TNF-alpha release in endotoxemia contributes to neutrophil-dependent pulmonary edema
Horgan, M.J.; Palace, G.P.; Everitt, J.E.; Malik, A.B.
American Journal of Physiology 264(4 Pt 2): H1161-H1165
1993
ISSN/ISBN: 0002-9513 PMID: 8476094 Document Number: 405644
We examined whether the generation of tumor necrosis factor (TNF-alpha) after lipopolysaccharide (LPS) challenge contributes to increases in lung vascular permeability and water content. Guinea pig lungs perfused at constant flow with Ringer-albumin solution (0.5 g/100 ml) were challenged for 120 min with LPS (Escherichia coli; final concentration 33 ng/ml; n = 5). Lung effluent samples were assayed for TNF-alpha activity using the modified L-929 fibroblast cytolytic assay. TNF-alpha concentrations increased in a time-dependent manner with a peak value of 100 +- 20 pg/ml noted 90-120 min after LPS. Human neutrophils (polymorphonuclear leukocytes (PMN; 2 times 10-7)) added to the perfusion solution after endotoxin challenge (n = 5) produced a threefold increase in lung tissue myeloperoxidase (MPO) activity over control values. PMN, added after LPS and activated using phorbol 12-myristate 13-acetate (PMA; 5 times 10-9 M; n = 6), produced three- to sixfold increases in mean pulmonary arterial pressure (P-pa) and pulmonary capillary pressure (P-cap), wet weight-to-dry weight ratio (W/D), and the pulmonary capillary filtration coefficient (K-f,c) over control values (P lt 0.05). Activation of PMN with PMA in non-LPS-challenged lungs produced only threefold increases in P-pa and P-cap and did not change W/D and K-f,c. Infusion of an anti-TNF-alpha antibody before the LPS challenge reduced by apprx 50% the increases in P-pa, P-cap, MPO content, K-fc, and lung wet weight gain (P lt 0.05). Therefore, endotoxin-induced TNF-alpha generation in lungs significantly contributes to pulmonary sequestration of PMN. Activation of the sequestered PMN increases pulmonary vascular permeability and tissue water content.