Local complement activation, thromboxane-mediated vasoconstriction, and vascular leakage in isolated lungs. Role of the terminal complement sequence.
In situ complement activation was induced in isolated, ventilated, and blood-free perfused rabbit lungs. Six to 11% human serum (vol/vol) was repeatedly admixed to the recirculating Krebs Henseleit buffer during 10-min periods, interrupted by rinsing phases with serum-free medium. This caused dose-dependent, reversible, and reproducible pulmonary artery pressor responses with pressure peaks or plateaus of 8 to 22 mm Hg. Pressor responses were paralleled by a marked release of thromboxane (TxA2) and prostaglandin I2 into the medium. Heat-inactivated serum, purified fluid-phase SC5b-9, and serum that had been activated with inulin in the absence or presence of a carboxypeptidase inhibitor all failed to elicit pressor responses. Both pressor response and prostanoid release were strictly dependent on complement factor C8, and evidence for C8 binding was obtained with the use of 125I-C8. Inhibitor studies collectively indicated that TxA2 was the predominant vasoconstrictive agent. Although repetitive short-term application of human serum induced no major lung weight gain, prolonged exposure to serum (40 to 80 min) without intermittent rinsing phases caused a delayed increase in the capillary filtration coefficient to maximally 3- to 4-fold values, with marked lung edema formation. We conclude that in situ activation of complement in the rabbit lung vasculature causes immediate intrapulmonary prostanoid generation and thromboxane-mediated vasoconstriction, independent of circulating leukocytes, but dependent on the formation of terminal membrane-complement complexes. Continuous complement activation results in a delayed increase in lung vascular permeability.
Seeger
W
W
Department of Internal Medicine, Justus-Liebig University, Giessen, Germany.
Hartmann
R
R
Neuhoff
H
H
Bhakdi
S
S
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001769:Blood; D001794:Blood Pressure; D002199:Capillary Permeability; D003167:Complement Activation; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins / Q000502:physiology; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007444:Inulin / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D011652:Pulmonary Circulation; D011817:Rabbits; D013931:Thromboxanes / Q000378:metabolism* / Q000502:physiology; D014655:Vascular Resistance; D014661:Vasoconstriction
D001095:Arachidonic Acids; D015938:Complement Membrane Attack Complex; D013931:Thromboxanes; D016718:Arachidonic Acid; D007444:Inulin; D003165:Complement System Proteins; D011464:Epoprostenol; D007770:L-Lactate Dehydrogenase