VLA-4 antagonist WAY160103 (WAY) inhibits VCAM-1 activated eosinophil (EOS) respiratory burst but promotes eosinophil derived neurotoxin (EDN) degranulation

EOS are selectively recruited to the lung during asthma exacerbations and play an important role in airway inflammation. EOS participation is initiated by adhesion of circulating cells via VLA-4 (a4β1) to VCAM-1 expressed on pulmonary endothelium. Inhibition of this process has been studied with a variety of VLA-4 antagonists as possible therapeutic agents to block the participation of EOS in allergic airway inflammation. Although integrin (b1, b2) ligation has been closely related to functional activation of EOS, studies on the effects of these antagonists on other EOS functions have been limited. We hypothesized that the small molecule VLA-4 inhibitor, WAY160103, affects not only EOS adhesion but also other b-integrin-dependent functions. Human peripheral blood EOS were isolated and assayed for transendothelial migration (TNF-a activated human pulmonary microvascular endothelial cells [HPMEC]), respiratory burst (superoxide anion generation) and EDN degranulation (RIA). Although WAY inhibited VCAM-1 adhesion, it had no effect on EOS transmigration across VCAM-1 upregulated HPMEC monolayers. WAY did, however, give a concentration-dependent inhibition of VCAM-1 activated superoxide anion generation similar to its effects on EOS adhesion. Finally, WAY promoted EDN degranulation possibly due to a shift from VLA-4 to b2-dependent adhesion necessary for EOS degranulation. Although inhibition of EOS adhesion to VCAM-1 may suppress an early step in cell infiltration, other pathways (selectins) can initiate EOS extravascular migration. The effects of VLA-4 inhibitors on other inflammatory EOS functions must be taken into account when testing these compounds as possible therapeutic agents in allergic disease and asthma.