The effects of IB4, a monoclonal antibody to the CD18 leukocyte integrin on phorbol myristate acetate (PMA)-induced polymorphonuclear leukocyte (PMN)accumulation and endothelial injury in rabbit lungs

A model of acute lung injury induced by intravenous phorbol myristate aceta te (PMA) is described. The model is characterized by the accumulation of po lymorphonuclear leukocytes (PMNs) and a hemorrhagic edema in bronchoalveola r lavage (BAL) fluid when measured 6 h following the administration of PMA (60 mu g/kg, i.v.). It was also determined that PMA induces acute leukopeni a and neutropenia which were maximal at 5 min following the injection of PM A and were sustained for at least 6 h, with circulating leukocyte numbers r eturning to control values by 24 h. The extents to which the inflammatory a nd systemic changes induced by PMA were dependent on the surface expression on leukocytes of the beta 2-integrins was assessed by comparing responses to PMA in control animals and animals pretreated with the anti-CD18 monoclo nal antibody IB4. The administration of IB4 (1 mg/kg, i.v.) 15 min before P MA did not alter the time course or extent of PMA-induced leukopenia and ne utropenia. In contrast IB4 administration (0.1 to 1 mg/kg) produced a dose dependent inhibition of PMN accumulation and plasma extravasation measured in BAL fluid. IB4 (1 mg/kg) completely inhibited PMA evoked increases in pl asma extravasation (94.5 +/- 1.7%, N = 4) and hemorrhage (95.2 +/- 2.1%, N = 4) whereas PMN accumulation in BAL fluid was inhibited by 77.8 +/- 3.8% ( mean +/- SEM, N = 4). Thus, a small, but reproducible, component of the PMA -induced PMN accumulation was not inhibited using this regimen of IB4 admin istration. If IB4 administration was delayed for 3 h post injection of PMA and bronchoalveolar lavage performed 3 h later, the extents of PMN accumula tion and edema formation were similar to those observed 3 h following PMA c hallenge in control animals not dosed with IB4. This suggests that administ ration of IB4 during an ongoing inflammatory response is capable of prevent ing the further development of inflammatory changes and further supports th e therapeutic potential of CD18 blockade in conditions such as adult respir atory distress syndrome.