Eicosanoids are involved in the permeability changes but not the pulmonary hypertension after systemic activation of complement.
Intravenous injection of the complement activator, cobra venom factor (CVF), produces acute lung injury that is neutrophil-dependent and oxygen radical mediated. Using the ex vivo model of lung perfusion, the current studies were designed to measure the appearance of eicosanoids in relation to the development of pulmonary arterial hypertension and vascular permeability. Inhibitors of the cyclooxygenase and lipoxygenase pathways were also employed to assess the possible role of eicosanoids in these two functional responses. Ten minutes after infusion of CVF, when the pulmonary hypertensive changes were maximal, no increases in eicosanoids could be detected in whole lung lavage fluid (TXB2, 6-keto-PGF1 alpha, LTB4, LTC4) or plasma (TXB2, 6-keto-PGF1 alpha) and the inhibitors failed to affect the pressor response. In contrast, lung injury as defined by increased vascular permeability was temporally associated with the appearance in whole lung lavage fluid of TXB2, LTB4 and LTC4, the presence of which was blocked by the relevant inhibitors. Lung injury was attenuated by both cyclooxygenase and lipoxygenase inhibitors. This effect was not peculiar to the isolated lung model since cyclooxygenase (ibuprofen, indomethacin) and lipoxygenase (nafazatrom, U66,855) inhibitors also attenuated the CVF-induced increased vascular permeability in intact rats. These data suggest that in the model system employed eicosanoid production is linked to increases in lung vascular permeability but not to pulmonary artery hypertension.
Morganroth
M L
ML
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Till
G O
GO
Schoeneich
S
S
Ward
P A
PA
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D002199:Capillary Permeability; D002851:Chromatography, High Pressure Liquid; D003167:Complement Activation; D016861:Cyclooxygenase Inhibitors; D004546:Elapid Venoms / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology*; D007213:Indomethacin / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009284:Naphthols / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D013189:SRS-A / Q000378:metabolism*; D013929:Thromboxane B2 / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D004546:Elapid Venoms; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; D013189:SRS-A; C016310:cobra venom factor; D007975:Leukotriene B4; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C050887:2,3-diethyl-4-methoxy-1-naphthalenol acetate; D007213:Indomethacin