This study investigates the role of the activated polymorphonuclear cell (APMN) products on sickle red blood cell (SRBC) retention/adherence in the pulmonary circulation. Isolated rat lungs were perfused with (51)Cr-labeled normal RBCs (NRBC) or SRBCs (10% hematocrit) suspensions +/- PMNs. Specific activities of lung and perfusate were measured and retention (the number of SRBC/g lung) was calculated. SRBC retention was 3.5 times greater than NRBC retention. PMN activation was required to increase SRBC retention. Supernatants from APMN increased SRBC retention, which suggested soluble products such as oxidants, PAF, and/or leukotriene (LTB(4)) are involved. Heat inactivation of PMN NADPH oxidase had no effect on retention. Whereas neither platelet-activating factor (PAF) nor LTB(4) (secreted by APMN) increased SRBC retention, PAF+LTB(4) did. The PAF antagonist, WEB-2170, attenuated SRBC retention mediated by PAF+LTB(4) and APMNs. Similarly, zileuton (5-lipoxygenase inhibitor) attenuated APMN-mediated SRBC retention. We conclude the concomitant release of PAF and LTB(4) from APMN is involved in the initiation of microvascular occlusion by SRBCs in the perfused rat lung.