Ms. Mulligan et al., PROTECTIVE EFFECTS OF COMBINED ADHESION MOLECULE BLOCKADE IN MODELS OF ACUTE LUNG INJURY, Proceedings of the Association of American Physicians, 108(3), 1996, pp. 198-208
In various models of lung inflammatory injury in rats, individual requ
irements for leukocytic and endothelial adhesion molecules have been e
stablished. In the current study dose-response interventions were empl
oyed and comparisons made to protective effects of single and dual blo
ckade of adhesion molecules. In lung injury following systemic activat
ion of complement, single blockade of P- or L-selectin produced dose-d
ependent protective effects, while combined blocking of L- and P-selec
tin 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 wit
h dual blockade of CD11a and CD11b. In the IgG immune complex model of
lung injury, combined blocking of L- and E-selectin was more effectiv
e than blocking of either selectin alone. Combined blockade of CD11a a
nd CD18 was also more effective than either blocking intervention alon
e. However, blocking of CD11b was ineffective and was not associated w
ith increased protection when combined with anti-CD18, confirming earl
ier indications that, under the conditions employed, Mac-1 plays no me
asurable 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 simultane
ous blocking of E-selectin and ICAM-1 resulted in protection that was
no different from the effects of blocking ICAM-1 alone, confirming tha
t 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. F
inally, combined blockade of CD18 and VLA-4 in the two models of immun
e complex-induced injury was more effective than individual blockade.
These data substantiate the multiple requirements for adhesion molecul
es in the three models of lung injury. The findings raise questions as
to why dual blockade of adhesion molecules produces less than complet
ely additive effects of the individual interventions and why the prote
ctive effects of blocking antibodies seem to have an upper limit.