IL—10抑制人肾系膜细胞环氧化酶—2及其介导的前列腺素E2的释放

目的观察白细胞介素-10(IL-10)对IL-1β诱导的人系膜细胞(HMC)前列腺素E2(PGE2)释放及环氧化酶-2(COX-2)基因和蛋白表达的影响.方法应用放射免疫测定法检测HMC培养上清中PGE2,应用RT-PCR和westernblot检测COX-2mRNA和蛋白水平.结果①IL-1β显著上调PGE2释放及COX-2基因和蛋白的表达(P均＜0.01);②IL-10对基础状态下PGE2释放及COX-2基因和蛋白表达无明显影响(P＞0.05);③IL-10可呈剂量依赖性地下调IL-1β诱导的PGE2释放及COX-2mRNA和蛋白表达(P＜0.01).结论IL-10抑制IL-1β诱导的HMCPGE2释放及COX-2表达,提示IL-10对HMC具有多方面抗炎作用.     

1alpha,25(OH)2D3 regulation of integrin expression is substrate dependent

Osteoblasts are attachment-dependent cells that interact with their surface through integrin-mediated mechanisms. Their differentiation is regulated by 1,25-dihydroxyvitamin D3 [1alpha,25(OH)(2)D(3)] and is affected by substrate chemistry and microtopography, suggesting that 1alpha,25(OH)(2)D(3) may regulate integrin expression in a surface-specific manner. To test this hypothesis, osteoblast-like human MG63 cells were grown on tissue culture plastic and on grit-blasted and acid-etched titanium disks with a complex microtopography to induce osteoblast differentiation. Expression of alpha(2), alpha(5), alpha(v), beta(1), and beta(3) integrins were quantified by real-time polymerase chain reaction (PCR) as a function of time in culture and treatment with 1alpha,25(OH)(2)D(3). Results were correlated with expression of osteocalcin, a marker of a differentiated osteoblast. Osteocalcin mRNA increased with time and 1alpha,25(OH)(2)D(3) treatment and these changes were greater in cultures on the titanium disks. Integrin expression varied with time in culture and this was also surface dependent. At each time point, beta(1) and alpha(2) mRNAs were greater on titanium than on plastic, whereas alpha(5) expression was reduced and alpha(v),beta(3) expression was unaffected. 1alpha,25(OH)(2)D(3) increased beta(1) mRNA on both surfaces at all time points, but it increased alpha(2) expression only in 8-d cultures. 1alpha,25(OH)(2)D(3) caused reduced alpha(5) expression only in cultures grown on plastic for 8 d, and had no effect on either alpha(v) or beta(3) expression regardless of surface. These results show that integrin expression in human osteoblast-like cells is differentially modulated by 1alpha,25(OH)(2)D(3) in a time-dependent manner that is sensitive to the surface on which the cells are grown.     

Expression of PGE2 EP3 receptor subtypes in the mouse preoptic region

Inflammatory-induced fever is dependent on prostaglandin E(2) (PGE(2)) binding to its EP(3) receptor in the thermoregulatory region of the hypothalamus, but it is not known which EP(3) receptor isoform(s) that is/are involved. We identified the EP(3) receptor expression in the mouse preoptic region by in situ hybridization and isolated the corresponding area by laser capture microdissection. Real-time RT-PCR analysis of microdissected tissue revealed a predominant expression of the EP(3alpha) isoform, but there was also considerable expression of EP(3gamma), corresponding to approximately 15% of total EP(3) receptor expression, whereas EP(3beta) was sparsely expressed. This distribution was not changed by immune challenge induced by peripheral administration of LPS, indicating that EP(3) receptor splicing and distribution is not activity dependent. Considering that EP(3alpha) and EP(3gamma) are associated with inhibitory and stimulatory G-proteins, respectively, the present data demonstrate that the PGE(2) response of the target neurons is intricately regulated.     

Endometrial vascular and glandular expression of integrin alpha(v)beta3 in women with and without endometriosis

The integrin alpha(v)beta3 functions in both cell-cell and cell- extracellular matrix adhesion, and has reported roles in platelet aggregation, immune function, tissue repair, tumour invasion, angiogenesis and uterine receptivity. The aim of this study was to use immunohistochemistry to describe the vascular and glandular expression of integrin alpha(v)beta3 in formalin fixed, paraffin embedded endometrium obtained from women with (n = 29) and without (n = 24) endometriosis. The results showed a significant increase in the percentage of vessels expressing alpha(v)beta3 in the endometrium of women with endometriosis compared with controls (P = 0.0001). This difference was more pronounced in the secretory phase (P = 0.001) than the proliferative phase (P = 0.016). There was no correlation between vascular alpha(v)beta3 expression and the endothelial cell proliferation index (P > 0.05). Vascular sprouts were not observed in any of the 53 endometrial tissues obtained from women with or without endometriosis throughout the menstrual cycle. Results from semi- quantitative scoring of gland immunostaining showed that neither controls (P = 0.3329) nor the endometriosis group (P = 0.2260) had any significant changes in terms of alpha(v)beta3 expression between the different stages of the menstrual cycle. There was also no difference in glandular alpha(v)beta3 expression between women with and without endometriosis (P = 0.4302). These results provide evidence for increased endometrial angiogenesis in women with endometriosis compared with controls, and suggest that glandular expression of alpha(v)beta3 is not related to uterine receptivity per se.      

Distribution of alpha3, alpha5 and alpha(v) integrin subunits in mature and immature human oocytes

The distribution of three integrin subunits, alpha3, alpha5 and alpha(v), in immature and mature human oocytes has been examined using immunofluorescence and confocal microscopy. The results demonstrate that both alpha5 and alpha(v) are present at the germinal vesicle stage, while alpha3 was only detected in oocytes after germinal vesicle breakdown, in metaphase I and II stage oocytes. The cortical concentration of integrin subunits alpha3 and alpha5 is consistent with their localization in the oolemma. In contrast, the homogeneous distribution of alpha(v) throughout the oocyte suggests the existence of cytoplasmic reservoirs of this protein in the oocyte.      

Streptococcal pyrogenic exotoxin B-induced apoptosis in A549 cells is mediated through alpha(v)beta(3) integrin and Fas

Our previous work suggested that streptococcal pyrogenic exotoxin (SPE) B-induced apoptosis is mediated through a receptor-like mechanism. In this study, we have identified alpha(v)beta(3) and Fas as the SPE B receptors for this function. The SPE B fragment without the RGD motif and G308S, a SPE B mutant with the RSD motif, induced less apoptosis than did native SPE B, suggesting that the RGD motif is critical for SPE B-induced apoptosis. Fluorescein isothiocyanate-SPE B binding assays and immunoprecipitation analysis showed that SPE B specifically interacted with alpha(v)beta(3). Anti-alpha(v)beta(3) antibody partially inhibited SPE B-induced apoptosis but had no effect on G308S-induced apoptosis. In addition, Fas binding to SPE B was verified in an affinity column and an immunoprecipitation analysis. Anti-Fas antibody inhibited SPE B- and G308S-induced apoptosis in a dose-dependent manner, suggesting that Fas-mediated SPE B-induced apoptosis also occurs RGD independently. Both anti-alpha(v)beta(3) and anti-Fas antibodies synergistically inhibited SPE B-induced apoptosis. The apoptotic cascades were activated by SPE B and G308S, with a little delay by the latter. After SPE B binding, the cell surface level of alpha(v)beta(3), but not of Fas, was decreased. The decreased alpha(v)beta(3) level was restored by treatment with the proteasome inhibitor MG132, suggesting a SPE B-mediated endocytosis of integrin alpha(v)beta(3) via the ubiquitin-proteasome system. Taken together, our results demonstrate that SPE B-induced apoptosis is mediated through alpha(v)beta(3) integrin and Fas in a synergistic manner.     

机动车尾气诱发大鼠慢性阻塞性肺疾病并上调气道上皮细胞COX-2/PGE2/EP受体信号通路

目的：探究机动车尾气(MVE)长期暴露引起大鼠慢性阻塞性肺疾病(COPD)发生时,气道上皮细胞中环加氧酶2(COX-2)/前列腺素E₂(PGE₂)/E-前列腺素类激素(EP)受体信号通路成员的表达变化。方法：(1)动物实验：健康雄性SD纯系大鼠(SPF级)16只,随机分为2组：MVE暴露组(n=8)和空白对照(CTL)组(n=8)。采用MVE暴露6个月的方法建立COPD大鼠模型。造模结束后,使用Buxco小动物有创肺功能仪检测大鼠肺功能;肺组织切片行HE染色并评估肺组织病理变化;ELISA法检测大鼠支气管肺泡灌洗液(BALF)中炎症因子白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)和PGE₂的水平,评估大鼠肺部炎症情况;采用免疫荧光及Western blot法检测肺组织COX-2及EP受体蛋白水平;提取肺组织核蛋白,Western blot检测MVE对肺组织NF-κB核转位的影响。(2)细胞实验：采用MVE细颗粒物(PM2.5)标准品刺激人正常支气管上皮细胞BEAS-2B。ELISA法检测细胞培养液中PGE     

Cyclooxygenase-1-derived PGE2 promotes cell motility via the G-protein-coupled EP4 receptor during vertebrate gastrulation

Gastrulation is a fundamental process during embryogenesis that shapes proper body architecture and establishes three germ layers through coordinated cellular actions of proliferation, fate specification, and movement. Although many molecular pathways involved in the specification of cell fate and polarity during vertebrate gastrulation have been identified, little is known of the signaling that imparts cell motility. Here we show that prostaglandin E(2) (PGE(2)) production by microsomal PGE(2) synthase (Ptges) is essential for gastrulation movements in zebrafish. Furthermore, PGE(2) signaling regulates morphogenetic movements of convergence and extension as well as epiboly through the G-protein-coupled PGE(2) receptor (EP4) via phosphatidylinositol 3-kinase (PI3K)/Akt. EP4 signaling is not required for proper cell shape or persistence of migration, but rather it promotes optimal cell migration speed during gastrulation. This work demonstrates a critical requirement of PGE(2) signaling in promoting cell motility through the COX-1-Ptges-EP4 pathway, a previously unrecognized role for this biologically active lipid in early animal development.     

Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells

Early metastasis is the primary cause of death in melanoma patients. The adhesion receptor integrin αvβ3 contributes to tumor cell functions that are potentially involved in melanoma growth and metastasis. We tested whether integrin αvβ3 supports metastasis of human melanoma cells when injected into the bloodstream of immune deficient mice. Comparing variants of the same melanoma cell type that expressed either αvβ3, αIIbβ3 or no β3 integrin, we found that only αvβ3 strongly supported metastasis. Inhibition of tumor cell αvβ3 function reduced melanoma metastasis significantly and prolonged animal survival. To understand mechanisms that allow αvβ3, but not αIIbβ3 to support melanoma metastasis, we analyzed proteolytic and migratory activities of the melanoma cell variants. Melanoma cells expressing αvβ3, but not those expressing αIIbβ3 or no β3 integrin, produced the active form of metalloproteinase MMP-2 and expressed elevated mRNA levels of MT1-MMP and TIMP-2. This indicates an association between αvβ3 expression and protease processing. Furthermore, αvβ3 expression was required for efficient melanoma cell migration toward the matrix proteins fibronectin and vitronectin. The results suggest that expression of integrin αvβ3 promotes the metastatic phenotype in human melanoma by supporting specific adhesive, invasive and migratory properties of the tumor cells and that the related integrin αIIbβ3 cannot substitute for αvβ3 in this respect. This revised version was published online in July 2006 with corrections to the Cover Date.     

Integrin alpha(v)beta(3) expression in colon carcinoma correlates with survival.

Integrin alpha(v)beta(3) is expressed by newly formed blood vessels in diseased and neoplastic tissue and can therefore be used as a marker for angiogenesis. We investigated its expression on the vasculature of 40 colon carcinomas using the anti-alpha(v)beta(3)-specific monoclonal antibody LM609. The average relapse-free interval and overall survival in patients suffering from colon carcinomas with high vascular expression of alpha(v)beta(3) integrin was significantly reduced compared with that in patients with low alpha(v)beta(3) integrin expressing tumor vasculature. Moreover, the expression level of alpha(v)beta(3) integrin correlated with the presence of liver metastases. In conclusion, we propose vascular expression of alpha(v)beta(3) integrin as a prognostic indicator for colon carcinoma.     

GPx2 counteracts PGE2 production by dampening COX-2 and mPGES-1 expression in human colon cancer cells

GPx2, the gastrointestinal glutathione peroxidase, is a selenoprotein predominantly expressed in the intestine. An anti-inflammatory and anticarcinogenic potential has been inferred from the development of colitis and intestinal cancer in GPx1 and GPx2 double knockout mice. Further, induction by Nrf2 activators classifies GPx2 as a protective enzyme. In contrast, enhanced COX-2 expression is consistently associated with inflammation. The antagonistic roles and an intriguing co-localization of GPx2 and COX-2 prompted us to investigate their possible mutual regulation. Both enzymes were upregulated in tissues of patients with colorectal cancer and colitis, and co-localized in the endoplasmic reticulum. A stable knockdown of GPx2 in HT-29 cells by siRNA resulted in a high basal and IL-1-induced expression of COX-2 and mPGES-1, enzymes required for the production of the pro-inflammatory PGE(2). Accordingly, si-GPx2 cells released high concentrations of PGE(2). Observed effects were specific for GPx2, since COX-2 and mPGES-1 expression was not affected by selenium-deprivation which resulted in the disappearance of GPx1. It is concluded that GPx2 by compartmentalized removal of hydroperoxides silences COX-2 activity and suppresses PGE(2)-dependent COX-2 expression. Thus, GPx2 may prevent undue responses to inflammatory stimuli and, in consequence, inflammation-driven initiation of carcinogenesis.     

Distribution of prostaglandin EP(3) and EP(4) receptor mRNA in the rat parabrachial nucleus

By using in situ hybridization, the distribution of mRNA for the PGE(2) receptors EP(3) and EP(4) was examined in the rat parabrachial nucleus (PB), a major brain stem relay for autonomic and nociceptive processing. EP(3) receptor mRNA was present in most subnuclei, with the densest labeling in the external lateral, dorsal lateral, superior lateral, central lateral and K?lliker-Fuse nuclei. EP(4) receptor mRNA expressing cells had a more restricted distribution, largely being confined to the superior lateral and adjacent parts of the dorsal and central lateral nuclei in a pattern complementary to that for EP(3) receptor mRNA. These findings suggest that EP(3) and EP(4) receptors in PB have distinct functional roles that include nociceptive processing, blood pressure regulation and feeding behavior.     

Role of integrin alpha(v)beta3 in the early phase of liver metastasis: PET and IVM analyses

To clarify the function of integrin αvβ3 in the early stage of liver metastasis, we investigated the interactions of metastatic cells with their target organ under the actual blood flow by using positron emission tomography (PET). The cells used were CHO-K1 cells and their transfectants bearing human integrin αvβ3 cDNA (αvβ3-CHO-K1 cells). The liver accumulation of αvβ3-CHO-K1 cells was significantly higher than that of CHO-K1 cells after injection via the portal vein, whereas no significant difference was observed in the lung accumulation after tail vein injection, suggesting a specific interaction of αvβ3-CHO-K1 cells with the hepatic sinusoids. Furthermore, to clarify the precise location of each cell in the liver, i.e., to determine whether individual cells were intravascularly localized or had extravasated, we performed intravital fluorescence microscopy (IVM) on the liver by using stable transfectants bearing the green fluorescent protein (GFP) gene, namely, GFP-CHO-K1 and GFP-αvβ3-CHO-K1 cells. Both types of cells remained in the hepatic blood vessels 1 h after injection via the portal vein. On the other hand, expression of integrin αvβ3 promoted the cells to reach the extravascular region after 24 h. These results suggest the possibility that the specific accumulation of αvβ3-CHO-K1 cells in the liver is followed by migration of the cells into the extravascular region. Interestingly, the adhesion of the two types of cells to hepatic sinusoidal endothelial cells in vitro did not correspond to in vivo accumulation of these cells. Therefore, integrin αvβ3 may function to promote extravasation of integrin αvβ3-expressing tumor cells in liver through a process possibly mediated by vitronectin produced by this organ. This revised version was published online in July 2006 with corrections to the Cover Date.     

COX-2 and Prostaglandin EP3/EP4 Signaling Regulate the Tumor Stromal Proangiogenic Microenvironment via CXCL12-CXCR4 Chemokine Systems

Bone marrow (BM)–derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)−2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. In this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E₂ enhanced stromal formation and CXCL12/CXCR4 expression. In addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3^−/− mice and EP4^−/− mice, in which stromal expression of CXCL12/CXCR4 and S100A4 was reduced. The EP3 or EP4 knockout suppressed S100A4⁺ fibroblasts, CXCL12⁺, and/or CXCR4⁺ stromal cells as well. Immunofluorescent analyses revealed that CXCL12⁺CXCR4⁺S100A4⁺ fibroblasts mainly comprised stromal cells and most of these were recruited from the BM. Additionally, either EP3- or EP4-specific agonists stimulated CXCL12 expression by fibroblasts in vitro. The present results address the novel activities of COX-2/PGE₂-EP3/EP4 signaling that modulate tumor biology and show that CXCL12/CXCR4 axis may play a crucial role in tumor stromal formation and angiogenesis under the control of prostaglandins.Recent advances in tumor biology have identified the stroma as an important regulator of carcinogenesis and a potentially valuable therapeutic target. Although interactions between the epithelium and stroma have long been considered to be important in tumor progression, the efficacy of targeting stromal components as a therapeutic strategy has not been established, because the specific regulators of such interactions remain unclear. In addition to endothelial cells, macrophages and fibroblasts¹ are the major stromal components of the tumor microenvironment, and they play key roles in the enhancement of angiogenesis. It has recently been established that bone marrow (BM)–derived hematopoietic cells are the major components of the stroma of tumors, and that they determine the tumor microenvironment^2–8; however, the specific factors that enhance the functions of BM-derived precursor cells, and the mechanism of recruitment of these cells during tumor angiogenesis, are not fully understood. Tumor-associated angiogenesis in the tumor stroma is a prerequisite for invasive growth of a tumor larger than 2 to 3 mm in diameter, and then metastasis occurs. Tumor-associated angiogenesis is caused by a shift in the local balance of proangiogenic and antiangiogenic factors toward the proangiogenic state.^9–11 This angiogenic switch in the tumor stroma may be important in the control of cancer progression and may be regulated by the recruitment of BM-derived cells.Chemokines and their receptors play critical roles in leukocyte trafficking during inflammatory processes; however, a growing body of data suggests that a number of chemokines and their receptors also play diverse roles in cancer growth, cancer metastasis, cancer angiogenesis, or modulation of the cancer microenvironment.^12–15 Preclinical tumor models indicate that some chemokine receptor antagonists can block cancer growth either directly or by altering the cancer stroma.^16–21 However, there is a need to extend our understanding of the signaling pathways by which chemokines and chemokine receptors facilitate cancer processes. Further, the interactions between the inflammatory mediators and chemokine systems are poorly understood.Cyclooxygenase (COX)−2 is one of two forms of COX and is expressed at sites of inflammation and malignancies, suggesting that COX-2 inhibition may be useful in the treatment or prevention of inflammatory diseases and various cancers.²² In previous studies, we determined that inhibition of the COX-2/VEGF-dependent pathway suppresses tumor-associated angiogenesis and tumor growth in mice.^23,24 COX-2–lacking mice were found to be resistant to the development of colorectal neoplasia.²⁵ The same may be true in humans, because epidemiological studies have shown that nonsteroidal anti-inflammatory drugs, the prototypic inhibitors of COX, reduce the risk of several types of cancer.²⁶ The relevant endogenous prostaglandins (PGs) may be PGE_2, which is generated from arachidonic acid and other polyunsaturated fatty acids, in a reaction catalyzed by COX-2.²⁷ Four G protein–coupled receptors, which respond to the PGE₂ are designated subtypes EP1, EP2, EP3, and EP4.²⁸ Stromal tissues in COX-2 inhibitor–treated mice and EP3 receptor knockout mice are very thin and appeared to be pale in color.^23,24 COX-2 inhibition and EP3 receptor knockout markedly reduce the formation of stromal tissues around the tumors besides the attenuation of angiogenesis, suggesting that COX-2–derived PGE₂ has a crucial role in tumor stroma formation and also in the enhancement of tumor-associated angiogenesis.In the present study, we tested whether COX-2–derived PGE₂ upregulates the expression of chemokines and their receptors, and further clarified whether the upregulated chemokine systems enhance stromal formation and PG-dependent tumor angiogenesis. We showed that the chemokine systems and PGE₂ may be useful therapeutic targets for cancers that modulate tumor microenvironment.     

Immunohistochemical expression of COX-2, mPGES and EP2 receptor in normal and reactive canine bone and in canine osteosarcoma

Accumulating evidence suggests that cyclooxygenase (COX)-2 is involved in the pathogenesis of human and canine osteosarcoma. The aim of this study was to investigate the expression of COX-2 in normal, reactive and neoplastic canine bone and the events downstream to COX-2 that lead to prostaglandin E(2) (PGE(2)) production. COX-2, microsomal PGE(2) synthase-1 (mPGES-1) and the PGE(2) receptor (EP2) were assessed by immunohistochemistry in 12 samples of normal bone, 14 cases of fracture callus and 27 appendicular osteosarcomas. No immunoreactivity to COX-2, mPGES-1 or EP2 receptor was observed in normal bone. Fifty percent of reactive bone samples expressed COX-2 and 57% expressed mPGES-1 and EP2 receptor, although with weak labelling intensity. Ninety-three percent of osteosarcomas expressed COX-2, while mPGES-1 was expressed by 85% and EP2 receptor by 89% of the tumours. The data confirm that COX-2 is expressed at high level in osteosarcoma and support the use of COX-2 inhibitors to improve the response to chemotherapy. The possibility of blocking the EP2 or the selective inhibition of mPGES-1, rather than COX-2 activity, might decrease the incidence of adverse effects that occur due to the inhibition of prostanoids other than PGE(2).     

Mycobacterium avium-M. intracellulare binds to the integrin receptor alpha v beta 3 on human monocytes and monocyte-derived macrophages.

Mycobacterium avium-M. intracellulare is an intracellular pathogen responsible for the highest incidence of disseminated bacterial infection in patients with AIDS. Treatment of the infection is difficult and has been of limited efficacy. Attachment of the organism to macrophages is a critical early step in the establishment of the disease. In the present study, we isolated and identified a receptor that mediates attachment of M. avium-M. intracellulare to human peripheral blood monocytes and monocyte-derived macrophages. On Western blotting, (immunoblotting), the receptor was found to cross-react with antibodies against a human vitronectin receptor (alpha v beta 3). The receptor could be purified from monocyte extracts by using monoclonal antibodies (MAbs) against the alpha v subunit of vitronectin receptor coupled to CNBr-Sepharose 4B, as well as with the adhesive tripeptide sequence arginine-glycine-aspartic acid (RGD) coupled to CNBr-Sepharose 4B. Surface-bound MAbs directed against alpha v beta 3 were found to inhibit the attachment of M. avium-M. intracellulare to monocyte-derived macrophages in an in vitro inhibition assay, while MAbs directed against CD14, CD18, alpha 2 beta 1 and platelet glycoprotein gpIIb/IIIa receptors did not inhibit this attachment. These observations suggest that alpha v beta 3 on the surface of human monocytes and monocyte-derived macrophages may function as a receptor for M. avium-M. intracellulare. Identification of a receptor for M. avium-M. intracellulare on macrophages may offer new approaches to the prevention and control of M. avium-M. intracellulare infection at the cellular level.     

细胞相互作用对PAF、系膜细胞paf-R基因表达的影响及阿托伐他汀的干预作用

目的:探讨高糖高脂条件下内皮细胞与系膜细胞相互作用对PAF产生、系膜细胞paf-R基因表达的影响及阿托伐他汀的干预作用。方法:内皮细胞与系膜细胞共培养和系膜细胞单独培养后随机,分为对照组、甘露醇组、高糖高脂组、阿托伐他汀组,培养24h后,ELISA法检测各组细胞上清液PAF含量,实时荧光定量检测系膜细胞paf-RmRNA表达。结果:(1)高糖高脂促进共培养组和单培养组PAF升高(P0.05),共培养组PAF均较单培养组升高(P0.05);(2)高糖高脂可上调系膜细胞paf-R mRNA表达(P0.05);(3)共培养和单培养条件下,阿托伐他汀可抑制高糖高脂引起的PAF升高(P0.05),并可抑制高糖高脂引起的系膜细胞paf-RmRNA表达上调(P0.05)。结论:(1)高糖高脂环境下,系膜细胞和内皮细胞存在异常的相互作用,这种作用促进PAF产生;(2)高糖高脂促进系膜细胞paf-R基因表达,使PAF的生物效应进一步放大;(3)阿托伐他汀可影响高糖高脂条件下内皮细胞与系膜细胞之间的相互作用。