Selectin blockade prevents antigen-induced late bronchial responses and airway hyperresponsiveness in allergic sheep

Antigen challenge can elicit an allergic inflammatory response in the airwa ys that involves eosinophils, basophils, and neutrophils and that is expres sed physiologically as a late airway response (LAR) and airway hyperrespons iveness (AHR). Although previous studies have suggested that E-selectin par ticipates in these allergic airway responses, there is little information c oncerning the role of L-selectin. To address this question, we examined the effects of administering an L-selectin-specific monoclonal antibody, DU1-2 9, as well as three small molecule selectin binding inhibitors, on the deve lopment of early airway responses (EAR), LAR and AHR in allergic sheep unde rgoing airway challenge with Ascaris suum antigen. Sheep treated with aeros ol DU1-29 before antigen challenge had a significantly reduced LAR and did not develop postchallenge AHR. No protective effect was seen when sheep wer e treated with a nonspecific control monoclonal antibody. Treatment with DU 1-29 also reduced the severity of the EAR to antigen. Similar results were obtained with each of the three small molecule selectin inhibitors at doses that depended on their L-, but not necessarily E-selectin inhibitory capac ity. The inhibition of the EAR with one of the inhibitors, TBC-1269, was as sociated with a reduction in histamine release. Likewise, treatment with TB C-1269 reduced the number of neutrophils recovered in bronchoalveolar lavag e (BAL) during the time of LAR and AHR. TBC-1269, given 90 min after antige n challenge also blocked the LAR and the AHR, but this protection was lost if the treatment was withheld until 4 h after challenge, a result consisten t with the proposed time course of L-selectin involvement in leukocyte traf ficking. These are the first data indicating that L-selectin may have a uni que cellular function that modulates allergen-induced pulmonary responses.