化与中药现代化发展的探讨[J].中国医药导报,2010,7(02)：76-77.
[178]方圣鼎,陈仁通,韦璧瑜.中药现代化的思考[J].中草药,2007,38(05)：641-646.
[179]张立煌,李杰.中药现代化的现状及发展趋势[J].浙江大学学报(医学版),2011,40(04)：349-353.
[180]蒋文跃.寻找物质基础非当前中药现代化关键[J].中草药,2003,34(01)：1-3.
[181]朱大元.中药活性成分研究是中药现代化的重要组成部分[J].化学进展,2009,21(01)：24-29.
[182]屠鹏飞.姜勇.中药创新药物的发现与研发[J].中国天然药物.2007.5(02)：81-86.
[183]况荣华,周林,傅颖珺.中药以LPS-TLR4为作用靶点的抗炎机制的研究进展[J].南昌大学学报(医学版).2011,51(10)：89-92.
[184]Shin K. M., Kim I. T., Park Y. M.et al. Anti-inflammatory effect of caffeic acid methyl ester and its mode of action through the inhibition of prostaglandin E2, nitric oxide and tumor necrosis factor-alpha production[J]. Biochem Pharmacol,2004,68 (12):2327-2336.
[185]Jung J. E., Kim H. S., Lee C. S.et al. Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells[J]. Carcinogenesis,2007,28 (8):1780-1787.
[186]Bufalo M. C., Ferreira I.. Costa G.et al. Propolis and its constituent caffeic acid suppress LPS-stimulated pro-inflammatory response by blocking NF-kappaB and MAPK activation in macrophages[J]. J Ethnopharmacol,2013
[187]Riollet C., Rainard P., Poutrel B. Differential induction of complement fragment C5a and inflammatory cytokines during intramammary infections with Escherichia coli and Staphylococcus aureus[J]. Clin Diagn Lab Immunol,2000,7 (2):161-167.
[188]Vangroenweghe F., Rainard P., Paape M.et al. Increase of Escherichia coli inoculum doses induces faster innate immune response in primiparous cows[J]. J Dairy Sci,2004,87 (12): 4132-4144.
[189]王亨.牛乳腺上皮细胞培养及乳房炎致病菌与细胞相互作用的研究[D]：中国农业大学,2007.
[190]李忠秋.牛乳腺上皮细胞研究进展[J].黑龙江农业科学,2008,5：130-133.
[191]陈建晖,高学军,李庆章.奶牛乳腺上皮细胞体外培养技术研究进展[J].东北农业大学学报,2009,40(07)：132-135.
[192]Flint D. J., Tonner E., Knight C. H.et al. Control of mammary involution by insulin-like growth factor binding proteins:role of prolactin[J]. Livestock Production Science,2001,70 (1-2):115-120.
[193]Lamote I., Meyer E., Massart-Leen A. M.et al. Sex steroids and growth factors in the regulation of mammary gland proliferation, differentiation, and involution[J]. Steroids, 2004,69 (3):145-159.
[194]Woodward T. L., Xie J., Fendrick J. L.et al. Proliferation of mouse mammary epithelial cells in vitro:interactions among epidermal growth factor, insulin-like growth factor I, ovarian hormones, and extracellular matrix proteins[J]. Endocrinology,2000,141 (10):3578-3586.
[195]Burvenich C., Bannerman D. D., Lippolis J. D.et al. Cumulative physiological events influence the inflammatory response of the bovine udder to Escherichia coli infections during the transition period[J]. J Dairy Sci,2007,90 Suppl 1:E39-E54.
[196]Akers R. M., Thompson W. Effect of induced leucocyte migration on mammary cell morphology and milk component biosynthesis[J]. J Dairy Sci,1987,70 (8):1685-1695.
[197]Zhao X., Lacasse P. Mammary tissue damage during bovine mastitis:causes and control[J]. J Anim Sci,2008,86 (13 Suppl):57-65.
[198]Semba R. D. Mastitis and transmission of human immunodeficiency virus through breast milk[J]. Ann N Y Acad Sci,2000,918:156-162.
[199]Willumsen J. F., Filteau S. M., Coutsoudis A.et al. Subclinical mastitis as a risk factor for mother-infant HIV transmission[J]. Adv Exp Med Biol,2000,478:211-223.
[200]Moussaoui F., Michelutti I., Le Roux Y.et al. Mechanisms involved in milk endogenous proteolysis induced by a lipopolysaccharide experimental mastitis[J]. J Dairy Sci,2002,85 (10):2562-2570.
[201]Capuco A. V., Paape M. J., Nickerson S. C. In vitro study of polymorphonuclear leukocyte damage to mammary tissues of lactating cows[J]. Am J Vet Res,1986,47 (3):663-668.
[202]凌云,燕鲍燕,张永林,等.兴安蒲公英的化学成分研究[J].海军总医院学报,1999,12(04)：233-235.
[203]赵守训,杭秉倩.蒲公英的化学成分和药理作用[J].中国野生植物资源,2001,20(03)：1-3.
[204]杨九凌,祝晓玲,李成文,等.咖啡酸及其衍生物咖啡酸苯乙酯药理作用研究进展[J].中国药学杂志,2013,48(08)：577-582.
[205]Lyczak J. B., Cannon C. L., Pier G. B. Lung infections associated with cystic fibrosis[J]. Clin Microbiol Rev,2002,15 (2):194-222.
[206]Dosogne H., Vangroenweghe F., Barrio B.et al. Decreased number and bactericidal activity against Staphylococcus aureus of the resident cells in milk of dairy cows during early lactation[J]. J Dairy Res,2001,68 (4):539-549.
[207]Rainard P., Riollet C., Poutrel B.et al. Phagocytosis and killing of Staphylococcus aureus by bovine neutrophils after priming by tumor necrosis factor-alpha and the des-arginine derivative of C5a[J]. Am J Vet Res,2000,61 (8):951-959.
[208]Capuco A. V., Paape M. J., Nickerson S. C. In vitro study of polymorphonuclear leukocyte damage to mammary tissues of lactating cows[J]. Am J Vet Res,1986,47 (3):663-668.
[209]Lahouassa H., Moussay E., Rainard P.et al. Differential cytokine and chemokine responses of bovine mammary epithelial cells to Staphylococcus aureus and Escherichia coli[J]. Cytokine,2007,38 (1):12-21.
[210]Buitenhuis B., Rontved C. M., Edwards S. M.et al. In depth analysis of genes and pathways of the mammary gland involved in the pathogenesis of bovine Escherichia coli-mastitis[J]. BMC Genomics,2011,12:130.
[211]Elazar S., Gonen E., Livneh-Kol A.et al. Essential role of neutrophils but not mammary alveolar macrophages in a murine model of acute Escherichia coli mastitis[J]. Vet Res, 2010,41 (4):53.
[212]Kumar H., Kawai T., Akira S. Pathogen recognition by the innate immune system[J]. Int Rev Immunol,2011,30 (1):16-34.
[213]Hines D. J., Choi H. B., Hines R. M.et al. Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides[J]. PLoS One,2013,8(3):e60388.
[214]宋舟,张立艳,董海兵,等.JAK-STAT信号通路研究进展[J].中国畜牧兽医,2012,39(06)：128-132.
[215]Kacimi R., Giffard R. G., Yenari M. A. Endotoxin-activated microglia injure brain derived endothelial cells via NF-kappaB, JAK-STAT and JNK stress kinase pathways[J]. J Inflamm (Lond),2011,8:7.
[216]Platanias L. C. Map kinase signaling pathways and hematologic malignancies[J]. Blood, 2003,101 (12):4667-4679.
[217]Guha M., Mackman N. LPS induction of gene expression in human monocytes[J]. Cell Signal,2001,13 (2):85-94.
[218]Cho S. Y., Park S. J., Kwon M. J.et al. Quercetin suppresses proinflammatory cytokines production through MAP kinases andNF-kappaB pathway in lipopolysaccharide-stimulated macrophage[J]. Mol Cell Biochem,2003,243 (1-2):153-160.
[219]Vanden Berghe W., Plaisance S., Boone E.et al. p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor[J]. J Biol Chem,1998,273 (6): 3285-3290.
[220]Parthasarathy G., Philipp M. T. The MEK/ERK pathway is the primary conduit for Borrelia burgdorferi-induced inflammation and P53-mediated apoptosis in oligodendrocytes[J]. Apoptosis,2014,19(1):76-89.
[221]Xu X., Yin P., Wan C.et al. Punicalagin Inhibits Inflammation in LPS-Induced RAW264.7 Macrophages via the Suppression of TLR4-Mediated MAPKs and NF-kappaB Activation[J]. Inflammation,2014
[222]Sung M. H., Li N., Lao Q.et al. Switching of the relative dominance between feedback mechanisms in lipopolysaccharide-induced NF-kappaB signaling[J]. Sci Signal,2014,7 (308):a6.
[223]Liu H. T., He J. L., Li W. M.et al. Geniposide inhibits interleukin-6 and interleukin-8 production in lipopolysaccharide-induced human umbilical vein endothelial cells by blocking p38 and ERK1/2 signaling pathways[J]. Inflamm Res,2010,59 (6):451-461.
[224]Ryu M., Kim E. H., Chun M.et al. Astragali Radix elicits anti-inflammation via activation of MKP-1, concomitant with attenuation of p38 and Erk[J]. J Ethnopharmacol,2008,115 (2): 184-193.
[225]Dudhgaonkar S., Thyagarajan A., Sliva D. Suppression of the inflammatory response by triterpenes isolated from the mushroom Ganoderma lucidum[J]. Int Immunopharmacol, 2009,9(11):1272-1280.
[226]黄田英,李庆章,侯晓明.乳腺中JAK-STAT信号通路的研究进展[J].中国乳品工业,2010,38(02)：41-44.
[227]Philp J. A., Burdon T. G., Watson C. J. Differential activation of STATs 3 and 5 during mammary gland development[J]. FEBS Lett,1996,396 (1):77-80.
[228]Desrivieres S., Kunz C., Barash I.et al. The biological functions of the versatile transcription factors STAT3 and STAT5 and new strategies for their targeted inhibition[J]. J Mammary Gland Biol Neoplasia,2006,11(1):75-87.
[229]Khaled W. T., Read E. K., Nicholson S. E.et al. The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development[J]. Development,2007,134 (15): 2739-2750.
[230]Santos S. J., Haslam S. Z., Conrad S. E. Signal transducer and activator of transcription 5a mediates mammary ductal branching and proliferation in the nulliparous mouse[J]. Endocrinology,2010,151 (6):2876-2885.
[231]王文正,赵素梅,高士争.Leptin介导的JAK/STAT信号通路对脂类代谢调节的研究进展[J].中国细胞生物学学报,2011,33(05)：584-589.
[232]Shillingford J. M., Hennighausen L. Experimental mouse genetics-- answering fundamental questions about mammary gland biology[J]. Trends Endocrinol Metab,2001,12 (9): 402-408.
[233]Brym P., Kaminski S., Rusc A. New SSCP polymorphism within bovine STAT5A gene and its associations with milk performance traits in Black-and-White and Jersey cattle[J]. J Appl Genet,2004,45 (4):445-452.
[234]Liu X. F., Li M., Li Q. Z.et al. Stat5a increases lactation of dairy cow mammary gland epithelial cells cultured in vitro[J]. In Vitro Cell Dev Biol Anim,2012,48 (9):554-561.
[235]Ghosh S., Hayden M. S. New regulators of NF-kappaB in inflammation[J]. Nat Rev Immunol,2008,8(11):837-848.
[236]Lenardo M. J., Baltimore D. NF-kappa B:a pleiotropic mediator of inducible and tissue-specific gene control[J]. Cell,1989,58 (2):227-229.
[237]Li J., Peet G. W., Balzarano D.et al. Novel NEMO/IkappaB kinase and NF-kappa B target genes at the pre-B to immature B cell transition[J]. J Biol Chem,2001,276 (21): 18579-18590.
[238]Li X., Massa P. E., Hanidu A.et al. IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program[J]. J Biol Chem, 2002,277 (47):45129-45140.
[239]Hoffmann A., Baltimore D. Circuitry of nuclear factor kappaB signaling[J]. Immunol Rev, 2006,210:171-186.
[240]Croy C. H., Bergqvist S., Huxford T.et al. Biophysical characterization of the free IkappaBalpha ankyrin repeat domain in solution[J]. Protein Sci,2004,13 (7):1767-1777.
[241]Zhong H., SuYang H., Erdjument-Bromage H.et al. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism[J]. Cell,1997,89 (3):413-424.
[242]Scott M. L., Fujita T., Liou H. C.et al. The p65 subunit of NF-kappa B regulates I kappa B by two distinct mechanisms[J]. Genes Dev.1993,7 (7A):1266-1276.
[243]Ito C. Y.. Kazantsev A. G.. Baldwin A. S. Three NF-kappa B sites in the I kappa B-alpha promoter are required for induction of gene expression by TNF alpha[J]. Nucleic Acids Res, 1994,22 (18):3787-3792.
[244]Chiao P. J., Miyamoto S., Verma I. M. Autoregulation of I kappa B alpha activity[J]. Proc Natl Acad Sci U S A,1994,91 (1):28-32.
[245]Arenzana-Seisdedos F., Thompson J., Rodriguez M S.et al. Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B[J]. Mol Cell Biol.1995,15 (5):2689-2696.
[246]Arenzana-Seisdedos F., Turpin P., Rodriguez M.et al. Nuclear localization of I kappa B alpha promotes active transport of NF-kappa B from the nucleus to the cytoplasm[J]. J Cell Sci,1997,110 (Pt 3):369-378.
[247]Tam W. F., Lee L. H., Davis L.et al. Cytoplasmic sequestration of rel proteins by IkappaBalpha requires CRM1-dependent nuclear export[J]. Mol Cell Biol,2000,20 (6): 2269-2284.
[248]Hoffmann A., Levchenko A., Scott M. L.et al. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation[J]. Science,2002,298 (5596):1241-1245.
[249]Cheng J. D., Ryseck R. P., Attar R. M.et al. Functional redundancy of the nuclear factor kappa B inhibitors I kappa B alpha and I kappa B beta[J]. J Exp Med,1998,188 (6): 1055-1062.
[250]Lee S. H., Hannink M. Characterization of the nuclear import and export functions of Ikappa B(epsilon)[J]. J Biol Chem,2002,277 (26):23358-23366.
[251]Tergaonkar V., Correa R. G., Ikawa M.et al. Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity[J]. Nat Cell Biol,2005,7 (9):921-923.
[252]Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity:update on Toll-like receptors[J]. Nat Immunol,2010,11 (5):373-384.
[253]Beaudoin T., LaFayette S., Roussel L.et al. The level of p38alpha mitogen-activated protein kinase activation in airway epithelial cells determines the onset of innate immune responses to planktonic and biofilm Pseudomonas aeruginosa[J]. J Infect Dis,2013,207 (10): 1544-1555.
[254]Cario E., Rosenberg I. M., Brandwein S. L.et al. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors[J]. J Immunol,2000,164 (2):966-972.
[255]Guma M., Stepniak D., Shaked H.et al. Constitutive intestinal NF-kappaB does not trigger destructive inflammation unless accompanied by MAPK activation[J]. J Exp Med,2011, 208(9):1889-1900.
[256]Martel G., Rousseau S. TPL2 signalling:from Toll-like receptors-mediated ERK1/ERK2 activation to Cystic Fibrosis Lung disease[J]. Int J Biochem Cell Biol,2014 (In press).
[257]Kang N. J., Lee K. W., Shin B. J.et al. Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity and UVB-induced COX-2 expression[J]. Carcinogenesis,2009,30 (2):321-330.
[258]Lee Y., Shin D. H., Kim J. H.et al. Caffeic acid phenethyl ester-mediated Nrf2 activation and IkappaB kinase inhibition are involved in NFkappaB inhibitory effect:structural analysis for NFkappaB inhibition[J]. Eur J Pharmacol,2010,643 (1):21-28.
[259]Liu W., Ouyang X., Yang J.et al. AP-1 activated by toll-like receptors regulates expression of IL-23 p19[J]. J Biol Chem,2009,284 (36):24006-24016.
[260]Jung W. K., Choi I., Lee D. Y.et al. Caffeic acid phenethyl ester protects mice from lethal endotoxin shock and inhibits lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW 264.7 macrophages via the p38/ERK and NF-kappaB pathways[J]. Int J Biochem Cell Biol,2008,40 (11):2572-2582.
[261]Ha S. K., Moon E., Kim S. Y. Chrysin suppresses LPS-stimulated proinflammatory responses by blocking NF-kappaB and JNK activations in microglia cells[J]. Neurosci Lett, 2010,485 (3):143-147.
[262]Giinther J., Petzl W., Zerbe H.et al. Lipopolysaccharide priming enhances expression of effectors of immune defence while decreasing expression of pro-inflammatory cytokines in mammary epithelia cells from cows[J]. BMC Genomics,2012,13:17.
[263]Shuster D. E., Kehrli ME Jr, Rainard P.et al. Complement fragment C5a and inflammatory cytokines in neutrophil recruitment during intramammary infection with Escherichia coli[J]. Infect Immun,1997,65 (8):3286-3292.
[264]Scheibel M., Klein B., Merkle H.et al. IkBβ is an essential co-activator for LPS-induced IL-1β transcription in vivo[J]. J Exp Med,2010,207 (12):2621-2630.
[265]Wang L. C., Chu K. H., Liang Y. C.et al. Caffeic acid phenethyl ester inhibits nuclear factor-kappaB and protein kinase B signalling pathways and induces caspase-3 expression in primary human CD4+ T cells[J]. Clin Exp Immunol,2010,160 (2):223-232.
[266]Puangpraphant S., Berhow M. A., Vermillion K.et al. Dicaffeoylquinic acids in Yerba mate (Ilex paraguariensis St. Hilaire) inhibit NF-kappaB nucleus translocation in macrophages and induce apoptosis by activating caspases-8 and -3 in human colon cancer cells[J]. Mol Nutr Food Res,2011,55(10):1509-1522.
[267]杨九凌,祝晓玲,李成文,等.咖啡酸及其衍生物咖啡酸苯乙酯药理作用研究进展[J].中国药学杂志,2013,48(08)：577-582.
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