TUMOR-NECROSIS-FACTOR MEDIATES EXPERIMENTAL PULMONARY-EDEMA BY ICAM-1 AND CD18-DEPENDENT MECHANISMS

(TNF(alpha))-induced sequestration of neutrophils (PMN) in lungs and of the resultant PMN-dependent pulmonary edema. Guinea pig lungs perfused with Ringers-albumin were challenged with TNF(alpha) (1,000 U/ml) for 90 min, followed by addition of fresh perfusate containing 2 x 10(7) human PMN. TNF(alpha) challenge caused sequestration of PMN in the pulmonary vascular bed as indicated by a threefold increase in lung tissue myeloperoxidase activity (MPO). The activation of the sequestered PMN with phorbol 12-myristate 13-acetate (PMA; 5 x 10(-9) M) produced threefold increases in pulmonary artery (P(paBAR)) and pulmonary capillary hydrostatic (P(capBAR)) pressures, and twofold increases in lung wet-to-dry weight (W/D) ratio and capillary filtration coefficient (K(f,c)) over baseline. TNF(alpha) prestimulation was required for these responses since activation of PMN with PMA in control lungs produced smaller increases in P(paBAR) and P(capBAR) (P < 0.01) and did not change the W/D and K(f,c). TNF(alpha) prestimulation also induced the expression of intercellular adhesion molecule (ICAM-1) on pulmonary vascular endothelial cells. Monoclonal antibodies (mAbs) to the neutrophil CD18 integrin (beta-chain of CD11/CD18 complex) (mAb IB4) and to its endothelial cell ligand ICAM-1 (mAb RR1/1) were used to examine the role of PMN adhesion in the TNF(alpha)-induced responses. Pretreatment of PMN with mAb IB4 prevented PMN uptake and increases in P(paBAR), P(capBAR), K(f,c), and W/D ratio. Addition of mAb RR1/1 to the perfusate reduced PMN uptake by 58%, and prevented the increases in P(paBAR), P(capBAR), K(f,c), and W/D ratio, as with mAb IB4. The findings indicate that TNF(alpha) prestimulation of lungs mediates PMN uptake and that this requires the expression of ICAM-1 and its interaction with CD18 integrin on PMN. The activation of PMN sequestered by ICAM-1-dependent mechanism contributes to the development of pulmonary vascular injury and edema.