Human blood was separated into polymorphonuclear (PMN) and mononuclear (MN) leukocyte fractions, and 3 x 10(7) cells (PMN or MN) were added to isolated rat lungs perfused with 5% human albumin in buffer and stimulated with phorbol myristate acetate (PMA). Lungs perfused with either albumin alone, PMN, or MN but not stimulated with PMA showed no change in vascular resistance or endothelial permeability measured as the capillary filtration coefficient (Kf,c). Lungs that were stimulated with PMA with no cells showed no change in Kf,c (0.34 +/- 0.07 vs. 0.37 +/- 0.7), but vascular resistance increased in all segments of the circulation. Capillary pressure, the major force responsible for edema formation, nearly doubled in the absence of cells 40 min after PMA. Lungs perfused with either PMN or MN and stimulated with PMA were injured. Kf,c increased from 0.41 +/- 0.03 to 0.87 +/- 0.10 (PMN) and from 0.36 +/- 0.07 to 0.81 +/- 0.23 (MN) 90 min after PMA. In addition to the increased endothelial permeability, vascular resistances and pressures also increased in the cell-perfused PMA-stimulated lungs. These results demonstrate that cells other than granulocytes are capable of producing severe acute lung injury and cannot be ignored when the effects of PMA on neutrophil-depleted lungs are studied.