In acute respiratory distress syndrome (ARDS), the accumulation of neutrophils (PMN) within the pulmonary vasculature and alveolar interstitium may be key pathogenic events. Injection of FFA into experimental animals duplicates many of the symptoms of ARDS, including pulmonary accumulation of PMN. We earlier found that micromolar amounts of FFA such as 16:0, 18:0 and 18:1 promote the release of PMN primary granule contents and PMN-mediated killing of mammalian cells. PMN accumulation in tissues requires their primary adherence to vascular endothelial cells and one possible mediator is theβ2 integrin, CD11b/CD18. We now report that exposure of isolated human PMN to oleic acid (OA; 80 μM) causes rapid (beginning within 30-60 sec) and substantial (up to 10-fold) upregulation of surface CD11b/CD18, much of this in the `high affinity' state (as measured by flow cytometry using monoclonal antibodies LM2/1 and CBRM1/5). FFA-mediated upregulation is more pronounced at lower pH (6.6-6.9) and at lower pH exceeds that triggered by phorbol myristate acetate. Similar upregulation occurs in whole blood but higher concentrations of OA are required to overcome FFA binding by albumin. OA also triggers PMN aggregation and enhances ≈3-5 fold attachment of PMN to fibrin(ogen) coated surfaces and confluent cultures of human umbilical vein endothelial cells, both blocked by neutrophil inhibitory factor and anti-CD11b/CD18 monoclonal antibody. OA (and other FFA) may cause this effect through acting as a (cell cytoplasm acidifying) protonophore; OA methyl ester has no effect on integrin expression and `clamping' intracellular pH by addition of the ionophore, FCCP suppresses OA-mediated upregulation of CD11b/CD18. We conclude that micromolar amounts of FFA act as potent agonists of PMN aggregation and adherence to vascular endothelium. These results suggest one possible mechanism for the promotion, by FFA, of pro-inflammatory and tissue damaging effects of PMN, and may help explain the etiology of so-called fat embolism wherein trauma-induced release of fatty material, from adipose tissue or bone marrow, causes pulmonary PMN sequestration which may eventuate in the development of ARDS.