The β 2 integrin cell adhesion molecules (CAM) mediate polymorphonuclear leukocyte (PMNL) emigration in most inflamed tissues, but, in the lung, other yet to be identified CAMs appear to be involved. In Lewis rats, the intratracheal injection of Escherichia coli-LPS induced acute (6-h) PMNL accumulation in the lung parenchyma (280× 10 6 by myeloperoxidase assay; PBS control= 35× 10 6) and bronchoalveolar lavage fluid (BALF= 27× 10 6; PBS= 0.1× 10 6). Parenchymal accumulation was not inhibited by a blocking Ab to β 2 integrins and only minimally inhibited (20.5%; p< 0.05) in BALF. We examined the role of α 4 β 1 and α 5 β 1 integrins and of selectins in this PMNL recruitment. Treatment with mAbs to α 4 β 1 or α 5 β 1, even in combination, had no effect on PMNL accumulation induced by intratracheal LPS. However, anti-α 4 combined with anti-β 2 mAbs inhibited PMNL recruitment to the parenchyma by 56%(p< 0.001) and to BALF by 58%(p< 0.01). The addition of anti-α 5 mAb to β 2 plus α 4 blockade inhibited PMNL accumulation further (by 79%; p< 0.05). In contrast, blockade of L-, P-, and E-selectins in combination or together with β 2, α 4, and α 5 integrins had no effect. LPS-induced BALF protein accumulation was not inhibited by treatment with anti-β 2 plus α 4 mAbs, but was prevented when α 5 β 1 was also blocked. Thus, while selectins appear to play no role, α 4 β 1 and α 5 β 1 function as major alternate CAMs to the β 2 integrins in mediating PMNL migration to lung and to pulmonary vascular and epithelial permeability.