A small-molecule, tight-binding inhibitor of the integrin α4β1 blocks antigen-induced airway responses and inflammation in experimental asthma in sheep
A small-molecule, tight-binding inhibitor of the integrin α4β1 blocks antigen-induced airway responses and inflammation in experimental asthma in sheep
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DOI：
10.1164/ajrccm.162.2.9911061
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发表时间：
2000-08-01
影响因子：
24.7
通讯作者：
Adams, SP
中科院分区：
文献类型：
--
作者：
Abraham, WM;Gill, A;Adams, SP
白细胞整合素极晚期抗原-4（alpha（4）beta（1），CD 49 d/CD 29）是一种粘附受体，在过敏性炎症中起重要作用，并导致抗原诱导的晚期反应（LAR）和气道高反应性（AHR）。在这项研究中，我们表明，一种新的小分子，紧密结合的α（4），BIO-1211抑制剂，无论是通过气雾剂或静脉注射，在抗原激发前或1.5小时后，单剂量阻断过敏原诱导的LAR和抗原诱导后AHR在过敏性绵羊。单次给药无效的BIO-1211多次给药具有保护作用。810-1211还提供了对抗原的早期气道反应（ERI）的剂量依赖性抑制。结合针对抗原诱导的LAR和AHR的功能保护，在攻击前用810-1211处理的绵羊显示出显著降低：（1）支气管肺泡灌洗（BAL）中嗜酸性粒细胞的数量，（2）炎性标志物组织激肽释放酶的BAL水平，和（3）炎性细胞的数量在激发后获得的支气管活组织检查中，当与溶剂处理后的相应活组织检查相比时，支气管活组织检查中的淋巴细胞、嗜酸性粒细胞、异染性染色细胞和嗜中性粒细胞的数量。更重要的是，我们首次发现α 4抑制剂能够逆转抗原后诱导的AHR，从而将恢复时间从> 9 d的正常期缩短至3 d。我们的研究结果表明，有效抑制抗原诱导的气道反应，可以实现与α（4）的一个有效的小分子抑制剂的单剂量，这类药物可用于治疗，以及预防，以减轻过敏原诱导的炎症事件。这些数据为α 4整合素在气道抗原激发后的病理生理学事件中的作用提供了进一步的支持和证据。
The leukocyte integrin very late antigen-4 (alpha(4)beta(1), CD49d/CD29) is an adhesion receptor that plays an important role in allergic inflammation and contributes to antigen-induced late responses (LAR) and airway hyperresponsiveness (AHR). In this study, we show that single doses of a new small-molecule, tight-binding inhibitor of alpha(4), BIO-1211, whether given by aerosol or intravenously, either before or 1.5 h after antigen challenge blocks allergen-induced LAR and post-antigen-induced AHR in allergic sheep. Multiple treatments with doses of BIO-1211 that were ineffective when given singly, were protective. 810-1211 also provided dose-dependent inhibition of the early airway response (EAR) to antigen. In conjunction with the functional protection against the antigen-induced LAR and AHR, sheep treated with 810-1211 before challenge showed significantly reduced: (1) numbers of eosinophils in bronchoalveolar lavage (BAL), (2) BAL levels of the inflammatory marker tissue kallikrein, and (3) numbers of inflammatory cells (lymphocytes, eosinophils, metachromatic staining cells, and neutrophils) in bronchial biopsies obtained after challenge when compared with corresponding biopsies after vehicle treatment. More importantly, we show for the first time that an inhibitor of alpha(4) was able to reverse post-antigen-induced AHR, thereby decreasing the time of recovery from the normal period of > 9 d to 3 d. Our results show that effective inhibition of antigen-induced airway responses can be achieved with single doses of a potent small-molecule inhibitor of alpha(4) and that such agents may be used therapeutically, as well as prophylactically, to alleviate allergen-induced inflammatory events. These data provide further support and extend the evidence for the role of alpha(4) integrins in the pathophysiologic events that follow airway antigen challenge.