血小板活化因子拮抗剂对抗原引起气道嗜酸性粒细胞…

为探讨血小板活化因子（ＰＡＦ）拮抗剂消除哮喘气道炎症的价值，应用鸡卵清蛋白致敏和刺激小鼠复制过敏性气道炎症模型，研究ＰＡＦ拮抗剂对于抗原引起气道哮酸性粒细胞（ＥＯＳ）浸润的影响。体内实验结果表明，正常小鼠支气管肺泡灌洗液（ＢＡＬＦ）中未见到ＥＯＳ；致敏小鼠给予抗原多次反复吸入刺激后，ＢＡＬＦ中ＥＯＳ急剧增多。在ＰＡＦ一种选择性拮抗剂ＹＭ－２６４治疗各组中，ＹＭ－２６４的不同剂量０．１ｍｇ／ｋｇ、１     

雷公藤对哮喘豚鼠IL-5、GM-CSF基因转录的影响及作用机制

探讨雷公藤哮喘ＩＬ－５、ＧＭ－ＣＳＦ基因转录的影响及其机制,方法：采用卵蛋白（ＯＡ）致敏复制哮喘豚鼠模型,用原位杂交就雷公藤甲素对其肺组织和外周血单个核细胞ＩＬ－５、ＧＭ－ＣＳＦｍＲＮＡ表达的影响进行检测。并通过凝胶电泳迁移试验（ＥＭＳＡ）检测ＴＰ对伴刀豆蛋白或佛波脂（ＰＭＡ）刺激的人Ｔ细胞活化蛋白－１（ＡＰ－１）的ＤＮＡ结合活性的影响。结果：①哮喘豚鼠肺组织和ＰＢＭＣ－ＩＬ－５、ＧＭ－ＣＳＦｍＲ     

哮喘患儿外周血IL—2,IL—10与NO水平及其关系研究

采用双抗夹心ＥＬＩＳＡ技术检测了２８例哮喘患儿血浆及外周血单个核细胞（ＰＢＭＣ）在植物血凝素（ＰＨＡ）刺激下产生ＩＬ－１０水平，同时检测了ＮＯ和ＩＬ－２水平。结果：①急性发作期哮喘患儿血浆及ＰＢＭＣ在ＰＨＡ刺激下产生ＩＬ－１０水平均比正常儿童显著降低（Ｐ＜０．０１），在哮喘缓解期虽均有所恢复，但仍低于正常儿童（Ｐ＜０．０５）；②ＮＯ水平在急性发作期患儿明显升高（Ｐ＜０．０５），而在缓解期恢复正常（Ｐ＞０．０５）；③急性发作期哮喘患儿在ＰＨＡ刺激下ＰＢＭＣ产生ＩＬ－２水平明显升高（Ｐ＜０．０１），但在缓解期恢复正常（Ｐ＞０．０５）；④急性发作期哮喘患儿在ＰＨＡ刺激下ＰＢＭＣ产生ＩＬ－１０水平与ＩＬ－２呈显著负相关（ｒ＝－０．５０４，Ｐ＜０．０１），而与血浆ＮＯ水平相关不显著（ｒ＝－０．３１９，Ｐ＞０．０５）。提示：哮喘发作时ＩＬ－１０分泌及释放减少，ＮＯ和ＩＬ－２水平升高，导致或加重气道慢性炎症反应，引起气道高反应性而诱发或加重哮喘。     

黄芪多糖对IL－2／LAK抗肿瘤增强作用的动物实验研究

采用Ｃ５７ＢＬ／６鼠荷其自发产生的黑色素瘤Ｂ＿１６细胞，以生存期为指标，建立了黄茂多糖（ＡＰＳ）增强ＩＬ－２／ＬＡＫ抗肿瘤作用的动物模型，结果表明：ＡＰＳ自身具有一定的抗肿瘤作用，ＡＰＳ（５ｍｇ／ｋｇ）与ＩＬ－２／ＬＡＫ（５×１０￣３Ｕ／ｋｇ、５×１０￣７／ｋｇ）的抗肿瘤作用相似，荷瘤鼠生存期分别为２１．５７±１．８１天和２０．８６±１．８６天（荷瘤对照鼠为１５．７１±０．４９天）；ＡＰＳ对ＩＬ－２／ＬＡＫ的抗肿瘤效应有明显的增强作用，二者在上述剂量下联合应用，荷瘤鼠生存期为２４．８６±２．７３天（Ｐ＜０．０１）。并对荷瘤鼠进行动态细胞免疫功能观察，提示：ＡＰＳ和ＩＬ－２／ＬＡＭ均具有抵抗鼠脾ＮＫ细胞活性，ＩＬ－２产生能力和腹腔Ｍψ吞噬能力下降的作用，ＡＰＳ对ＩＬ－２／ＬＡＫ仍有显著增强效应。     

哮喘豚鼠IL-5、IL-3、GM-CSF mRNA表达及雷公藤内酯醇的影响

目的研究ＩＬ－５、ＩＬ－３、ＧＭ－ＣＳＦ在哮喘发病中的作用及雷公藤的干预。方法将实验豚鼠随机分为：①哮喘组（ｎ＝８）：用卵蛋白雾化吸入诱导哮喘模型；②处理组（ｎ＝８）：用雷公藤内酯醇腹腔注射处理哮喘模型；③正常对照组（ｎ＝８）。制备ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｃＤＮＡ探针，用斑点印迹杂交法检测以上三组豚鼠支气管肺组织ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ的表达。结果哮喘豚鼠支气管肺组织ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ表达显著高于对照组（Ｐ＜０．０５～０．００１）；雷公藤处理组ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ表达低于哮喘组（Ｐ＜０．０５～０．００１），与对照组无显著差异（Ｐ＞０．０５）。结论哮喘豚鼠肺组织中有明显的ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ表达增加。雷公藤内酯醇能抑制体内ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ的表达，可能在哮喘抗炎中具有潜在的临床价值。     

STUDY ON SOLUBILITY OF APATITE CERAMIES IN VITRO

ＳＴＵＤＹＯＮＳＯＬＵＢＩＬＩＴＹＯＦＡＰＡＴＩＴＥＣＥＲＡＭＩＥＳＩＮＶＩＴＲＯＳＴＵＤＹＯＮＳＯＬＵＢＩＬＩＴＹＯＦＡＰＡＴＩＴＥＣＥＲＡＭＩＥＳＩＮＶＩＴＲＯＬ．ＮｉｎｇＭ．Ｘｕｅ（ＳｈａｎｇｈａｉＳｅｃｏｎｄＭｅｄｉｃａｌＵｎｉｖｅｒｓｉｔｙ...     

血小板活化因子介导肾小球系膜细胞产生活性氧的研究

为探讨血小板活化因子（ＰＡＦ）对肾小球系膜细胞（ＧＭＣ）产生活性氧的调节作用，本研究观察了ＰＡＦ对体外培养的大鼠ＧＭＣ产生超氧化物阴离子（Ｏ）和过氧化氢（Ｈ－２Ｏ－２）的影响。结果表明１０￣（－９）Ｍ／Ｌ的ＰＡＦ已能诱导ＧＭＣ产生Ｏ和Ｈ２Ｏ２（１．１４±０．４２ｎｍｏｌ／１０￣５ＧＭＣ、０．９７±０．１６ｎｍｏｌ／１０－５ＧＭＣ），这一效应呈剂量依赖性；溶ＰＡＦ无诱导ＧＭＣ产生活性氧作用；特异性ＰＡＦ受体拮抗剂ＢＮ５２０２１抑制ＰＡＦ的刺激作用，抑制作用也呈剂量依赖性，５×１０￣（－５）Ｍ／ＬＢＮ５２０２１完全抑制ＧＭＣ合成活性氧。本研究说明ＰＡＦ可诱导ＧＭＣ合成活性氧。     

细胞因子与哮喘发病机理的关系

研究分设３组，哮喘发作组、哮喘缓解组和正常对照组各２０例，外周血ＩＦＮ－ｒ测定采用微量细胞病变抑制法。ＩＬ－４分泌细胞阳性率测定采用ＡＰＡＡＰ法。Ｃｏｎ－Ａ诱导Ｔｓ细胞活性测定采用Ｓｍｉｔｈ改良法。血清ＩｇＥ测定采用ＥＬＩＳＡ法。试验结果如下：（１）哮喘发作组外周血Ｔ淋巴细胞检测ＩＬ－４分泌细胞阳性率（７．６±３．５％）明显高于哮喘缓解组（３．８±２．０％），Ｐ＜０．０１，更高于正常对照组（１．８±０．５％），Ｐ＜０．０００１。在体外用ＰＨＡ诱导检测产生ＩＰＮ－Ｖ的能力，发现哮喘发作组（７３２．…     

外周血T细胞亚群及细胞因子对外源性哮喘IgE生成的作用

对３０例哮喘患者及３０例健康成年人的外周血，采用单克隆抗体（ＭｃＡｂ）间接免疫荧光法测定Ｔ细胞亚群；ＥＬＩＳＡ双抗体夹心法测定ＩｇＥ、ＩＬ－４；ＦＩ２细胞株，生物学方法测定ＩＬ－２；ＩＬ－６依赖细胞株７ＴＤ１，掺入法测定ＩＬ－６；用抗人ＣＤ２３的ＭｃＡｂ测定ＣＤ２３。为研究Ｔ细胞、细胞因子对哮喘ＩｇＥ生成调节机理及细胞因子在哮喘发病过程中的作用。结果显示：发作期ＩｇＥ、ＩＬ－２、ＩＬ－４、ＣＤ２３、ＣＤ８~＋、ＣＤ４／ＣＤ８~＋比值较对照组及缓解期有显著性差异（Ｐ＜０．０１）。缓解期ＩｇＥ与对照组之间无显著性差异（Ｐ＞０．０５）；ＣＤ８＋、ＣＤ４／ＣＤ８比值，ＣＤ２３与对照组之间有显著性差异（Ｐ＜０．０１）。ＣＤ２３、ＣＤ４、ＩＬ－６三组间无显著性差异（Ｐ＞０．０５）。结果表明，ＩｇＥ合成增加是哮喘发作的关键，Ｔ细胞对日细胞合成ＩｇＥ的调节是通过细胞因子实现的，细胞因子又参与气道炎症过程。     

羧甲基茯苓多糖对HPBL分泌IL—2,TNF,IL—6,IFN—γ的调节作用

用ＣＭＰ培养外周血淋巴细胞（ＨＰＢＬ）２４、３６、４８、７２ｈ采样检测的ＩＬ－２、ＴＮＦ、ＩＬ－６、ＩＦＮ－γ效价分别可达１３．６±４．３，４１．９±２．０，１８３７．４±４６４．３，１０３７．９±２１１．０Ｕ／ｍｌ，分别比无ＣＭＰ的细胞培养对照组的效价高０．８，７．４，０．５，１０．９倍（Ｐ＜０．０１），说明ＣＭＰ具有ＩＬ－２、ＴＮＦ、ＩＬ－６、ＩＦＮ－γ的诱生剂功能。由ＣＭＰ预处理ＨＰＢＬ后经ＰＨＡ和／或ＣｏｎＡ促诱生组的ＩＬ－２、ＴＮＦ、ＩＬ－６、ＩＦＮ－γ效价分别比无ＣＭＰ的ＰＨＡ和／或ＣｏｎＡ刺激的相应常规诱生组高１．２～２．８，０．５～１．１、０．５～０．８、０．４～０．６倍（Ｐ＜０．０１），尤以ＣＭＰ＋ＰＨＡ＋ＣｏｎＡ促诱生细胞因子效果最佳（Ｐ＜０．０１），说明ＣＭＰ又具有ＩＬ－２、ＴＮＦ、ＩＬ－６、ＩＦＮ－γ促诱生效应。     

Prolonged eosinophil production after allergen exposure in IFN-gammaR KO mice is IL-5 dependent

Asthma is a T helper 2 (Th2)-driven inflammatory process characterized by eosinophilia. Prolonged airway eosinophilia is commonly observed in asthma exacerbations. Our aim was to evaluate whether eosinophilia in prolonged allergic inflammation is associated with a continuous supply of new eosinophils to the airways, and how this is regulated. Ovalbumin (OVA)-sensitized interferon-γ receptor knockout mice (IFN-γR KO), known to maintain a long-lasting eosinophilia after allergen exposure, were compared to wild type (wt) controls. Animals were exposed to OVA or phosphate-buffered saline on three consecutive days, and bone marrow (BM), blood and bronchoalveolar lavage (BAL) samples were collected 24 h, 7 and 21 days later. Newly produced cells were labelled using bromodeoxyuridine (BrdU). Serum IL-5 was measured and its role was investigated by administration of a neutralizing anti-IL-5 antibody. In-vitro eosinophilopoiesis was examined in both groups by a colony-forming assay. Allergen challenge increased eosinophils in BM, blood and BAL, in both IFN-γR KO and wt mice, both 24 h and 7 days after the last allergen exposure. At 21 days after the last exposure, only IFN-γR KO mice maintained significantly increased eosinophil numbers. Approximately 50% of BAL granulocytes in IFN-γR KO were produced during the last 6 days. Interleukin (IL)-5 concentration was increased in IFN-γR KO mice, and anti-IL-5 reduced eosinophil numbers in all compartments. Increased numbers of eosinophil colonies were observed in IFN-γR KO mice after allergen exposure versus controls. In this model of a Th2-driven prolonged allergic eosinophilia, new eosinophils contribute to the extended inflammation in the airways by enhanced BM eosinophilopoiesis in an IL-5-dependent manner.     

Allergen-induced increase in airway responsiveness, airway eosinophilia, and bone-marrow eosinophil progenitors in mice.

Increases in bone-marrow (BM) inflammatory cell progenitors are associated with allergen-induced airway hyperresponsiveness and inflammation in asthmatics and dogs. Here, for the first time, we compare the time course of airway hyperresponsiveness, inflammation, and marrow progenitor responses in a mouse model of airway allergen challenge. Sensitized BALB/c mice were studied at 2, 12, 24, 48, and 72 h after intranasal ovalbumin or saline challenges. Outcome measurements included airway responsiveness, airway inflammation as assessed via bronchoalveolar lavage (BAL) and lung tissue sections, and BM eosinophil colony-forming units (Eo-CFU) as enumerated using a semisolid culture assay with optimal concentrations of interleukin-5. We observed significant increases in BAL fluid eosinophils, neutrophils, lymphocytes, and macrophages by 2 h after the second of two intranasal allergen challenges (P < 0.05). Significant increases in airway responsiveness or BM Eo-CFU were observed at 24 h and persisted until 48 h after the second challenge (P < 0.05). Airway inflammation, including eosinophils, persisted until at least 72 h (P < 0.05). We observed that allergen-induced airway eosinophilia is accompanied by increases in BM eosinophil progenitors, indicating that in this model, increased eosinophil production involves an expansion of the relevant stem-cell population. These findings support the use of this model to explore the mechanisms of increased eosinopoiesis observed in human asthma.     

alpha4 integrin-dependent eotaxin induction of bronchial hyperresponsiveness and eosinophil migration in interleukin-5 transgenic mice

We investigated the roles of eosinophil infiltration and activation induced by the eosinophil-selective chemokine eotaxin, and of the expression of eosinophil alpha4 and beta2 integrins in causing bronchial hyperresponsiveness (BHR) in interleukin (IL)-5 CBA/Ca transgenic mice. These mice did not show BHR, despite the presence of some eosinophils in the lungs. Intratracheal mouse recombinant eotaxin (3 micrograms) did not induce BHR in wild-type mice. In IL-5 transgenic mice, eotaxin (3 and 5 micrograms) increased responsiveness at 24 h and increased eosinophils in bronchoalveolar lavage (BAL) fluid by 9.4- and 14-fold by 24 h, respectively, together with augmentation of eosinophil peroxidase activity and eosinophil infiltration in the airway submucosa. Using flow cytometry, the expression of alpha4, CD11b, and CD18 was upregulated in BAL, but not in blood, eosinophils. A rat anti-alpha4 antibody inhibited eotaxin-induced BHR and eosinophil migration and activation, but an anti-CD11b antibody had no significant effects on BHR. A combination of both antibodies was more effective. IL-5 and eotaxin synergize in the induction of BHR and airway eosinophilia, effects that are dependent on the induction of eosinophil alpha4 integrin. Expression of BHR depends on the recruitment and activation of eosinophils.     

Involvement of the cysteinyl-leukotrienes in allergen-induced airway eosinophilia and hyperresponsiveness in the mouse

The leukotriene modifiers are a novel generation of therapeutic agents in the treatment of allergic asthma. However, the mechanisms by which the cysteinyl (cys) leukotrienes (LTs) participate in allergen-induced airway eosinophilia and airway hyperresponsiveness (AHR) are still unclear. In the present study, we have investigated the role of cys-LTs in ovalbumin (OVA)-induced airway responses in a murine model of asthma. Montelukast (3 or 10 mg/kg), a selective cys-LT1 receptor antagonist, reduced airway eosinophilia and AHR after OVA challenge. The levels of interleukin (IL)-5 and eotaxin in the bronchoalveolar lavage fluid (BALF) from montelukast-treated (3 mg/kg) mice were unaffected, although a decrease in IL-5 was observed with a dose of 10 mg/kg. LTD4 (50 ng) instilled intranasally to immunized mice augmented macrophages in the BALF, but in conjunction with OVA challenge it caused BALF eosinophilia and neutrophilia when given before challenge and BALF neutrophilia but not eosinophilia when given 2 h after challenge. However, there were no increases of IL-5 or eotaxin in BALF following LTD4 treatment. Repeated instillations of LTD4 to immunized mice, mimicking allergen challenge, did not induce AHR but in conjunction with OVA challenge LTD4 enhanced AHR. These results indicate that allergen-induced eosinophilia and AHR are in part mediated by the cys-LT1 receptor, and that, although LTD4 alone has no effect on airway eosinophilia, in conjunction with antigenic stimulation it potentiates the degree of airway inflammation and AHR.     

Antigen-induced airway hyperresponsiveness, pulmonary eosinophilia, and chemokine expression in B cell-deficient mice

Murine models of allergen-induced pulmonary inflammation share many features with human asthma, including the development of antigen-induced pulmonary eosinophilia, airway hyperresponsiveness, antigen-specific cellular and antibody responses, the elaboration of Th2 cytokines (interleukin [IL]-4 and IL-5), and the expression of chemokines with activity for eosinophils. We examined the role of B cells and antigen-specific antibody responses in such a model by studying the histopathologic and physiologic responses of B cell-deficient mice compared with wild-type controls, following systemic immunization and airway challenge with ovalbumin (OVA). Both OVA-challenged wild-type and B cell-deficient mice developed (1) airway hyperresponsiveness, (2) pulmonary inflammation with activated T cells and eosinophils, (3) IL-4 and IL-5 secretion into the airway lumen, and (4) increased expression of the eosinophil active chemokines eotaxin and monocyte chemotactic protein-3. There were no significant differences in either the pathologic or physiologic responses in the B cell-deficient mice compared with wild-type mice. These data indicate that B cells and antigen-specific antibodies are not required for the development of airway hyperresponsiveness, eosinophilic pulmonary inflammation, and chemokine expression in sensitized mice following aerosol challenge with antigen.     

An Essential Role for Interleukin-5 and Eosinophils in Helminth-Induced Airway Hyperresponsiveness

Infection with the parasitic helminth Brugia malayi can result in development of a severe asthmatic response termed tropical pulmonary eosinophilia. This disease, thought to result from a host inflammatory response to blood parasites which become trapped in the lung microvasculature, is characterized by a profound eosinophilic infiltration into the lungs. Recruitment of eosinophils also correlates with the development of airway hyperresponsiveness (AHR) to cholinergic agonists and severe asthmatic symptoms. Our studies examined the role of interleukin-5 (IL-5) in helminth-induced pulmonary eosinophilia and AHR. C57BL/6 mice immunized with killed B. malayi microfilariae and challenged intravenously with live microfilariae exhibit many of the characteristics of human disease, including peripheral and pulmonary eosinophilia. Cells recovered by bronchoalveolar lavage of sensitized mice consisted of 3.8% eosinophils on day 1 postchallenge and 84% on day 10. Extracellular major basic protein was present on the surface of airway epithelial cells as early as day 1 and continued to be evident after 8 days, indicating sustained activation and degranulation of eosinophils in the lung. These histologic changes correlated with the development of AHR to carbachol. In contrast to immunocompetent mice, immunization and challenge with B. malayi in IL-5^−/− mice did not induce peripheral or pulmonary eosinophilia, and these mice failed to show AHR in response to cholinergic agonists. Taken together, these data indicate that IL-5 and eosinophils are required for the induction of AHR by filarial helminths.     

Eotaxin-1-deficient mice develop airway eosinophilia and airway hyperresponsiveness.

BACKGROUND: The accumulation of eosinophils in the lung is a hallmark of asthma. In addition to cytokines such as IL-5 which are essential, chemokines have been implicated in the recruitment of eosinophils to the airway. In particular, eotaxin has been shown to be a selective and potent eosinophil chemoattractant, important in the pathogenesis of allergic disease. The goal of the present study was to define the role of eotaxin-1 in the development of allergen-induced eosinophilic airway inflammation and airway hyperresponsiveness (AHR) to inhaled methacholine (MCh). METHODS: Eotaxin-1-deficient mice were sensitized and exposed to a single challenge with allergen. Airway function and airway and tissue as well as peripheral blood and bone marrow eosinophilia were examined 18 and 48 h after the last challenge. RESULTS: Following allergen sensitization and challenge, eotaxin-1-deficient mice developed levels of AHR to inhaled MCh at 18 and 48 h comparable to controls. Further, levels of bronchoalveolar lavage (BAL) and tissue eosinophilia at the same time points were comparable in the two strains of mice. Tissue eosinophilia, assessed by quantitating major basic protein staining cells, preceded BAL eosinophilia in a similar manner. Bone marrow and peripheral blood eosinophilia were unimpaired in deficient mice. CONCLUSION: The results demonstrate that the major eotaxin, eotaxin-1 is not essential for the development of airway eosinophilia or AHR, implying that other chemokines, alone or in combination, can overcome this deficiency.     

Effects of a cysteinyl leukotriene receptor antagonist on eosinophil recruitment in experimental allergic rhinitis

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through a receptor (cysLT1-R) which can be targeted in rhinitis and asthma. We investigated the effects of cysLT1-R antagonism in experimental allergic rhinitis, focusing on bone marrow eosinophil progenitor responses. BALB/c mice were sensitized, then given daily intranasal ovalbumin for 2 weeks, with montelukast sodium (5 mg/kg or 2.5 mg/kg) or placebo by gavage. Bone marrow eosinophil/basophil colonies were enumerated, and colony cells were morphologically assessed as indices of eosinophil differentiation and maturation. Montelukast treatment resulted in a significant decrease of eosinophils in the nasal mucosa, and in either bone marrow interleukin (IL)-5-, but not IL-3-, or granulocyte-macrophage colony-stimulating factor-responsive eosinophil/basophil colony-forming units, and IL-5-stimulated eosinophil maturation. These results indicate that cysLT1-R antagonism in vivo limits both IL-5-responsive eosinophilopoiesis, acting at several stages of eosinophil differentiation and maturation. The anti-allergic effects of cysLT1-R antagonists are consistent with the concept that cysLTs and IL-5 act together in the recruitment of eosinophils and eosinophil progenitors from the marrow during upper airway allergic inflammation.     

Effects of an ATP-sensitive K+ channel activator, JTV-506, on antigen-induced early and late asthmatic responses in sensitized guinea pigs]

Effects of an ATP-sensitive K+ channel activator, JTV-506, on dual asthmatic responses and airway inflammation after antigen inhalation challenge were investigated in asthma model of guinea pigs. The animals were given an oral dose of 1 mg/kg of JTV-506 or vehicle (0.5% carboxymethyl cellulose sodium) 1 hour before and 3 hours after antigen inhalation challenge. Measurement of pulmonary resistance for 6 h was followed by bronchoalveolar lavage. After antigen challenge, all guinea pigs in the vehicle group displayed dual-phase airway obstruction and accumulation of eosinophils in the airways. After the treatment with JTV-506, the early asthmatic response was significantly inhibited, although the late asthmatic response or the recruitment of eosinophils into the airways were not inhibited. Therefore, we suggested that JTV-506 may inhibit airway smooth contraction induced by chemical mediators, but not function of CD4+ T lymphocytes.     

Induction, distribution and modulation of upper airway allergic inflammation in mice

BACKGROUND: To further elucidate mechanisms of human allergic rhinosinusitis, we studied the induction, distribution and modulation of allergen-induced upper airway inflammation in a BALB/c mouse model. METHODS: Allergic inflammation induced with ovalbumin (OVA) by intraperitoneal (IP) injection in alum was compared to repeated intranasal instillation. The type and distribution of inflammatory cells was compared in the respiratory and olfactory epithelial compartments. Eosinophil distribution was assessed using Scarlet Red stain and a polyclonal antibody recognizing eosinophil major basic protein (MBP). The role of interleukin (IL)-5 in upper airway inflammation was tested by administration of polyclonal anti-IL-5 antibody during the sensitization protocol. RESULTS: Unsensitized control mice receiving saline failed to develop upper airway eosinophil infiltration. IP OVA-sensitized mice developed marked upper airway mucosal eosinophil infiltration after aerosol OVA challenge, whereas repeated intranasal instillation of OVA produced qualitatively similar, but less intense eosinophil infiltration. Using either sensitization protocol, eosinophil infiltration was seen in areas of the lower portion of the nasal septum, the floor and the lower lateral walls of the mid-caudal region of the nasal cavity. Immunofluorescence staining for MBP confirmed this distribution of eosinophils but also demonstrated some eosinophils in the maxillary sinuses and in circumscribed regions of the ethmoturbinates. All areas of eosinophil infiltration were lined by respiratory epithelium. The selective infiltration of respiratory but not olfactory epithelium by eosinophils was unassociated with a measurable induction of epithelial ICAM-1 or eotaxin expression. OVA-induced upper airway eosinophil infiltration was found to be IL-5 dependent, since administration of a polyclonal anti-IL-5 antibody (TRFK-5) during OVA sensitization resulted in a marked modulation (80% decrease) in eosinophil infiltration in response to subsequent OVA challenge. CONCLUSION: The mouse upper airway, specifically in areas containing respiratory epithelium, is a target for OVA-induced allergic inflammation. This selective infiltration of respiratory, but not olfactory, epithelium is, in part, dependent upon IL-5. This model is useful for further dissection of the inflammatory response with genetic manipulations and targeted immunological approaches.