Abraham W M, Ahmed A, Sielczak M W, Narita M, Arrhenius T, Elices M J
Division of Pulmonary Disease, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.
Am J Respir Crit Care Med. 1997 Sep;156(3 Pt 1):696-703. doi: 10.1164/ajrccm.156.3.9609039.
The leukocyte integrin very late antigen-4 (VLA-4) (alpha 4 beta 1, CD49d/CD29) is an adhesion receptor predominantly expressed on lymphocytes, monocytes, and eosinophils, but not on neutrophils. Recent studies with monoclonal antibodies against VLA-4 suggest that antigen-induced late responses and airway hyperresponsiveness (AHR) may depend on the recruitment and/or activation of VLA-4-expressing leukocytes. To further test this hypothesis, we administered by aerosol either a potent small-molecule inhibitor of VLA-4, which prevents VLA-4-mediated binding to fibronectin (CS-1 ligand mimic), or an inactive control (30 mg twice daily for 3 d, and on the fourth day 0.5 h before and 4 h after antigen challenge) to six sheep with airway hypersensitivity to Ascaris suum antigen. Treatment with the small-molecule VLA-4 inhibitor resulted in a significant decrease in the early antigen-induced bronchial response (40%, p < 0.05), and almost complete blockade of the late-phase airway response (88%, p < 0.05). Moreover, at 24 h after antigen challenge, AHR to inhaled carbachol was not observed when the animals were dosed with the small-molecule VLA-4 inhibitor. In accord with protection against the functional abnormalities associated with antigen challenge, analysis of biopsy specimens taken 24 h after challenge indicated that the total numbers of VLA-4-positive cells (lymphocytes, eosinophils, and metachromatic-staining cells) in the group treated with the VLA-4 inhibitor did not increase, whereas these cells increased in the control group. The active agent, but not the inactive control, significantly blocked macrophage adherence to fibronectin (FN), indicating that the CS-1 ligand interfered with VLA-4-mediated adhesion in sheep cells. These results support our previous findings with a monoclonal antibody to VLA-4, and demonstrate that a small-molecule VLA-4 inhibitor, when given by aerosol, has a protective effect against antigen-induced late responses and AHR in allergic sheep.
白细胞整合素极迟抗原4（VLA-4）（α4β1，CD49d/CD29）是一种主要表达于淋巴细胞、单核细胞和嗜酸性粒细胞，而不表达于中性粒细胞的黏附受体。近期针对VLA-4的单克隆抗体研究表明，抗原诱导的迟发反应和气道高反应性（AHR）可能依赖于表达VLA-4的白细胞的募集和/或激活。为了进一步验证这一假设，我们对6只对猪蛔虫抗原具有气道超敏反应的绵羊进行雾化给药，分别给予一种强效的VLA-4小分子抑制剂（可阻止VLA-4介导的与纤连蛋白的结合，即CS-1配体模拟物）或无活性对照物（每日两次，每次30mg，共3天，在抗原激发前0.5小时和激发后4小时给予第4天的剂量）。用小分子VLA-4抑制剂治疗导致抗原诱导的早期支气管反应显著降低（40%，p<0.05），并几乎完全阻断了迟发性气道反应（88%，p<0.05）。此外，在抗原激发后24小时，当给动物注射小分子VLA-4抑制剂时，未观察到对吸入卡巴胆碱的气道高反应性。与预防抗原激发相关的功能异常一致，对激发后24小时采集的活检标本分析表明，用VLA-4抑制剂治疗的组中VLA-4阳性细胞（淋巴细胞、嗜酸性粒细胞和异染性染色细胞）总数未增加，而对照组中这些细胞增加。活性药物而非无活性对照物显著阻断巨噬细胞与纤连蛋白（FN）的黏附，表明CS-1配体干扰了绵羊细胞中VLA-4介导的黏附。这些结果支持了我们之前使用VLA-4单克隆抗体的研究结果，并表明小分子VLA-4抑制剂雾化给药时，对变应性绵羊的抗原诱导迟发反应和气道高反应性具有保护作用。
