Effect of inhaled lyso-platelet-activating factor on airway microvascular leakage in the guinea pig.
Lyso-platelet-activating factor (PAF), the precursor and metabolite of PAF, is considered inactive, although it may be converted to PAF by airway cells. We have investigated the effects of inhaled lyso-PAF on bronchoconstriction and airway microvascular leakage in anesthetized guinea pigs. Lung resistance (RL) was measured for 6 min after inhalation of lyso-PAF (0.3, 1, and 3 mM; 30 breaths) followed by measurement of extravasation of intravenous Evans blue dye into airway tissues, which was used as an index of airway microvascular leakage. Inhaled lyso-PAF caused an increase in RL and leakage of dye at all airway levels in a dose-dependent fashion, but intravenous lyso-PAF (0.25 mg/kg) had no airway effect. The maximum dose of inhaled lyso-PAF increased RL significantly by approximately 200%. The amount of extravasation of dye induced was 96 +/- 4 (SE) ng/mg of tissue in trachea, 77 +/- 8 ng/mg in main bronchi, and 65 +/- 7 and 25 +/- 1 ng/mg in proximal and distal intrapulmonary airways respectively; these values were all significantly higher (P < 0.01) than control values. These responses were completely abolished by a specific PAF-receptor antagonist WEB-2086 (2 mg/kg iv). Our results show that inhaled lyso-PAF is potent in increasing airway microvascular leakage. The effects of lyso-PAF may result from its metabolic transformation to PAF by lyso-PAF:acetyl-CoA acetyltransferase in the airway.
Sakamoto
T
T
Department of Thoracic Medicine, National Heart and Lung Institute, Royal Brompton Hospital, London, United Kingdom.
Elwood
W
W
Barnes
P J
PJ
Chung
K F
KF
D000280:Administration, Inhalation; D000336:Aerosols; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005070:Evans Blue; D005260:Female; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008244:Lysophosphatidylcholines / Q000008:administration & dosage / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012129:Respiratory Function Tests; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
D000336:Aerosols; D001381:Azepines; D008244:Lysophosphatidylcholines; C029271:O-deacetyl platelet activating factor; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; D005070:Evans Blue