Abraham W M, Gill A, Ahmed A, Sielczak M W, Lauredo I T, Botinnikova Y, Lin K C, Pepinsky B, Leone D R, Lobb R R, Adams S P
Division of Pulmonary Disease and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida, USA.
Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):603-11. doi: 10.1164/ajrccm.162.2.9911061.
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. BIO-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 BIO-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.
白细胞整合素极迟抗原-4（α4β1，CD49d/CD29）是一种黏附受体，在变应性炎症中起重要作用，并参与抗原诱导的迟发反应（LAR）和气道高反应性（AHR）。在本研究中，我们发现，新型小分子α4紧密结合抑制剂BIO-1211单剂量给药，无论是通过气雾剂还是静脉给药，在抗原激发前或激发后1.5小时给药，均可阻断变应性绵羊中变应原诱导的LAR和抗原激发后AHR。单剂量无效的BIO-1211多次给药具有保护作用。BIO-1211还可剂量依赖性抑制对抗原的早期气道反应（EAR）。与对抗原诱导的LAR和AHR的功能保护作用一致，激发前用BIO-1211治疗的绵羊显示：（1）支气管肺泡灌洗（BAL）中嗜酸性粒细胞数量显著减少；（2）炎症标志物组织激肽释放酶的BAL水平降低；（3）与载体治疗后的相应活检相比，激发后获得的支气管活检中炎症细胞（淋巴细胞、嗜酸性粒细胞、异染性染色细胞和中性粒细胞）数量减少。更重要的是，我们首次表明α4抑制剂能够逆转抗原激发后AHR，从而将恢复时间从正常的>9天缩短至3天。我们的结果表明，单剂量强效α4小分子抑制剂可有效抑制抗原诱导的气道反应，且此类药物可用于治疗以及预防，以减轻变应原诱导的炎症事件。这些数据进一步支持并扩展了α4整合素在气道抗原激发后病理生理事件中作用的证据。
