Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation
Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation
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DOI：
10.4049/jimmunol.174.2.783
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发表时间：
2005-01-15
影响因子：
4.4
通讯作者：
Braun, A
中科院分区：
文献类型：
--
作者：
Baelder, R;Fuchs, B;Braun, A
气道高反应性和气道炎症是过敏性哮喘的标志，其病因与Th 2细胞因子的存在密切相关。提示补体过敏毒素C3 a和C5 a在过敏性哮喘中的作用。如. C3 a受体（C3 aR）和补体因子C5的缺乏调节气道高反应性气道炎症。和Th 2细胞因子水平。然而，这样的模型不允许区分对过敏反应的致敏阶段和效应阶段的影响。在这项研究中，我们确定了过敏毒素在效应相的作用。通过药理学靶向过敏毒素受体来治疗哮喘。在烟曲霉提取物诱导的肺变态反应小鼠模型中，使用非肽C3 aR拮抗剂SB 290157和中和C5 aR mAb 20/70阻断C3 aR和C5 a受体（C5 aR）信号传导。C5 aR阻断后气道高反应性显著改善，但C3 aR阻断后无改善。在用C3 aR拮抗剂或抗C5 aR mAb处理的小鼠中，气道炎症显著减少，如支气管肺泡灌洗液中嗜中性粒细胞和嗜酸性粒细胞数量减少所证明的。值得注意。抑制C5 aR而非C3 aR可减少支气管肺泡灌洗液中的淋巴细胞数量。C3 aR或C5 aR阻断不改变支气管肺泡灌洗液中IL-5和IL-13的细胞因子水平。然而，阻断过敏毒素受体显着降低IL-4水平。这些数据表明，C5 aR信号传导在肺过敏原激发过程中对气道高反应性的发展具有重要和独特的作用，而过敏毒素有助于气道炎症和IL-4的产生。
Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested. as. deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresonsiveness airway inflammation. and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase. of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note. C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.