title: PAF potentiates protamine-induced lung edema: role of pulmonary venoconstriction.
abstract: We studied the synergistic interaction between platelet-activating factor (PAF) and protamine sulfate, a cationic protein that causes pulmonary endothelial injury, in isolated rat lungs perfused with a physiological salt solution. A low dose of protamine (50 micrograms/ml) increased pulmonary artery perfusion pressure (Ppa) but did not increase wet lung-to-body weight ratio after 20 min. Pretreatment of the lungs with a noninjurious dose of PAF (1.6 nM) 10 min before protamine markedly potentiated protamine-induced pulmonary vasoconstriction and resulted in severe lung edema and increased lung tissue content of 6-keto-prostaglandin F1 alpha, thromboxane B2, and leukotriene C4. Pulmonary microvascular pressure (Pmv), measured by double occlusion, was markedly increased in lungs given PAF and protamine. These potentiating effects of PAF were blocked by WEB 2086 (10(-5) M), a specific PAF receptor antagonist. Pretreatment of the lungs with a high dose of histamine (10(-4) M) failed to enhance the effect of protamine on Ppa, Pmv, or wet lung-to-body weight ratio. Furthermore, PAF pretreatment enhanced elastase-, but not H2O2-, induced lung edema. To assess the role of hydrostatic pressure in edema formation, we compared lung permeability-surface area products (PS) in papaverine-treated lungs given either protamine alone or PAF + protamine and tested the effect of mechanical elevation of Pmv on protamine-induced lung edema. In the absence of vasoconstriction, PAF did not potentiate protamine-induced increase in lung PS. On the other hand, mechanically raising Pmv in protamine-treated lungs to a level similar to that measured in lungs given PAF + protamine did not result in a comparable degree of lung edema. We conclude that PAF potentiates protamine-induced lung edema predominantly by enhanced pulmonary venoconstriction. However, a pressure-independent effect of PAF on lung vasculature cannot be entirely excluded.
authors.affiliation: Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
authors.forename: C R
authors.initials: CR
authors.lastname: Chen
authors.forename: N F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: S W
authors.initials: SW
authors.lastname: Chang
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004357:Drug Synergism; D066298:In Vitro Techniques; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D011479:Protamines / Q000008:administration & dosage / Q000633:toxicity*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D011479:Protamines; D014230:Triazoles; C052518:WEB 2086