摘要
第一部分大鼠脾脏巨噬细胞的分离与培养
目的:分离培养并鉴定大鼠脾脏巨噬细胞。
方法:SD大鼠,腹腔注射水合氯醛麻醉,无菌取脾脏,制备成脾脏组织细胞混悬液,裂解脾脏组织细胞混悬液中的红细胞;用RPIM-1640培养基重悬沉淀,接种于一次性塑料培养瓶中,在37℃,50ml·l-1CO2,100%湿度中分别培养1、2、3、6、12、24h,洗涤未贴壁细胞,相差显微镜下分别观察脾脏巨噬细胞的贴壁情况,确定最佳细胞贴壁时间。应用免疫组织化学等方法进行细胞的鉴定;台盼蓝染色鉴定细胞活力,瑞氏染色鉴定细胞纯度。
结果: 1.大鼠脾脏组织经过研磨等处理后,得到大量的脾细胞混悬液,可以满足进一步的分离培养的需要;2.观察贴壁细胞, 1-3h细胞少量贴壁,12h左右的贴壁细胞增多, 24h的贴壁细胞减少。12h是贴壁细胞合适时间; 3.相差显微镜下观察到贴壁培养的脾脏巨噬细胞多为圆形或椭圆形,少数呈梭形或多边形。镜下观察细胞体积较大,细胞膜完整,细胞核清晰可见,胞浆内容物丰富;免疫组织化学结果显示贴壁的脾脏巨噬细胞CD68表达阳性,提示所得的细胞是脾脏巨噬细胞,台盼蓝染色显示细胞活力>95%,瑞氏染色鉴定细胞纯度>90%。
结论:1分离培养出活力和纯度符合实验要求的大鼠脾脏巨噬细胞;2.贴壁12h是大鼠原代脾脏巨噬细胞的合适贴壁培养时间。
第二部分轻度热应激对大鼠脾脏巨噬细胞免疫功能的影响
目的:探讨轻度热应激对大鼠脾脏巨噬细胞免疫功能的影响。
方法:以始终处于37℃的大鼠原代脾脏巨噬细胞作为对照组,实验组将大鼠原代脾脏巨噬细胞置于41℃恒温箱中,使细胞轻度热应激1h,然后恢复到37℃,分成应激后0min,30min,60min,120min,180min五个亚组组,总共六个组;以吞噬中性红能力(OD540nm值)检测巨噬细胞的吞噬功能、噻唑蓝法测定巨噬细胞对L1210细胞的杀伤作用来反应巨噬细胞的杀伤活性,Transwell小室趋化装置观察巨噬细胞趋化活性变化;采用双抗夹心ABC-ELISA法检测大鼠脾脏巨噬细胞分泌的TNF-a,IL-12浓度的变化。
结果:轻度热应激(41℃、1h)后,实验组大鼠脾脏巨噬细胞的功能均发生了变化,而且与应激后恢复时间有关。热应激后0min,巨噬细胞的OD540nm值由正常的0.21±0.01上升到0.34±0.01(p<0.05),然后继续上升,至60min达最高值0.81±0.04(p<0.01),随后逐渐下降,应激后180min仍然有0.47±0.03(与对照组比较,p<0.05);杀伤活性由正常的35.30±4.37﹪上升到应激后0min的45.00±4.74﹪(p<0.05),在60min分钟达到最大值82.07±5.17﹪(p<0.01),随后逐渐下降,180min后杀伤活性基本恢复正常,为37.27±5.11﹪(与对照组比较,p>0.05);趋化作用也呈现大致相同的变化趋势,大鼠脾脏巨噬细胞正常趋化活性为23.40±5.32/HP;热应激1h后0min为34.60±5.22/HP(p<0.05),在60min分钟达到最大值60.80±4.02/HP(p<0.01)后逐渐下降,180min仍为31.60±4.21/HP(与对照组比较,p<0.05);在实验时间内,大鼠脾脏巨噬细胞分泌的TNF-α和IL-12均随着应激后时间的延长而增多,180min达到最高(与对照组比较,P < 0.01)。
结论:轻度热应激后,大鼠脾脏巨噬细胞的吞噬功能、杀伤活性、趋化活性都有上调;在实验时间内,大鼠脾脏巨噬细胞分泌的细胞因子TNF-α和IL-12在轻度热应激后随着时间的延长而增加。提示轻度热应激对大鼠脾脏巨噬细胞的免疫功能有促进作用。
第三部分Bip蛋白在轻度热应激大鼠脾脏巨噬细胞中的表达与意义
目的:探讨轻度热应激大鼠脾脏巨噬细胞Bip蛋白的表达及其对细胞功能改变的影响。
方法:原代培养大鼠脾脏巨噬细胞,将细胞置于41℃恒温箱中,使细胞轻度热应激,1h后恢复到37℃,分别检测应激后0min,30min,60min,120min,180min巨噬细胞BipmRNA、Bip蛋白的表达;同时段分别检测巨噬细胞吞噬功能、杀伤活性和趋化作用。
结果:(1)轻度热应激后,大鼠脾脏巨噬细胞BipmRNA的表达明显增加,30min后到达高峰,60min、120min时仍高于对照组(p<0.01),180min后恢复至正常水平。Bip蛋白的表达在轻度热应激60min后到达高峰,120min、180min时仍高于对照组(p<0.05)。(2)轻度热应激后,大鼠脾脏巨噬细胞的吞噬功能、杀伤活性和趋化作用均明显增强,且与BipmRNA、Bip蛋白表达的改变基本同步。
结论:轻度热应激大鼠脾脏巨噬细胞BipmRNA、Bip蛋白的表达与巨噬细胞功能发生同步改变,提示Bip蛋白表达上调与轻度热应激大鼠脾脏巨噬细胞功能增强可能有关。
第四部分BiP反义寡核苷酸对轻度热应激大鼠脾脏巨噬细胞免疫功能的影响
目的:探讨Bip反义寡核苷酸对体外轻度热应激大鼠脾脏巨噬细胞功能的影响,进一步证实Bip在轻度热应激大鼠脾脏巨噬细胞功能改变中的作用。
方法:设计特异性Bip寡核苷酸,反义序列为5’- CTTTGTCCTAGCCGCTCG - 3’;错义序列为5’- CTTTGTCCTAGCCGCTCG - 3’。通过脂质体包裹后将其转染至小鼠脾脏巨噬细胞,观察Bip反义寡核苷酸转染后及未转染组、Bip错义寡核苷酸转染后大鼠脾脏巨噬细胞BipmRNA的改变;然后分别观察正常对照组、轻度热应激组和Bip反义寡核苷酸转染并轻度热应激后脾脏巨噬细胞功能的改变。
结果:Bip反义寡核苷酸转染大鼠脾脏巨噬细胞后,与未转染组和错义组比较,轻度热应激后BipmRNA的表达明显减少;大鼠脾脏巨噬细胞吞噬功能、趋化活性和杀伤活性明显回落(P<0.01)。
结论:Bip反义寡核苷酸可显著抑制大鼠脾脏巨噬细胞BipmRNA的表达,并可降低轻度热应激大鼠脾脏巨噬细胞吞噬功能、趋化活性和杀伤活性。Bip对轻度热应激大鼠脾脏巨噬细胞的免疫功能有促进作用。
第五部分P38MAPK信号途径在轻度热应激大鼠脾脏巨噬细胞免疫功能改变中的作用
目的:研究MAPK信号途径在Bip蛋白介导的体外轻度热应激大鼠脾脏巨噬细胞免疫功能改变中的作用。
方法:P38MAPK抑制剂预处理大鼠脾脏巨噬细胞,将细胞置于41℃恒温箱中,使细胞轻度热应激,1h后恢复到37℃(抑制组),以未应激(对照组)和单纯41℃热应激1h后60min大鼠脾脏巨噬细胞(应激组)为对照,分别检测三组大鼠脾脏巨噬细胞吞噬、杀伤、趋化功能。同时检测P38MAPK蛋白和Bip蛋白的表达。
结果:轻度热应激后60min,应激组大鼠脾脏巨噬细胞吞噬、趋化和杀伤活性增强,与对照组、抑制组比较差异有显著性(P<0.01)。P38MAPK抑制剂预处理大鼠脾脏巨噬细胞,与应激组比较,热应激后巨噬细胞吞噬、趋化和杀伤活性明显降低(P<0.01),与对照组比较无显著差异(P>0.05)。应激组P38MAPK蛋白表达明显上调,与对照组和抑制组比较差异有显著性(P<0.01);P38MAPK抑制剂预处理后,抑制组P38MAPK蛋白表达受到抑制,与应激组比较(P<0.01)。Bip蛋白的表达也因P38MAPK抑制剂预处理而发生改变,由应激组的1.2702±0.5345(Bip/β-actin)下降到抑制组的1.0281±1.0614(P<0.05)。
结论:轻度热应激可增强大鼠巨噬细胞吞噬、趋化和杀伤作用的同时,P38MAPK、Bip蛋白表达上调。P38MAPK抑制剂可显著抑制大鼠巨噬细胞吞噬、趋化和杀伤功能以及P38MAPK、Bip蛋白的表达。P38 MAPK信号途径参与Bip蛋白介导的轻度热应激后大鼠脾脏巨噬细胞免疫功能的调节。
Part I Isolation and cultivation of rat splenic macrophage
Objective: To isolate and culture the primary rat splenic macrophage .
Method: Sprague-Dawley rats were given intraperitoneal chloral hydrate anaesthesia and spleen was resected aseptically. Spleen cells suspension were prepared and the erythrocytes in suspension were decomposed. RPIM-1640 medium with re-suspended sediments were inoculated into disposable plastic flasks added 50ml·l-1 CO2 kept in 100% humidity at 37℃and cultured for 1,2,3,6,12 and 24 hour respectively. Non-adherent cells were washed and splenic macrophage adherent cells were observed under phase contrast microscope to determine their optimum adherent time. Immunohistochemical methods were used to identify cells; trypan blue staining to identify the cell viability and Wright’s staining used to identify cell purity.
Results: 1.Large numbers of rat spleen cells were obtained from suspension after spleen tissue grinding which were enough to fulfil the requirements of further isolation and culture. 2. Observation of adherent cells found small amount of adherent cells in 1-3h, most of cells adhere in 12h and few adherent cells in 24h. 3. Adherent culture splenic macrophage were observed under phase contrast microscope; most were round or oval and a few were spindle or polygonal. It was observed that cells were large with intact cell membrane, clearly visible nuclei and cytoplasm with rich contents. Immunohistochemistry results showed positive expression of CD68 of adherent splenic macrophage suggesting that derived spleen cells are macrophages. Trypan blue staining showed cell viability> 95% and Wright stain identified cell purity> 90%.
Conclusion: 1. Rat splenic macrophage were obtained by adherent culture method and their viability and purity meet the requirement of experiment. 2. Adherent for 12h is appropriate adherent time for rat splenic macrophage .
Part II Effect of mild heat stress on immune function of rat splenic macrophage
Objective:To investigate the effect of mild heat stress on immune function of rat splenic macrophage.
Method:Rat primary splenic macrophages constantly kept at 37℃were assigned as control group. In the experimental group, rat splenic macrophage were placed in 41℃incubator for mild heat stress and temperature restored to 37℃after an hour. After being heat stressed cells were divided into five sub-groups of 0min, 30min, 60min, 120min and 180min ,with a total of six groups. The ability to engulf neutral red dye(OD540nm value) was used to detect macrophage phagocytosis, MTT assay was used to measured the macrophage cytocidal effect towards L1210 cells which determined the macrophage cytotoxicity ,macrophage Chemotaxis was observed in Costar Transwell chemotaxis chamber inserts, concentration changes of macrophage’s secretions of TNF-a and IL-12 were measured by using Enzyme-linked Immunosorbnent Assay method .
Results In experimental group, functions of macrophages were changed after mild heat stress (41℃for 1h) and changes were directly related to the recovery time after being mild heat stressed. In 0min group after mild heat stress, OD540nm value of macrophages increased from normal value 0.21±0.01 to 0.34±0.01 (p <0.05) and then continue to rise and reached to a maximum value of 0.81±0.04 (p <0.01) at 60min. Then OD540nm value decreased gradually and after 180min of mild heat stress was still on 0.47±0.03 levels (compared with the control group, p <0.05). Cytotoxicity of 0min group increased from normal value of 35.30±4.37% to 45.00±4.74% (p <0.05) after mild heat stress and reached to maximum of 82.07±5.17% (p <0.01) in 60min group and then decreased gradually. In 180min group Cytotoxicity returned to normal value of 37.27±5.11% (compared with the control group, p> 0.05).Macrophages secretion of cytokines TNF-αand IL-12 increased with the time after mild heat stress.
Conclusion:After mild heat stress phagocytosis, cytotoxicity and Chemotaxis of rat splenic macrophage has increased and gradually restored to normal with the extended recovery time after mild heat stress. During experimental period; macrophages secretion of cytokines TNF-αand IL-12 increased with the time after mild heat stress, which suggested that mild heat stress has promoting role on immune function of rat splenic macrophage .
Part III Expressions and role of Bip protein in rat splenic macrophage during mild heat stress.
Objective:To investigate Bip protein expressions and its role in rat splenic macrophage functions changes after mild heat stress.
Method:Rat splenic macrophage constantly kept at 37℃were assigned as control group. In the experimental group , rat splenic macrophage were placed in 41℃incubator for mild heat stress and temperature restored to 37℃after an hour. After being mild heat stressed cells were divided into five sub Groups of 0min, 30min, 60min, 120min and 180min. BipmRNA and Bip protein expression were detected in each group. At the same time phagocytosis, cytotoxicity and chemotaxis was measured in each group.
Result : 1. There were a significant increase in expression of splenic macrophage BipmRNA after mild heat stress ,which reached to maximum in 30min group after stress and still remain higher in 60min and 120min group (p <0.01),BipmRNA level restored to normal in 180min group. Bip protein expression reached to peak levels in 60min group after stress and still remained higher in 120min and 180min groups (p <0.05). 2. After mild heat stress phagocytosis, cytotoxicity and Chemotaxis of splenic macrophage were significantly increased with synchronous increasing levels of BipmRNA and Bip protein.
Conclusion:Changes in BipmRNA and Bip protein expression and functions of mild heat stressed splenic macrophage happened at the same pace. It suggested that after mild heat stress increasing Bip expression and enhanced splenic macrophage function are closely related.
Part IV. Effect of BiP antisense oligonucleotide on immune functions of mild heat stressed rat splenic macrophage
Objective:To investigate Bip antisense oligonucleotides role on immune functions of mild heat stressed rat splenic macrophage and to determine the Bip role on immune function changes of mild heat stressed rat splenic macrophage in vitro.
Methods:Bip-specific oligonucleotide were designed with antisense sequence and mismatch sense sequence of 5'-CTTTGTCCTAGCCGCTCG-3' and 5'- CTTTGTCCTAGCCGCTCG-3' respectively. Liposome-mediated transfection method was used for transfection of them to ret splenic macrophage. Bip mRNA levels were observed in rat splenic macrophage of Bip antisense oligonucleotide transfected group(Bip AS--ODN) ,Bip mismatch sense oligonucleotide transfected group(Bip MS-ODN) and non transfected group(control group). Then functional changes of rat splenic macrophage were observed in control group, non transfested mild heat stressed group and Bip antisense oligonucleotide transfected mild heat stressed group.
Results : As compared to control group and Bip mismatch sense oligonucleotide transfected group, significant reduction in expressions of BipmRNA and phagocytosis, cytotoxicity and Chemotaxis of rat splenic macrophage were observed in Bip antisense oligonucleotide transfected mild heat stressed group (P <0.01).
Conclusion:Bip antisense oligonucleotide can significantly inhibit splenic macrophage BipmRNA expressions and decrease phagocytosis, cytotoxicity and chemotaxis of mild heat stressed rat splenic macrophage ;Bip play promoting role on immune function of mild heat stressed rat splenic macrophage.
Part V. The role of P38MAPK in immune functional changes of heat stressed rat splenic macrophage
Objective: Research on MAPK signaling role in Bip protein-mediated immune functional changes of mild heat stressed rat splenic macrophage in vitro.
Methods: Rat splenic macrophage were pretreated with P38MAPK inhibitor and then placed in 41℃incubator for mild heat stress,after 1h temerature restored to 37℃in inhibition group. Non stressed rat splenic macrophage were assigned as control group , macrophages which simply heat stressed at 41℃for 1h as 60min group(stress group) used as control ,too. Three groups were detected for macrophage phagocytosis, cytotoxicity and chemotaxis. At the same time P38MAPK protein and Bip protein expressions were detection.
Results: After 60min of mild heat stress; macrophages phagocytosis, cytotoxicity and chemotaxis in stress group greately increased which was significantly different from the control group and inhibition group (P <0.01). P38MAPK inhibitor pretreated rat splenic macrophage , when compared with the stress group, phagocytosis, cytotoxicity and chemotaxis significantly lowered after heat stress (P <0.01). P38MAPK inhibitor pretreated group when compared with the control group , there was no significant difference (P> 0.05). In stress group P38MAPK protein expressions were significantly increased and were significantly different from inhibition control group (P <0.01).As compared with the stress group, P38MAPK protein expressions were inhibited after P38MAPK inhibitor pretreatment in inhibition group (P <0.01) . P38MAPK inhibitor pretreatment also caused changes in Bip protein expressions i.e. in the stress group from 1.2702±0.5345 (Bip /β-actin)dropped to 1.0281±1.0614 in inhibition group (P <0.05).
Conclusion: Mild heat stress can enhance phagocytosis, cytotoxicity and chemotaxis of rat splenic macrophage and at the same time promote their P38MAPK and Bip protein expressions. P38 inhibitors can significantly inhibit mild heat stressed rat splenic macrophage phagocytosis, cytotoxicity and chemotactic functions as well as these inhibit P38MAPK and Bip protein expressions. P38MAPK may be involved in Bip protein-mediated immune modulation of mild heat stressed rat splenic macrophage .
引文
[1] Park HG, Han SI, Oh SY, et al. Cellular responses to mild heat stress. Cell Mol Life Sci. 2005;62(1):10–23.
[2] Hatzfeld-Charbonnier AS , Lasek A , Castera L,et al. Influence of heat stress on human monocyte-derived dendritic cell functions with immunotherapeutic potential for antitumor vaccines. J Leukoc Biol. 2007 ; 81(5): 1179–1187.
[3] Feder M, Cartano ENV, Milos L, et al. Effect of engineering Hsp70 copy number on Hsp70 expression and tolerance of ecologically relevant heat shock in larvae and pupae of Drosophila melanogaster. J Exp Biol. 1996;199(8):1837–1844.;
[4] Krebs RA, Feder ME. Hsp70 and larval thermotolerance in Drosophila melanogaster: how much is enough and when is more too much? J Insect Physiol. 1998;44(1):1091–1101
[5] Morrow G, Samson M, Michaud S, Tanguay RM. Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J. 2004;18(3):598–599.
[6] Barbara E. Slack and Marina S. Siniaia. Adhesion-Dependent Redistribution of MAP Kinase and MEK Promotes Muscarinic Receptor-Mediated Signaling to the Nucleus. J Cell Biochem. 2005 15; 95(2): 366–378.
[7] Ten Hagen TLM, van Vianen W, Bakker-woudenberg IAJM. Isolation and characterization of murine Kupffer cells and splenic macrophage. J Immunol Methods,1996,193(1):81-91.
[8] Cai S, Shimizu T and Tomioka H. Comparative studies on the roles of mediator molecules in expression of the suppressor activity of Mycobacterium avium complex-induced immunosuppr- essive macrophages against T cell and B cell mitogenic responses. Clinical and Experimental Immunology, 2006; 143(3) :560–571.
[9] Schulert GS, Allen LAH. Differential infection of mononuclear phagocytes by Francisella tularensis: role of the macrophage mannose receptor. Journal of leukocyte biology . 2006 ; 80(3): 563–571.
[10] Rottier PJM, Nakamura K, Schellen P,et al. Acquisition of Macrophage Tropism during the Pathogenesis of Feline Infectious Peritonitis Is Determined by Mutations in the Feline Coronavirus Spike Protein. JOURNAL OF VIROLOGY, 2005, 79(22): 14122–14130.
[11] Alatery A and Basta S. An efficient culture method for generating large quantities of mature mouse splenic macrophage. Journal of Immunological Methods,2008,338(1-2):47-57.
[12]闫峰,李宗芳,张澍,等.人脾脏巨噬细胞的分离与纯化.西安交通大学学报(医学版),2004,25(5):513-516.
[13]Janckila AJ, Slone SP,Lear SC ,et al. Tartrate-resistant acid phosphatase as an immunohist- ochemical marker for inflammatory macrophages. American journal of clinical pathology. 2007; 127(4):556-566.
[14]Lloyd CM, Phillips AR,Cooper GJ ,et al. Three-colour fluorescence immunohistochemistry reveals the diversity of cells staining for macrophage markers in murine spleen and liver. Journal of Immunological Methods. 2008;334(1-2):70-81.
[15]Kunisch E, Fuhrmann R, Roth A et al.Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1,EBM11,and PGM1) widely used for immunohistochemistry and flow cytometry. Ann Rheum Dis.2004;63(7):774-784.
[16]Zheng H, Benjamin IJ, Basu S, Li Z. Heat shock factor 1-independent activation of dendritic cells by heat shock: implication for the uncoupling of heat-mediated immunoregulation from the heat shock response. Eur J Immunol 2003;33(6):1754–1762.
[17] Hatzfeld-Charbonnier AS, Lasek A, Castera L,et al. Influence of heat stress on human monocyte-derived dendritic cell functions with immunotherapeutic potential for antitumor vaccines. J Leukoc Biol. 2007 ; 81(5): 1179–1187.
[18] Park HG, Han SI, Oh SY, et al. Cellular responses to mild heat stress. Cell Mol Life Sci 2005;62(1):10–23.
[19]Hanson DF. Fever, temperature, and the immune response. Ann N Y Acad Sci 1997;813: 453–464.
[20]Wang WC, Goldman LM, Schleider DM, et al. Fever-range hyperthermia enhances L-selectin-dependent adhesion of lymphocytes to vascular endothelium. J Immunol 1998;160(2):961–969.
[21] Hanson DF. Fever and the immune response. The effects of physiological temperatures on primary murine splenic T-cell responses in vitro. J Immunol 1993;151(1):436–448.
[22]Hanson AJ,Quinn MT. Effeet of fibrin sealant composition on human neutrophil chemotaxis. J Biomed Mater Res,2002,61(3):474-481.
[23] Hanson DF. Fever and the immune response. The effects of physiological temperatures on primary murine splenic T-cell responses in vitro. J Immunol 1993;151(1):436–448.
[24] Periago PM, Schaik WV, Abee T,et al. Wouters. Identification of Proteins Involved in the Heat Stress Response of Bacillus cereus ATCC 14579. APPLIED AND ENVIRONMEN- TAL MICROBIOLOGY, 2002, 68(7): 3486–3495.
[25] Hatzfeld-Charbonnier AS, Lasek A, Castera L,et al. Influence of heat stress on human monocyte-derived dendritic cell functions with immunotherapeutic potential for antitumor vaccines. J Leukoc Biol. 2007; 81(5): 1179–1187.
[26] Rees AD , Donatit Y, Lombardi G,et al. Stress-induced modulation of antigen-presenting cell function. Immunology. 1991,74(3):386-392
[27] Viswanathan K and Firdaus S. Dhabhar. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Immunology. 2005,102(16): 5808–5813.
[28]Beedholm R, Clark BFC, and Rattan SLS. Mild heat stress stimulates 20S proteasome and its 11S activator in human fibroblasts undergoing aging in vitro. Cell Stress & Chaperones. 2004, 9(1) : 49–57.
[29] Morino S, Kondo T, Sasaki K, et al . Mild Electrical Stimulation with Heat ShockAmeliorates Insulin Resistance via Enhanced Insulin Signaling. PLoS ONE. 2008; 3(12): e4068.
[30]Pritts TA, Wang Q, Sun X, et al. The stress response decreases NF-kappaB activation in liver of endotoxemic mice. Shock. 2002;18(1):33–37.
[31] Setroikromo R , Wierenga PK, Waarde MA,et al. Heat shock proteins and Bcl-2 expression and function in relation to the differential hyperthermic sensitivity between leukemic and normal hematopoietic cells. Cell Stress & Chaperones.2007,12(4) : 320–330.
[32]Dat JF, Foyer CH, Scott IM. Changes in salicylic acid and antioxidants during induced of thermotolerance in mustard seedlings. Plant Physiol. 1998;118(4):1455–1461.;
[33]Lopez-Delgado H, Dat JF, Foyer CH, et al. Induction of thermotolerance in potato microplants by acetylsalicylic acid and H2O2. J Exp Bot. 1998;49:713–720.
[34] Bubliy OA, Loeschcke V. Correlated responses to selection for stress resistance and longevity in a laboratory population of Drosophila melanogaster. J Evol Biol. 2005;18(4):789–803.
[35]Kuckelkorn U, Knuehl C, Boes-Fabian B, et al. The effect of heat shock on 20S/26S proteasomes. Biol Chem. 2000;381(9-10):1017–1023.
[36]Rattan SI. Applying hormesis in aging research and therapy. Hum Exp Toxicol. 2001;20(6): 281– 285.
[37]Calabrese EJ, Baldwin LA. Toxicology rethinks its central belief. Nature. 2003;421 (6924): 691– 692.
[38] Stout RD, Suttles J. Immunosenescence and macrophage functional plasticity:dysregulation of macrophage function by age-associated microenvironmental changes. Immunol Rev. 2005,205: 60–71.
[39] Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol. 2004,76(3): 509–513.
[40]Ostberg JR, Repasky EA. Emerging evidence indicates that physiologically relevant thermal stress regulates dendritic cell function. Cancer Immunol Immunother. 2006;55(3):292–298.
[41]Otero M, Lago R,Gomez R,et al.Leptin:a metabolic hormone that functions like a proinflammatory adipokine[J].Drug News Perspect,2006,19(1):21-26.
[42]Wang J, Asensio VC, and Campbell IL. Cytokines and chemokines as mediators of protection and injury in the central nervous system assessed in transgenic mice. Curr. Top. Microbiol. Immunol. 2002;265(1):23-48
[43]Hehlgans T, Pfeffer K. The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 2005;115(1):1–20.
[44] Bette M , Kaut O, Schafer MK,et al. Constitutive expression of p55TNFR mRNA and mitogen-specific up-regulation of TNF alpha and p75TNFR mRNA in mouse brain. J. Comp. Neurol. 2003.465(3):417-430.
[45]Blum A and Miller H. The major histocompatibility complex and inflammation. South Med. J. 2000;93(2):169-172.
[46] Seo SH and Webster RG. Tumor necrosis factor alpha exerts powerful anti-influenza virus effects in lung epithelial cells. J. Virol. 2002;76(3):1071-1076.
[47]Turrin NP, Rivest S. Tumor necrosis factor alpha but not interleukin 1beta mediates neuroprotection in response to acute nitric oxide excitotoxicity. J Neurosci. 2006;26(1): 143–151.
[48]Nguyen MD, Julien JP, Rivest S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci. 2002;3(3):216–227.
[49]Asher AL, MuléJJ, Reichert CM, et al. Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo. J Immunol. 1987;138(3):963-74.
[50]Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF) I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent and limited by severe toxicity. J Exp Med. 1988;167(3):1067-85.
[51]Palladino Jr MA, Shalaby MR, Kramer SM, et al. Characterization of the anti-tumor activities of tumor necrosis factor-alpha and the comparison with other cytokines: induction of tumor specific immunity. J Immunol. 1987;138(11):4023-32.
[52] Calzascia T, Pellegrini M, Hall H, et al. TNF-αis critical for antitumor but not antiviral T cell immunity in mice. J Clin Invest. 2007 ; 117(12): 3833–3845.
[53]Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 2003. 3(2):133-146.
[54] Szabo SJ, Sullivan BM, Peng SL, et al. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol. 2003;21(4):713–58.
[55] Colombo MP, Trinchieri G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 2002;13(2):155–168.
[56]Harada M,Tamada K,Abe K,etal.Role of the endogenous Produetion of interleukin 12 in immunotherapy.Caneer-Res.1998,58(14):3073-3082
[57] Melero I, Mazzolini G, Narvaiza I, et al. IL-12 gene therapy for cancer: in synergy with other immunotherapies. Trends Immunol. 2001.22(3):113-115.
[58] Ruan S, McKinley L, Zheng MQ, et al. Interleukin-12 and Host Defense against Murine Pneumocystis Pneu. Infect Immun. 2008 May; 76(5): 2130–2137.
[59] Sun K, Salmon SL, Lotz SA, et al. Interleukin-12 Promotes Gamma Interferon-Dependent Neutrophil Recruitment in the Lung and Improves Protection against Respiratory Streptococcus pneumoniae Infection. Infect Immun. 2007; 75(3): 1196–1202.
[60] Nolt D and Flynn JL. Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected with Mycobacterium tuberculosis. Infect Immun. 2004 ; 72(5): 2976–2988.
[61]Goebel A , Kavanagh E, Lyons A, et al. Injury induces deficient interleukin-12 production, but interleukin-12 therapy after injury restores resistance to infection. Ann. Surg. 2000. 231(2): 253- 261.
[62]Jacobson MA, Spritzler J, et al. A phase I, placebo-controlled trial of multi-dose recombinant human interleukin-12 in patients with HIV infection. AIDS . 2002.16(8):1147-1154.
[63] Kobayashi M, Takahashi H, Herndon DN, et al. Therapeutic effects of IL-12 combined with benzoylmesaconine, a non-toxic aconitine-hydrolysate, against herpes simplex virus type 1 infection in mice following thermal injury. Burns . 2003.29(1):37-42.
[64] Coma G, Pe?a R, Blanco J, et al . Treatment of monocytes with interleukin (IL)-12 plus IL-18 stimulates survival, differentiation and the production of CXC chemokine ligands (CXCL)8, CXCL9 and CXCL10. Clin Exp Immunol. 2006; 145(3): 535–544.
[65]Halford WP, Kemp CD, Isler JA, et al. ICP0, ICP4, or VP16 expressed from adenovirus vectors induces reactivation of latent herpes simplex virus type 1 in primary cultures of latently infected trige minalganglion cells [J]. Virol, 2001, 75(13): 6143-6153.
[66]Bermudez LE, Parker A, Petrofsky M. Apoptosis of mycobacterium aviu minfected macrophages is mediated by both tumor necrosis factor (TNF) and Fas , and involves the activation of caspases. [J]. Clin Exp Immunol, 1999, 116 (1): 94-99.
[67]Schell MT, Spitzer AL, Johnson JA, et al. Heat shock inhibits NF-kB activation in a dose- and time-dependent manner. J Surg Res. 2005;129(1):90–93.
[68]Curry HA, Clemens RA, Shah S, et al. Heat shock inhibits radiation-induced activation of NF-kappaB via inhibition of I-kappaB kinase. J Biol Chem. 1999;274(33):23061–23067.
[69]Chan JY, Ou CC, Wang LL, et al. Heat shock protein 70 confers cardiovascular protection during endotoxemia via inhibition of nuclear factor-kappaB activation and inducible nitric oxide synthase expression in the rostral ventrolateral medulla. Circulation. 2004;110(23): 3560–3566.
[70]Chen Y, Arrigo AP, Currie RW. Heat shock treatment suppresses angiotensin II-induced activation of NF-kappaB pathway and heart inflammation: a role for IKK depletion by heat shock? Am J Physiol. 2004;287(3):H1104–H1114.
[71]De Vera ME, Kim YM, Wong HR, et al. Heat shock response inhibits cytokine-inducible nitric oxide synthase expression in rat hepatocytes. Hepatology. 1996;24(5):1238–1245.
[72]Ostberg JR, Taylor SL, Baumann H, et al. Regulatory effects of fever-range whole-body hyperthermia on the LPS-induced acute inflammatory response. J Leukoc Biol. 2000; 68(6): 815–820.
[73]Rattan SI. Repeated mild heat shock delays ageing in cultured human skin fibroblasts. Biochem Mol Biol Int. 1998;45(4):753–759.
[74] Verbeke P, Clark BF, Rattan SI. Reduced levels of oxidized and glycoxidized proteins in human fibroblasts exposed to repeated mild heat shock during serial passaging in vitro. Free Radic Biol Med. 2001 ;31(12):1593–1602.
[75] Verbeke P, Deries M, Clark BF, et al. Hormetic action of mild heat stress decreases the inducibility of protein oxidation and glycoxidation in human fibroblasts. Biogerontology. 2002;3(1-2):117–120.
[76]Fonager J, Beedholm R, Clark BF, et al. Mild stress-induced stimulation of heat-shock proteinsynthesis and improved functional ability of human fibroblasts undergoing aging in vitro. Exp Gerontol. 2002;37(10-11):1223–1228.
[77]Wust P, Hildebrandt B, Sreenivasa G, et al. Hyperthermia in combined treatment of cancer. Lancet Oncol. 2002;3(8):487–497.
[78]Todryk S, Melcher AA, Hardwick N, et al. Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake. J Immunol. 1999;163(3):1398–1408.
[79].Hantschel M, Pfister K, Jordan A, et al. HSP 70 plasma membrane expression on primary tumor biopsy material and bone marrow of leukemic patients. Cell Stress Chaperones. 2000;5(5):438–442.
[80]Guzhova I, Kislyakova K, Moskaliova O, et al. In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res. 2001;914(1–2):66–73.
[81]Feng H, Zeng Y, Whitesell L, et al. Stressed apoptotic tumor cells express heat shock proteins and elicit tumor-specific immunity. Blood. 2001;97(11):3505–3512.
[82]Barreto A, Gonzalez JM, Kabingu E, et al. Stress-induced release of HSC70 from human tumors. Cell Immunol. 2003;222(2):97–104.
[83]Martin CA, Carsons SE, Kowalewski R, et al. Aberrant extracellular and dendritic cell (DC) surface expression of heat shock protein (hsp)70 in the rheumatoid joint: possible mechanisms of hsp/DC-mediated cross-priming. J Immunol. 2003;171(11):5736–42.
[84]Gastpar R, Gross C, Rossbacher L, et al. The cell surface-localized heat shock protein 70 epitope TKD induces migration and cytolytic activity selectively in human NK cells. J Immunol. 2004;172(2):972–980.
[85]Bausero MA, Page DT, Osinaga E, et al. Surface expression of Hsp25 and Hsp72 differentially regulates tumour growth and metastasis. Tumour Biol. 2004;25(5-6):243–251.
[86]Korbelik M, Sun J, Cecic I. Photodynamic therapy-induced cell surface expression and release of heat shock proteins: Relevance for tumor response. Cancer Res. 2005;65(3): 1018–1026.
[87]Lang A, Benke F, Eitner D, et al. Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: In vivo evidence for an immunologic danger signal. J Am Soc Nephrol. 2005;16(2):383–391.
[88]Bausero M, Gastpar R, Multhoff G, et al. Alternative mechanism by which IFN-gamma enhances tumor recognition: Active release of heat shock protein 72. J Immunol. 2005;175(5):2900–2912
[89]Nover L, Scharf KD, Neumann D. Formation of cytoplasmic heat shock granules in tomato cell cultures and leaves. Mol Cell Biol. 1983;3(9):1648–1655.
[90]Fisher EA, Zhou MY, Mitchell DM, et al. The degradation of apolipoprotein B100 is mediated by the ubiquitin-proteasome pathway and involves heat shock protein 70. J Biol Chem 1997. 272(33): 20427–20434.
[91]Wierenga PK, Setroikromo R, Kamps G, et al. Differences in heat sensitivity between normal and acute myeloid leukemic stem cells: feasibility of hyperthermic purging of leukemic cells from autologous stem cell grafts. Exp Hematol. 2003.31(5): 421–427.
[92] Setroikromo R, Wierenga PK, van Waarde MAWH, et al .Heat shock proteins and Bcl-2 expression and function in relation to the differential hyperthermic sensitivity between leukemic and normal hematopoietic cells. Cell Stress & Chaperones (2007) 12 (4), 320–330.
[93]Linda M. Hendershot. The ER Chaperone Bip Is a Master Regulator of ER Function. The Mount Sina Journal of Medicine .2004; 71(5 ):289-299.
[94] Nielsen MM, S?rensen JG, Kruh?ffer M, et al. Phototransduction genes are up-regulated in a global gene expression study of Drosophila melanogaster selected for heat resistance. Cell Stress Chaperones. 2006; 11(4): 325–333.
[95]S?rensen JG, Nielsen MM, Kruh?ffer M, et al. Full genome gene expression analysis of the heat stress response in Drosophila melanogaster. Cell Stress Chaperones. 2005;10(4):312–328
[96] Oehler R, Pusch E, Zellner M, et al. Cell type–specific variations in the induction of hsp70 in human leukocytes by feverlike whole body hyperthermia. Cell Stress Chaperones. 2001; 6(4): 306–315.
[97]Haas IG. Bip(GRP78),an essential hsp70 resident protein in the endoplasmic reyiculum. Experientia.1994;50(11-12):1012-1220.
[98]Bole DG, Hendershot LM and Kearney JF. Posttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas. J. Cell Biol. 1986.102(5):1558–1566.
[99]Haas IG and Wabl M. Immunoglobulin heavy chain binding protein. Nature . 1983.306 (5941):387–389.
[100]Munro S and Pelham HR. An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell . 1986. 46(2):291–300.
[101]Kim YK and Jang SK. Continuous heat shock enhances translational initiation directed by internal ribosomal entry site. Biochem Biophys Res Commun. 2002. 297(2):224–231.
[102] Alder NN, Shen Y, Brodsky JL, et al. The molecular mechanisms underlying Bip-mediated gating of the Sec61 translocon of the endoplasmic reticulum.The Journal of Cell Biology;2005,168(3):389-299.
[103] Patil C and Walter P. Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals.Curr Opin Cell Biol. 2001.13(3):349–355.
[104]Schroder M and Kaufman RJ. The mammalian unfolded protein response. Annu. Rev. Biochem. 2005.74(6):739–789.
[105]Travers KJ, Patil CK, Wodicka L, et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell . 2000. 101(3):249–258.
[106]Kampinga HH. Thermotolerance in mammalian cells—protein denaturation and aggregation, and stress proteins. J Cell Sci. 1993. 104(PT1):11–17.
[107]Kaufman RJ, Scheuner D, Schroder M, et al. The unfolded protein response in nutrient sensing and differentiation. Nat. Rev. Mol. Cell Biol.. 2002.3(6):411–421.
[108] Rawson RB. The SREBP pathway—insights from Insigs and insects. Nat. Rev. Mol. Cell Biol. 2003. 4(8):631–640.
[109]Lee AS.The glucose regulation protein: stree induction and clinical applications. Trends Bio chem Sci,2001,26(8):504-510.
[110]Hammond C and Helenius A. Quality control in the secretory pathway: retention of a misfolded viral membrane glycoprotein involves cycling between the ER, intermediate compartment, and Golgi apparatus. J. Cell Biol. 1994. 126(1):41–52.
[111]Yamamoto K , Fujii R, Toyofuku Y, et al. The KDEL receptor mediates a retrieval mechanism that contributes to quality control at the endoplasmic reticulum. EMBO J. 2001.20(12):3082–3091.
[112]Mimura N, Hamada H, Kashio M, et al. Aberrant quality control in the endoplasmic reticulum impairs the biosynthesis of pulmonary surfactant in mice expressing mutant BiP. Cell Death Differ. 2007.14(8):1475–1485.
[113] Mimura N, Yuasa S, Soma M,et al. Altered Quality Control in the Endoplasmic Reticulum Causes Cortical Dysplasia in Knock-In Mice Expressing a Mutant BiP. Molecular and Cellular Biology.2008,28(1): 293–301.
[114]Luo S , Mao C, Lee B, et al. GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol. Cell. Biol. 2006.26(15):5688–5697.
[115]Singh IS, Viscardi RM, Kalvakolanu I, et al. Inhibition of tumor necrosis factor-alpha transcription in macrophages exposed to febrile range temperature: a possible role for heat shock factor-1 as a negative transcriptional regulator. J Biol Chem. 2000;275(13):9841–9848.
[116]黄长文,傅华群.血脾屏障的功能及其调节.中华普通外科学文献. 2008,2(6):53-55.
[117]黄长文,傅华群.血脾屏障结构和功能的研究进展.国际外科学2008;35(12):829-831.
[118] Stein CA. The experimental use of antisense oligonucleotides: a guide for the perplexed. J. Clin. Invest.2001, 108(5): 641-644.
[119] Ziegler A, Luedke GH, Fabbro D, et al. Induction of apoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotide targeting the Bcl-2 coding sequence. JNCI Journal of the National Cancer Institute 1997 89(14):1027-1036.
[120] Rudin CM, Kozloff M, Hoffman PC,et al. Phase I Study of G3139, a bcl-2 Antisense Oligonucleotide, Combined With Carboplatin and Etoposide in Patients With Small-Cell Lung Cancer . Journal of Clinical Oncology.2004,22( 6 ): 1110-1117.
[121] Chi KN, Gleave ME, Klasa R, et al. A Phase I Dose-finding Study of Combined Treatment with an Antisense Bcl-2 Oligonucleotide (Genasense) and Mitoxantrone in Patients with Metastatic Hormone-refractory Prostate Cancer. Clinical Cancer Research.2001, 7(12),3920-3927.
[122] Chi KN, Eisenhauer E, Fazli L,et al. A Phase I Pharmacokinetic and Pharmacodynamic Study of OGX-011, a 2'-Methoxyethyl Antisense Oligonucleotide to Clusterin, in Patients With Localized Prostate Cancer . Journal of the National Cancer Institute .2005 , 97(17):1287-1296.
[123] Marcucci G, Byrd JC. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood. 2003, 101(2): 425-432.
[124] O'Brien SM, Cunningham CC, Golenkov AK,et al. Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia . Journal of Clinical Oncology.2005, 23(30) : 7697-7702.
[125] Morris MJ, Tong WP, Cordon-Cardo C,et al. Phase I Trial of BCL-2 Antisense Oligonucleotide (G3139) Administered by Continuous Intravenous Infusion in Patients with Advanced Cancer. Clinical Cancer Research .2002, 8(3): 679-683.
[126] Olie RA, Sim?es-Wüst AP, Baumann B, et al. A Novel Antisense Oligonucleotide Targeting Survivin Expression Induces Apoptosis and Sensitizes Lung Cancer Cells to Chemotherapy. Cancer Research. 2000 60(11): 2805-2809
[127]Dean NM, Bennett CF. Antisense oligonucleotide-based therapeutics for cancer. Oncogene.2003, 22(56): 9087–9096.
[128] Leamon CP, Cooper SR, and Hardee GE. Folate-Liposome-Mediated Antisense Oligodeoxynucleotide Targeting to Cancer Cells: Evaluation in Vitro and in Vivo. Bioconjugate Chem.2003, 14 (4):738–747.
[129] Offensperger WB, Offensperger S, Walter E, et al. In vivo inhibition of duck hepatitis B virus replication and gene expression by phosphorothioate modified antisense oligodeoxyn- ucleotides. EMBO J. 1993; 12(3): 1257–1262.
[130] Mayne M, MSc WN, Yan HJ,et al. Antisense Oligodeoxynucleotide Inhibition of Tumor Necrosis Factor-αExpression Is Neuroprotective After Intracerebral Hemorrhage. Stroke. 2001;32(1):240-248.
[131] Crooke RM, Graham MJ, Lemonidis KM,et al. An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis. Journal of Lipid Research .2005,46(5):872-884.
[132] Yacyshyn BR, Chey WY, Goff J,et al. Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynu- cleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease. Gut. 2002,51(1):30-36.
[133]Chang L and Karin M. Mammalian MAP kina sesignalling cascades.Nature,2001,410(6824):37-40.
[134]Johnson GL, Laadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002 Dec 6;298(5600):1911-2.
[135] RouxP P,BlenisJ.ERK and p38 M APK-activated protein kinases:a family of protein kinases with diverse biological functions.M icrobiolM olBiolRev,2004,68 (2):320-344.
[136] Slack BS and Siniaia MS. Adhesion-Dependent Redistribution of MAP Kinase and MEK Promotes Muscarinic Receptor-Mediated Signaling to the Nucleus. J Cell Biochem. 2005 15; 95(2): 366-378.
[137]Kyriakis JM. Making the connection: coupling of stress-activated ERK/MAPK (extracellular-signal-regulated kinase/mitogen-activated protein kinase) core signalling modules to extracellular stimuli and biological responses. Biochem Soc Symo 1999;64:29-48.
[138] Kurata S. Selective Activation of p38 MAPK Cascade and Mitotic Arrest Caused by Low Level Oxidative Stress. J Biol Chem .2000;275(31): 23413–23416.
[139] Clerk A, Fuller SJ, Michael A,et al. Stimulation of“Stress-regulated”Mitogen-activated Protein Kinases (Stress-activated Protein Kinases/c-Jun N-terminal Kinases and p38-Mitogen- activated Protein Kinases) in Perfused Rat Hearts by Oxidative and Other Stresses. J Biol Chem. 1998;273(13):7228-7234.
[140] O'Rourke SM and Herskowitz I. Unique and Redundant Roles for HOG MAPK Pathway Components as Revealed by Whole-Genome Expression Analysis. Mol Biol Cell. 2004; 15(2): 532–542.
[141]Gorostizaga A, Brion L, Maloberti P. The Journal of Biological Chemistry. Heat shock triggers MAPK activation and MKP-1 induction in Leydig testicular cells. Biochem Biophys Res Commun. 2005;327(1):23–28.
[142] Sanlorenzo L, Zhao B, Spight D, et al. Heat shock inhibition of lipopolysaccharide- mediated tumor necrosis factor expression is associated with nuclear induction of MKP-1 and inhibition of mitogen-activated protein kinase activation. Crit Care Med. 2004;32(11): 2284–92.
[143] Jones CA, Greer-Phillips SE and Borkovich KA. The Response Regulator RRG-1 Functions Upstream of a Mitogen-activated Protein Kinase Pathway Impacting Asexual Development, Female Fertility, Osmotic Stress, and Fungicide Resistance in Neurospora crassa. Mol Biol Cell. 2007; 18(6): 2123–2136.
[144] Chen RE and Thorner J. Function and Regulation in MAPK Signaling Pathways. Biochim Biophys Acta. 2007 ; 1773(8): 1311–1340.
[145] Craig CR, Fink JL, Yagi Y,et al. A Drosophila p38 orthologue is required for environmental stress responses . EMBO Rep. 2004; 5(11): 1058–1063.
[146] Thorsen M, Di Y, T?ngemo C,et al. The MAPK Hog1p Modulates Fps1p-dependent Arsenite Uptake and Tolerance in Yeast. Mol Biol Cell. 2006; 17(10): 4400– 4410.
[147] Bruchas MR, Benjamin BL , Aita M, et al.Stress-Induced p38 Mitogen- Activated Protein Kinase Activation Mediatesκ-Opioid-Dependent Dysphoria. J Neurosci. 2007 ; 27(43): 11614–11623.
[148] Lobo VJSA, Luquero CIA,álvarez-Vallina L,et al. Modulation of the p38 MAPK (mitogen-activated protein kinase) pathway through Bcr/Abl: implications in the cellularresponse to Ara-C. Biochem J. 2005; 387(Pt 1): 231–238.
[149] Lawrence CL, Botting CH, Antrobus R,et al. Evidence of a New Role for the High-Osmolarity Glycerol Mitogen-Activated Protein Kinase Pathway in Yeast: Regulating Adaptation to Citric Acid Stress. Mol Cell Biol. 2004 ; 24(8): 3307–3323.
[150] Jin Y, Weining S and Nevo E. A MAPK gene from Dead Sea fungus confers stress tolerance to lithium salt and freezing–thawing: Prospects for saline agriculture. Proc Natl Acad Sci U S A. 2005; 102(52): 18992–18997.
[151] W?ll S, Windoffer R, and Leube RE. p38 MAPK-dependent shaping of the keratin cytoskeleton in cultured cells. J Cell Biol. 2007; 177(5): 795–807.
[152] Malago JJ, Koninkx JFJG. The Journal of Biological Chemistry. The heat shock response and cytoprotection of the intestinal epithelium. Cell Stress Chaperones. 2002; 7(2): 191–199.
[153]Zhang Y L,Dong C.MAP kinasesin immune responses.Cell Mol Immunol,2005,2 (1):20-27.
[154]Olsson AK,Vadhammar K,NanbergE. Activation and protein kinase C-dependent nuclear accumulation of ERK indifferentiating human neuroblastoma cells.Experimental Cell Researeh,2000,256(2):454-467.
[155]Lenrunyr F,KarlssonS,Gerwins P etal.Activation of mitogen aetivated protein kinase inexperimental cerebral isehemia. Acta Neurologica Scandinavica,2002,106(6):333-340.
[156] El-Remessy AB, Tang Y, Zhu G,et al. Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation. Mol Vis. 2008; 14: 2190–2203.
[157] Elsea CE, Roberts DA, Druker BJ,et al. Inhibition of p38 MAPK Suppresses Inflammatory Cytokine Induction by Etoposide, 5-Fluorouracil, and Doxorubicin without Affecting Tumoricidal Activity. PLoS ONE. 2008; 3(6): e2355.
[158] An WW, Wang MW, Tashiro S, et al. Mitogen-activated protein kinase-dependent apop tosis in norcan-tharidin-treatedA375-S2 cells is proceeded by the activation of protein kinase C. ChinMed J , 2005, 118 (3) : 198 - 203.
[159]Irving EA,Bamford M.Role of mitogen-and stress-activated kinases in ischemic injury .J Cereb Blood Flow Metab,2002,22(6) :631-647.
[160]Fukunaga K, Miyamoto E. Role of MAP kinase in neurons . Mol Neurobiol, 1998, 16 (1) : 79 - 95.
[161] Dodeller F and Schulze-Koops H. The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells. Arthritis Res Ther. 2006; 8(2): 205.
[162]Li H,Xu H,Zhou Y,et al.The phosphothreonine lyase activity of a bacterial typeⅢeffector family.Science,2007,315 (5814):1000-1003.
[163]Mukherjee S,Keitany G,LiY,et al.Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science,2006,312 (5777):1211-1214.
[164]Zhang K,Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology . 2006 ;66(2 Suppl 1):S102-109.
[165] Ranganathan AC, Zhang L, Adam AP,et al. Functional Coupling of p38-InducedUp-regulation of BiP and Activation of RNA-Dependent Protein Kinase–Like Endoplasmic Reticulum Kinase to Drug Resistance of Dormant Carcinoma Cells. Cancer Res. 2006; 66(3): 1702–1711.
[166] Misra UK, Pizzo SV. Upregulation of GRP78 and antiapoptotic signaling in murine peritoneal macrophages exposed to insulin. J Leukoc Biol. 2005; 78(1): 187–194.
[167] Truman AW, Millson SH, Nuttall JM, et al. In the Yeast Heat Shock Response, Hsf1-Directed Induction of Hsp90 Facilitates the Activation of the Slt2 (Mpk1) Mitogen-Activated Protein Kinase Required for Cell Integrity. Eukaryot Cell. 2007; 6(4): 744–752.
[168] Winkler A, Arkind C, Mattison CP, et al. Heat Stress Activates the Yeast High-Osmolarity Glycerol Mitogen-Activated Protein Kinase Pathway, and Protein Tyrosine Phosphatases Are Essential under Heat Stress. Eukaryot Cell. 2002; 1(2): 163–173.
[169] Cho S, Park SM, Kim TD,et al. BiP Internal Ribosomal Entry Site Activity Is Controlled by Heat-Induced Interaction of NSAP. Mol Cell Biol. 2007; 27(1): 368–383.
[170] Sepp? L and Makarow M. Regulation and Recovery of Functions of Saccharomyces cerevisiae Chaperone BiP/Kar2p after Thermal Insult. Eukaryot Cell. 2005; 4(12): 2008–2016.
[1] Weiss L,Geduldig U,Weidanz W.Mechanisms of splenic control of murine malaria : reticular cell activation and the development of a blood-spleen barrier .Am J Anat,1986, 176: 251-285.
[2]蒋登金,郭光金,陈维佩,等.血脾屏障结构与功能的实验研究[J].中华肝胆外科杂志,2002,8:49-52.
[3]郭光金,叶明福.血脾屏障的形态学研究.第四军医大学学报,2000,21:177-179.
[4]蒋登金,郭光金,张天飞,等.脾脏边缘窦内皮细胞的实验观察,解剖学杂志.2002,25:178-180.
[5] Kraal G.Cell in the marginal zone of the spleen. Int Rev Cytol ,1992, 132:31-74.
[6] van den Berg TK, Breve JJ , Damoisequx JG ,et al. Sialoadhesin on macrophages: its identification as a lymphocyte adhesion molecule. J. Exp. Med. 1992,176:647–655.
[7] Namikawa R., Mizuno T, Matsuoka H,et al.Ontogenic development of T and B cells and non-lymphoid cells in the white pulp of human spleen. Immunology ,1986, 57 :61-69.
[8] Steiniger B, Barth P, Hellinger A . The perifollicular and marginal zones of the human splenic white pulp.Am J Pathol. 2001, 159:501–512.
[9] Nolte MA, Hoen ENM‘t, Van Stijn A,et al. Isolation of the intact white pulp quantitative and qualitative analysis of the cellular composition of the splenic compartments.Eur. J. Immunol. 2000.30:626–634.
[10] Steiniger B, Barth P, Herbst B ,et al. The speciesspecific structure of microanatomical compartments in the human spleen: strongly sialoadhesin-positive macrophages occur in the perifollicular zone, but not in the marginal zone. Immunology ,1997, 92:307–316.
[11] Togni De, Goellner PJ,Ruddle NH , et al.. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin.Science. 1994, 264:703–707.
[12] Alimzhanov, MB, Kuprash DV,Kosco-Vilbois MH, et al. Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice. Proc. Natl. Acad. Sci. USA. 1997, 94:9302–9307.
[13] Kuprash DV, Alimzhanov MB, Tumanov AV, et al. TNF and lymphotoxin beta cooperate in the maintenance of secondary lymphoid tissue microarchitecture but not in the development of lymph nodes. J. Immunol. 1999., 163:6575–6580.
[14] Wu Q, Wang Y, Wang J , et al. The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues.J. Exp. Med. 1999, 190:629–638.
[15] Schmidt EE, MacDonald IC,Groom AC, et al. Comparative aspects of splenic microcirculatory pathways in mammals: the region bordering the white pulp.Scanning Microsc. 1993.7:613–628.
[16] Timens W,Poppema S .Lymphocyte compartments in human spleen. An immunohistologic study in normal spleens and noninvolved spleens in Hodgkin's disease. Am. J. Pathol. 1985,120, 443.
[17] Keuning FJ,Bos WH. Regeneration patterns of lymphoid follicles in the rabbit spleen after sublethal xirradiation. Cell Tissue Res. 1967,113:250-257.
[18] Bazin HD, Gray B,Platteau IC, et al. Distinct &+ and &- B lineages in the rat. Ann. N.Y. Acad. Sci. 1982,399:157-173.
[19] Dijskstra CD, Van Vliet E, Dopp EA, et al. Marginal zone macrophages identified by a monoclonal antibody: characterization of immuno- and enzymehistochemical propertiesand functional properties. Immunology ,1985,55:23-30.
[20] Humphrey JH., Grennan D. Different macrophage populations distinguished by means of fluorescent polysaccharides.Recognition and properties of marginal zone macrophages.Eur. J. Immunol. 1981,11:221-235.
[21] MacLennan ICM, Gray D, Kumararatne DS, et al. The lymphocytes of splenic marginal zones: a distinct B-cell lineage. Immunol. Today ,1982.3:305-307.
[22] Yamamoto K,Kobayashi T, Murakami T . Arterial terminals in the rat spleen as demonstrated by scanning electron microscopy of vascular casts. Scan. Electron Microsc. 1982.1:455–458.
[23] Ford WL. The kinetics of lymphocyte recirculation within the rat spleen. Cell Tissue Kinet. 1969. 2:171–191.
[24] Brelinska R, Pilgrim, C. The significance of the subcompartments of the marginal zone for directing lymphocyte traffic within the splenic pulp of the rat. Cell Tissue Res. 1982. 226:155–165.
[25] Van Ewijk W, Nieuwenhuis P. Compartments,domains and migration pathways of lymphoid cells in the splenic pulp. Experientia. 1985.41:199–208.
[26] Ferguson AR, Youd ME, Corley RB. Marginal zone B cells transport and deposit IgM-containing immune complexes onto follicular dendritic cells. Int Immunol .2004, 16:1411-1422.
[27] Steinman RM., Pack M, Inaba K . Dendritic cells in the T-cell areas of lymphoid organs. Immunol. Rev .1997.156:25–37.
[28] Kumararatne DS, MacLennan ICM. Cells of the marginal zone of the spleen are derived from recirculating precursors. Eur J Immunol. 1981; 11:865-869.
[29] MacLennan ICM, Liu YJ. Marginal zone B cells respond to both polysaccharide antigens and protein antigens. Res Immunol .1991;142:346-351.
[30] Susan A. Elmore.Enhanced Histopathology of the Spleen. Toxicol Pathol. 2006 ; 34: 648–655.
[31] Jeurissen SHM., Claassen E, Janse E.M. Histological and functional differentiation of non-lymphoid cells in the chicken spleen. Immunology, 1992;77, 75.
[32] Pongponratn E, Riganti M,Bunnag D , et al. Spleen in falciparum malaria: ultrastructural study. Southeast Asian J. Trop. Med. Public Health. 1987;18:491–501.
[33] Pongponratn E, Viriyavejakul P , Wilairatana P ,et al. Absence of knobs on parasitized red blood cells in a splenectomized patient in fatal falciparum malaria. Southeast Asian. J. Trop. Med. Public Health . 2000;31:829–835.
[34] Jakubovsky J,Hromec A. Current knowledge on the functional morphology of the human spleen. Bratisl Lek Listy. 1998 ;99(6):287-290.
[35] Steiniger B, Barth P , Hellinger A.. The perifollicular and marginal zones of the human splenic white pulp: do fibroblasts guide lymphocyte immigration? Am. J. Pathol. 2001;159:501–512.
[36] Franzoso G, Carlson L, Scharton-Kersten T,et al. Critical roles for the Bcl-3 oncoprotein in T cell-mediated immunity, splenic microarchitecture, and germinal center reactions.Immunity 1997, 6:479–490 .
[37] Poljak L, Carlson L, Cunningham K, et al.Distinct activities of p52/NF-kappa B required for proper secondary lymphoid organ microarchitecture: functions enhanced by Bcl-3.J Immunol .1999, 163:6581–6588.
[38] Korner H, Cook M, Riminton DS,et al.Distinct roles for lymphotoxin-alpha and tumor necrosis factor in organogenesis and spatial organization of lymphoid tissue. Eur J Immunol. 1997, 27:2600–2609.
[39] Weih DS, Yilmaz ZB, Weih F. Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J Immunol .2001, 167:1909–1919.
[40] Franzoso G, Carlson L, Poljak L,et al. Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions,and splenic microarchitecture. J Exp Med .1998, 187:147–159.
[41] Alexopoulou L, Pasparakis M, Kollias G.A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling. Eur J Immunol . 1997, 27:2588–2592.
[42] Stuart A, Warford A . Staining of human splenic sinusoids and demonstration of unusual banded structures by monoclonal antisera. J Clin Pathol. 1983;36:1176-1180.
[43] Basir MA , Pasparakis MB.The histology of the spleen and suprarenals of echidna. Journal of Anatomy, 1992;66:628-649.
[44] Weiss L. Barrier cells in the spleen. Immunol Today; 1991; 12:24–69.
[45] Chris A,Benedict,Carl De Trez,et al.Specific remodeling of splenic architecture by cytomegalovirus. PLoS Pathogens.2006,12:164-174.
[46] Van Rooijen N, Wijburg OLC., Ven Den Dobbelsteen GPJM,et al. Macrophages in host defense mechanisms. Curr Top Microbiol Immunol. 1996; 210, 159.
[47] Wijburg 0LC, Heemskerk MHM,Boogt CJP,et al. Role of splenic macrophage in innate and acquired immune responses against mouse hepatitis virus strain A59. Immunology. 1997 ;92: 252-258.
[48] Kaufmann SHE. Immunity to intracellular bacteria.Annu Rev Immunol, 1993; 11, 129.
[49] Ben-Nathan B, Huitinga I, Lustig S ,et al. West Nile virus neuroinvasion and encephalitis induced by macrophage depletion in mice. Arch Virol. 1996 ; 141, 459.
[50] Karupiah G, Buller RML,Van Rooijen N, et al. Different roles for CD4 + and CD8 + T lymphocytes and macrophage subsets in the control of a generalized virus infection. J Virol ,1996;70:8301-8309.
[51] Zisman B, Wheelock EF,Allison AC. Role of macrophages and antibody in resistance of mice against yellow fever virus. J Immunol . 1971;107, 236.
[52] Qian Q, Jutila MA, Van Rooijen N. Elimination of mouse splenic macrophage correlates with increased susceptibility to experimental disseminated candidiasis.J Immunol. 1994;152, 5000.
[53] Uuanue ER, Allen PM. The basis for the immunoregulatory role of macrophages and other accessory cells. Science . 1987;236, 551.
[54] Delemarre FGA, Kors N,Van Rooijen N. Elimination of spleen and of lymph node macrophages and its difference in the effect on the immune response to particulate antigens. Immunobiology . 1991;182, 70.
[55] Van Rooijen N. Macrophages as accessory cells in the in vivo humoral immune response: From processing of particulate antigens to regulation by suppression. Sem Immunol . 1992;4, 237.
[56] Jadwiga J, Kurt E. Dittmar T,et al. Essential role of CCL2 in clustering of splenic ERTR-9+ macrophages during infection of BALB/c Mice by listeria monocytogenes. Infection and Immunity. 2007,75:462–470 .
[57] Ato M, Iwabuchi K, Shimada S, er al. Augmented expression of tumour necrosis factor-a induced by lipopolysaccharide in spleen of human monocyte chemoattractant protein-1 transgenic mouse enhances the lipopolysaccharide sensitivity of the marginal zone macrophages. Immunology. 2002 ,106: 554–563.
[58] Ford WL. The kinetics of lymphocyte recirculation within the rat spleen. Cell Tissue Kinet. 1969; 2:171–191.
[59] Brelinska R,Pilgrim C. The significance of the subcompartments of the marginal zone for directing lymphocyte traffic within the splenic pulp of the rat. Cell Tissue Res. 1982; 226:155–165.
[60] Van Ewijk W, Nieuwenhuis P. Compartments, domains and migration pathways of lymphoid cells in the splenic pulp. Experientia. 1985;41:199–208.
[61] Goldschenider I, Mcgregor DD. Migration of lymphocytes and thymocytes in the rat. I. The route of migration from blood to spleen and lymph nodes. J Exp Med . 1968;127:155-168.
[62] Marciesi VT, Gowans JL. The migration of lymphocytes through the endothelium of venules in lymph nodes: an electron microscope study.Proc Roy Soc (Biol). 1964 ;159: 283-290.
[63] Willfuhr KU, Westermann J, Pabst R. Absolute numbers of lymphocyte subsets migrating through the compartments of the normal and transplanted rat spleen. Eur J Immunol .1990; 20:903.
[64] Maclennan ICM. Germinal centers. Annu Rev Immunol 1994;12:117–39.
[65] Liu YJ, Arpin C. Germinal center development. Immunol Rev 1997; 156:111–26.
[66] Kelsoe G. The germinal center: a crucible for lymphocyte selection.Semin Immunol 1996; 8:179–84.
[67] Olding LB. Interactions between maternal and fetal/neonatal lymphocytes. In: Current Topics in Pathology . 1979; 66:83.
[68] Andersson U, Bird AG, Britton S,et al. Humoral and cellular immunity in humans studied at the cell level from birth to two years of age. Immunol. 1981; 57:5.
[69] Hayward AR. Development of lymphocyte responses and interactions in the human fetus andnewborn. Immunol. 1981; 57:39.
[70] Chassoux D, Kolb JP, Bazin H, et al. Antibody-dependent cellular cytotoxicity (K) and natural killing (NK) in B-suppressed germ-free nude rats. Immunology, 1983; 50, 327.
[71] Oldenborg, P A, Zheleznyak A , Fang YF, et al. Role of CD47 as a marker of self on red blood cells. Science . 2000;288:2051–2054.
[72] Bohnsack JF, Brown EJ. The role of the spleen in resistance to infection. Annu. Rev. Med. 1986;37:49–59.
[73] Groom AC, Schmidt EE, MacDonald IC. Microcirculatory pathways and blood flow in spleen: new insights from washout kinetics,corrosion casts, and quantitative intravital videomicroscopy. Scanning Microsc. 1991;5:159–173.
[74] Martijn A, Jeroen A, Beli?n M ,et al.A Conduit System Distributes Chemokines and Small Blood-borne Molecules through the Splenic White Pulp. The Journal of Experimental Medicine. 2003 505–512.
[75] Nolte MA, kt Hoen ENM, Van Stijn A,et al.Isolation of the intact white pulp. Quantitative and qualitative analysis of the cellular composition of the splenic compartments. Eur J Immunol .2000; 30:626–634.
[76] David J,Wyler M,Thomas C. Relationship of Alterations in Splenic Clearance Function and Microcirculation to Host Defense in Acute Rodent Malaria. J. Clin. Invest. 1981 ,67:1400-1404.
[77] Connor J, Pak CC , Schroit A J. Exposure of phosphatidylserine in the outer leaflet of human red blood cells. Relationship to cell density, cell age, and clearance by mononuclear cells. J. Biol. Chem. 1994; 269:2399–2404.
[78] Janicik JM., Schauer R, Andres KH, et al. Sequestration of neuraminidase- treated erythrocytes. Studies on its topographic,morphologic and immunologic aspects. Cell Tissue Res. 1978; 186:209–226.
[79] Chotivanich K, Udomsangpetch R , McGready R ,et al. Central role of the spleen in malaria parasite clearance. J. Infect. Dis. 2002;184:1538–154
[80] Ho M, White NJ , Looareesuwan S, et al. Splenic Fc receptor function in host defense and anemia in acute Plasmodium falciparum malaria. J. Infect.Dis. 1990;161:555–561.
[81] Lee SH, Looareesuwan S, Wattanagoon Y , et al. Antibody-dependent red cell removal during P. falciparum malaria: the clearance of red cells sensitized with an IgG anti-D. Br. J. Haematol. 1989;73:396–402..
[82] Looareesuwan S, Ho M, Wattanagoon Y,et al. Dynamic alteration in splenic function during acute falciparum malaria. N Engl. J. Med. 1987;317:675–679.
[83] Michael B, Fischer M, Beate R, et al. The presence of MOMA-2+ macrophages in the outer B cell zone and protection of the splenic microarchitecture from LPS-induced destruction depend on secreted IgM. Eur. J. Immunol. 2007. 37: 2825–2833.
[84] Stoddart CA., Cardin RD , Boname JM ,et al. Peripheral blood mononuclear phagocytes mediate dissemination of murine cytomegalovirus. J. Virol. 1994; 68:6243–6253.
[85] Miyake Y , Asano K , Kaise H ,et al. Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell–associated antigens. The Journal of Clinical Investigation, 2007,117:2268-2278.
[86] Bourguin I, Moser M, Buzoni-Gatel D, et al. Murine dendritic cells pulsed in vitro with Toxoplasma gondii antigens induce protective immunity in vivo. Infect. Immun. 1998;66:4867– 4874.
[87] Sousa CR, Hieny S, Scharton-Kersten T, et al. In vivo microbial stimulation induces rapid CD40 ligand- independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J. Exp. Med. 1997;186:1819–1829.
[88] Yadava A, Kumar S , Dvorak JA , et al.Trafficking of Plasmodium chabaudi adami-infected erythrocytes within the mouse spleen. Proc. Natl. Acad. Sci. USA . 1996,93:4595–4599.
[89] Banchereau J, Briere F, Caux C , et al. Immunobiology of dendritic cells. Annu.Rev. Immunol. 2000; 18:767–811.
[90] Humphrey JH, Grennan D. Different macrophage populations distinguished by means of fluorescent polysaccharides. Recognition and properties of marginal zone macrophages. Eur. J.Immunol. 1981; 11, 221.
[91] Van Den Eertwegh AJM, Fasbender MJ, Schellekens MM,et al. In vivo kinetics and characterization of IFN-y-producing cells during a thymus-independent immune response. J. Immunol. 1991; 147,439.
[92] Kashimura M, Shibata A. Structure and functions of the human spleen: relationship between microcirculation and splenic functions. Rinsho Ketsueki. 1989;30:1234-8.
[93] Kashimura M, Fujita TA. Scanning electron microscopy study of human spleen: relationship between the microcirculation and functions. Scanning Microsc. 1987;1:841-51.
[94] Britta C, Tran T,Nicholas P,et al. Fatal Plasmodium falciparum Malaria Causes Specific Patterns of Splenic Architectural Disorganization. Infection and Immunity, 2005: 1986–1994.
[95] Stevens SK, Weissman IL, Butcher EC. Differences in the migration of B and T lymphocytes: organ selective localization in vivo and the role of lymphocyte-endothelial cell recognition. J Immunol 1982, 128:844-851.
[96] Kraal G, Weissman IL, Butcher EC. Differences in in vivo distribution and homing of T cell subsets to mucosal versus non-mucosal lymphoid organs. J Immunol 1983, 130:1097-1102.
[97] Kraal G, Rodrigues H, Hoeben K,et al. Lymphocyte migration in the spleen: the effect of macrophage elimination on lymphocyte distribution Immunology 1989, 68:227-232.
[98] Hammond BJ. A compartimental analysis of circulatory lymphocytes in the spleen. Cell Tissue Kinet 1975, 8:153-169.
[99] Pabst R. The spleen in lymphocyte migration. Immunol Today 1988, 9:43-45.
[100] Leonardo JM, Maria F ,Claudio T,et al. Germinal center architecture disturbance during Plasmodium berghei ANKA infection in CBA mice. Malaria Journal 2007, 6:59doi:10.1186/1475-2875-6-59.
[101] Susan A. Elmore.Enhanced Histopathology of the Spleen. Toxicol Pathol. 2006 ; 34: 648–655.
[102] Valledor F, Hsu LC, Ogawa S, et al. Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Medical Sciences I. 2004 , 101: 17813–17818 .
[103] Amlot PL, Grennan D, Humphrey JH. Splenic dependence of the antibody response to thymus-independent (TI-2) antigens. Eur.J. Immunol. 1985; 15, 508.
[104] Gray D, CHAssoux D, Maclennan ICM ,et al. Selective depression of thymus- independent anti-DNP antibody responses induced by adult but not neonatal splenectomy. Clin. exp.Immunol. 1985;60, 78.
[105] Van Krieken J, Te Velde J. Normal histology of the human spleen. Am J Surg Pathol 1988; 12:777–785.
[106] Leisewitz AL, Rockett KA, Gumede B, et al. Response of the splenic dendritic cell population to malaria infection. Infect Immun 2004; 72:4233–4239.
[107] Fukaya H, Xiao W, Inaba K, et al. Codevelopment of dendritic cells along with erythroid differentiation from human CD34(+) cells by tumor necrosis factor-alpha. Exp Hematol 2004; 32:450–460.
[108] Weiss L, Geduldig U, Weidanz, W. Mechanisms of splenic control of murine malaria: reticular cell activation and the development of a blood-spleen barrier. Am. J. Anat. 1986; 76:251–285.
[109] Krucken J, Mehnert LI, Dkhil MA,et al. Massive destruction of malaria-parasitized red blood cells despitespleen closure. Infection and Immunity. 2005: 6390–6398.
[110] Mansfield JM, Helmby H, Jonsson G ,et al. Cellular changes and apoptosis in the spleens and peripheral blood of mice infected with blood-stage plasmodium chabaudi chabaudi AS. Infection and Immunity. 2000, 3:1485–1490.
[111] Takeuchi O, Fisher J,Suh H,et al. Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease. Biochemistry. 2005;102: 11272–11277 .
[112] Wouter J, Jonge M, Karin L, et al. Arginine deficiency affects early B cell maturation and lymphoid organ development in transgenic mice J. Clin. Invest.2002; 110: 1539–1548.
[113] Lopez Z, Prats N, Marco AJ. Expression of E-Selectin, P-Selectin, and Intercellular Adhesion Molecule-1 during Experimental Murine Listeriosis. American Journal of Pathology, 1999, 155: 1391–1397.
[114] Cherla RP, Ganju RK. Stromal cell-derived factor 1 alphainduced chemotaxis in T cells is mediated by nitric oxide signaling pathways. J Immunol 2001; 166:3067–3074.
[115] Foussat A, Balabanian K, Amara A et al. Production of stromal cell-derived factor 1 by mesothelial cells and effects of this chemokine on peritoneal B lymphocytes. Eur J Immunol 2001;31:350–359.
[116] Lee Y, Gotoh A, Kwon HJ ,et al. Enhancement of intracellular signaling associated withhematopoietic progenitor cell survival in response to CXCL12/CXCL12 in synergy with other cytokines. Blood 2002; 99:4307–4317.
[117] Lo CG, Lu TT, Cyster JG. Integrin-dependence of Lymphocyte Entry into the Splenic White Pulp. The Journal of Experimental Medicine. 2003,197; 353–361.
[118] Harleman JH. Approaches to the identification and recording of findings in the lymphoreticular organs indicative for immunotoxicity in regulatory type toxicity studies. Toxicology 2000;142:213–9.
[119] Kuper CF, Harleman JH, Richter-Reichelm HB ,et al. Histopathologic approaches to detect changes indicative of immunotoxicity. Toxicol Pathol 2000;28:454–66.
[120] Ohl L, Henning G, Krautwald S,et al. Cooperating mechanisms of CXCR5 and CCR7 in development and organization of secondary lymphoid organs . The Journal of Experimental Medicine .2003 1199–1204.
[121] Deonarain R,Verma A,Porter ACG,et al. Critical roles for IFN-βin lymphoid development,myelopoiesis, and tumor development: Links to tumor necrosis factorα. Immunol. 2003,100: 13453–13458.
[122] Ettinger R, Browning JL, Michie SA,et al. Disrupted splenic architecture, but normal lymph node development in mice expressing a soluble lymphotoxin-b receptor–IgG1 fusion protein. Immunology, 1996 :13102–13107.
[123] Gorshina EN. Comparative analysis of seasonal changes in the hematopoietic processes in the spleen and peripheral blood of the common frog .II.Thrombocyte and neutrophil series.Tsitologiia,1983; 25: 667-677.
[124] Shadduck RK,Waheed A,Wing EJ.Demonstration of a blood–bone marrow barrier to macrophage colony-stimulating factor .Blood,1989,73:68-73.
[1] Pard on MC,Ma S,Morilak DA. Chronic cold stress sensitizes brain noradrenergic Reactivity and noradrenergic facilitation of the HPA stress response in Wistar Kyoto rats. Brain Res, 2003,971(1):55-65.
[2] Hatzfeld-Charbonnier AS, Lasek A, Castera L, et al . Influence of heat stress on human monocyte-derived dendritic cell functions with immunotherapeutic potential for antitumor vaccines . J Leukoc Biol,2007, 81(5): 1179–1187.
[3] Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury,2007,38(12):1336-45.
[4]黄长文,傅华群.血脾屏障结构和功能的研究进展.国际外科学杂志,2008,35(12):829-832.
[5]李志清,黄跃生,杨宗城.严重烧伤早期大鼠中性粒细胞、巨噬细胞凋亡实验研究.中华烧伤杂志, 2001, 17(3):171-173.
[6] Canthaboo C, Xing D , Wei X Q,et al. Investigation of Role of Nitric Oxide in Protection from Bordetella pertussis Respiratory Challenge . Infection and Immunity,2002,70(2):679-684.
[7] Jedynak M, Siemiatkowski A. The role of monocytes/macrophages and their cytokines in the development of immunosuppression after severe injury. Pol Merkur Lekarski ,2002 ,13(75):238-241.
[8] Hildebrand F, Pape HC, Krettek C. The importance of cytokines in the posttraumatic inflammatory reaction .Unfallchirurg,2005 ,108 (10):793-794.
[9] Kn?ferl MW,Liener UC,Perl M,et al. Blunt chest trauma induces delayed splenic immunosuppression. Shock,2004 , 22(1):51-56.
[10] Osuchowski MF, Welch K, Siddiqui J, et al. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol,2006 ,177(3) :1967-1974.
[11] Xu Y X, Ayala A , Chaudry I H. Prolonged immunodepression after trauma and hemorrhagic shock . J Trauma ,1998 ,44(2) :335 - 341.
[12] Ferlito M, Maio AD.Enhanced LPS-induced TNFa production in heat-shocked human promonocytic cells: Regulation at the translational/post-translational level . BBA - Molecular Cell Research,2005,1743(1-2): 20– 28.
[13] Pittet JF, Lee H, Morabito D, et al. Serum levels of Hsp 72 measured early after trauma correlate with survival. J. Trauma ,2002,52(4):611– 617.
[14] Paidas CN, Mooney ML, Theodorakis NG, et al.Accelerated recovery after endotoxic challenge in heat shock-pretreated mice. Am J Physiol Regul Integr Comp Physiol. 2002,282(5):1374– 1381.
[15] Sasara T, Cizkova D, Mestril R, et al. Spinal heat shock protein (70) expression: effect of spinal ischemia,hyperthermia (42 degrees C)/hypothermia (27 degrees C), NMDAreceptor activation and potassium evoked depolarization on the induction. Neurochem Int, 2004,44 (1): 53–64.
[16] Perl M, Gebhard F, Brückner UB,et al. Pulmonary contusion causes impairment of macrophage and lymphocyte immune functions and increases mortality associated with a subsequent septic challenge. Crit Care Med,2005,33(6) :1351-1358.
[17] Hume D A , Ro ss IL , H imes S R, et al. The mononuclear phagocyte system revisited . J Leukoccyte Bio l, 2002, 72(4): 621-627.
[18] Smyth GP, Stapleton PP, Freeman TA, et al. Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor -kappaB activation in macrophages. J Surg Res,2004, 116(2):253-261.
[19] John J H , Nayef ES , Bared SG. Cytokine and neuro-immune endocrine interactions : a role for the hypothalamic pituitary adrenal revolving axis. Journal of Neuroimmunology , 2002 ,133(1-2): 1-19.
[20] Greenwood BN,Kenned y S,Smith TP,et a1.Voluntary freewheel running selectively modulates catecholamine content in peripheral tissue and c-fos expression in the central sympathetic circuit following exposure to uncontrollable stress in rats.Neuroscience,2003,l20(1):269—281.
[21] Deng J, Muthu K, Gamelli R, et al. Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis. Am J Physiol Cell Physiol. 2004 ,287 (3): 730-736.
[22] Luo G, Peng D, Zheng J, et al. The role of NO in macrophage dysfunction at early stage after burn injury. Burns. 2005 ,31(2) :138-144.
[23] Pruett SB. Stress and the immune system. Pathophysiology , 2003 ,9(3):133-153.