Lipoxygenase products induce neutrophil activation and increase endothelial permeability after thrombin-induced pulmonary microembolism.
We examined the mechanism of the neutrophil (PMN)-dependent increase in pulmonary vascular permeability to protein after thrombin-induced pulmonary microembolism. Humoral factors that activate PMNs after thrombin-induced pulmonary microembolism were characterized in pulmonary lymph obtained from unanesthetized sheep challenged with intravenous infusion of alpha-thrombin. Time-dependent increases in PMN migration, aggregation, and superoxide anion (O2-) generation were induced by the pulmonary lymph obtained within 20 minutes after thrombin infusion. The pulmonary lymph neutrophil activating factors present in ether extracts of lymph had retention times of leukotriene B4 (LTB4) and monohydroxyeicosatetraenoic acids (HETEs) by high-performance liquid chromatography. The postthrombin lymph samples containing the LTB4 and HETEs increased PMN O2- generation and endothelial monolayer permeability to 125I-albumin in the presence of PMNs layered on the endothelial monolayers. Control lymph samples replete with LTB4, 5-HETE, and 15-HETE induced increases in PMN O2- generation and endothelial monolayer permeability to 125I-albumin in the presence of PMNs layered on the endothelial monolayers. Maximal increases in PMN O2- production and endothelial permeability occurred when LTB4, 5-HETE, and 15-HETE were coincubated with PMNs, indicating a synergistic action of these mediators in inducing PMN activation. Endothelial monolayer permeability to 125I-albumin did not increase with postthrombin lymph samples obtained after pretreatment with the 5-lipoxygenase inhibitor, L-651,392. The results indicate that lipoxygenase products generated in the lungs after thrombin-induced microembolism contribute to increased endothelial permeability secondary to PMN activation.
Perlman
M B
MB
Department of Pediatrics, Albany Medical College, Union University, New York.
Johnson
A
A
Jubiz
W
W
Malik
A B
AB
D000818:Animals; D002199:Capillary Permeability; D008084:Lipoxygenase / Q000378:metabolism*; D008196:Lymph / Q000032:analysis / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D010640:Phenothiazines / Q000494:pharmacology; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D012709:Serum Albumin / Q000493:pharmacokinetics; D012756:Sheep; D013917:Thrombin
D010640:Phenothiazines; D012709:Serum Albumin; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one; D008084:Lipoxygenase; D013917:Thrombin