Protective effects of combined adhesion molecule blockade in models of acute lung injury

In various models of lung inflammatory injury in rats, individual requirements for leukocytic and endothelial adhesion molecules have been established. In the current study dose-response interventions were employed and comparisons made to protective effects of single and dual blockade of adhesion molecules. In lung injury following systemic activation of complement, single blockade of P- or L-selectin produced dose-dependent protective effects, while combined blocking of L- and P-selectin produced protection that was incremental to either blockade alone but less than completely additive. The blocking of selectins seemed to have limited effects. Additive protective effects were also found with dual blockade of CD11a and CD11b. In the IgG immune complex model of lung injury, combined blocking of L- and E-selectin was more effective than blocking of either selectin alone. Combined blockade of CD11a and CD18 was also more effective than either blocking intervention alone. However, blocking of CD11b was ineffective and was not associated with increased protection when combined with anti-CD18, confirming earlier indications that, under the conditions employed, Mac-1 plays no measurable role in this model of lung injury. Increased protection also occurred when mAb to E-selectin was combined with mAb to either ICAM-1 or CD18. In the IgA immune complex model of lung injury the simultaneous blocking of E-selectin and ICAM-1 resulted in protection that was no different from the effects of blocking ICAM-1 alone, confirming that E-selectin plays no role in this model of lung injury. Dual blockade of CD11b and CD18 was more effective than blockade of either alone. Finally, combined blockade of CD18 and VLA-4 in the two models of immune complex-induced injury was more effective than individual blockade. These data substantiate the multiple requirements for adhesion molecules in the three models of lung injury. The findings raise questions as to why dual blockade of adhesion molecules produces less than completely additive effects of the individual interventions and why the protective effects of blocking antibodies seem to have an upper limit.