THE ROLE OF THE LEUKOCYTE ADHESION MOLECULES VLA-4, LFA-1, AND MAC-1 IN ALLERGIC AIRWAY RESPONSES IN THE RAT

Chronic airway inflammation is involved in the pathogenesis of asthma. The leukocyte adhesion molecules VLA-4 of the beta(1) integrin family , and LFA-1 and Mac-1 of the beta(2) family have a demonstrated role i n leukocyte-endothelial adherence and may play a role in airway inflam mation in asthma. We studied the effects of blocking VLA-4 (CD49d/CD29 ) and both LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) on allergen induc ed airway responses and inflammation in rats. BN rats were sensitized with ovalbumin (OA) subcutaneously and were challenged 14 d later with aerosolized OA. Twelve rats were treated prior to challenge with anti -rat VLA-4 monoclonal antibody(mAb), 10 rats received both anti-LFA-l and anti-Mac-1 mAb, and 14 rats received a control mAb. The pulmonary resistance (RL) was measured for 8 h after challenge. The inflammatory response was evaluated by bronchoalveolar lavage (BAL) and by measuri ng the lung and airway inflammatory cells retrieved by enzymative disp ersion. The early response was significantly decreased in both the ant i-VLA-4 group (131% baseline RL) and the anti-LFA-1/Mac-1 group (118%; p < 0.05) compared with the control group (202%). The late response w as also significantly decreased in both the anti-VLA-4 (3.7) and anti- LFA-1/Mac-1 (2.6) groups compared with the control group (19.7). The s ignificant differences in bronchoalveolar lavage were a decrease in ne utrophils in the LFA-1/Mac-1 group and an increase in macrophages in t he anti-VLA-4 group. Airway cells were unaffected by mAb pretreatments and the only change in lung parenchyma was an increase in lymphocytes in the anti-VLA-4 group. This study shows that the VLA-4 and LFA-1/Ma c-1 integrins play a role in the early and late airway responses after antigen challenge in the rat. Effects on cell migration alone seem un likely to account for the findings.