PAF antagonists inhibit monocrotaline-induced lung injury and pulmonary hypertension.
Lung platelet-activating factor (PAF) levels increased in some rats at 1-3 wk after subcutaneous injection of monocrotaline (MCT). We tested the effect of specific PAF antagonists, WEB 2086 and WEB 2170, on MCT-induced lung injury and subsequent pulmonary hypertension and right ventricular hypertrophy. Treatment with either agent decreased MCT-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk after injection. Treatment with WEB 2170 reduced MCT-induced pulmonary vascular leak at 1 wk after injection, and WEB 2086-treatment exclusively during the early leak phase also decreased MCT-induced right ventricular hypertrophy at 3 wk. Treatment with WEB 2170 between the 3rd and 4th wk after MCT injection inhibited the progression of right ventricular hypertrophy at 4 wk. These results suggest that PAF contributes to the early pulmonary vascular leak, and this leak phase is important for the development of pulmonary hypertension and right ventricular hypertrophy in MCT-treated rats. Furthermore, it appears that PAF action contributes to the maintenance of a chronic inflammatory process that involves the synthesis of other lipid mediators (prostaglandins and leukotrienes) and leads to pulmonary hypertension. We conclude that PAF has a role in the MCT-induced inflammatory lung injury and pulmonary hypertension.
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Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Voelkel
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D000818:Animals; D001381:Azepines / Q000494:pharmacology; D006332:Cardiomegaly / Q000139:chemically induced / Q000517:prevention & control; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D055370:Lung Injury; D008297:Male; D016686:Monocrotaline; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; D016686:Monocrotaline; C063964:bepafant