title: Increased eicosanoid levels in the Sugen/chronic hypoxia model of severe pulmonary hypertension.
abstract: Inflammation and altered immunity are recognized components of severe pulmonary arterial hypertension in human patients and in animal models of PAH. While eicosanoid metabolites of cyclooxygenase and lipoxygenase pathways have been identified in the lungs from pulmonary hypertensive animals their role in the pathogenesis of severe angioobliterative PAH has not been examined. Here we investigated whether a cyclooxygenase-2 (COX-2) inhibitor or diethylcarbamazine (DEC), that is known for its 5-lipoxygenase inhibiting and antioxidant actions, modify the development of PAH in the Sugen 5416/hypoxia (SuHx) rat model. The COX-2 inhibitor SC-58125 had little effect on the right ventricular pressure and did not prevent the development of pulmonary angioobliteration. In contrast, DEC blunted the muscularization of pulmonary arterioles and reduced the number of fully obliterated lung vessels. DEC treatment of SuHx rats, after the lung vascular disease had been established, reduced the degree of PAH, the number of obliterated arterioles and the degree of perivascular inflammation. We conclude that the non-specific anti-inflammatory drug DEC affects developing PAH and is partially effective once angioobliterative PAH has been established.
authors.affiliation: Pulmonary and Critical care Medicine Division, Victoria Johnson Center for Lung Research, Richmond, Virginia, United States of America; Department of Internal Medicine, Montefiore Mount Vernon Hospital, Westchester, New York, United States of America.
authors.forename: Aysar
authors.initials: A
authors.lastname: Al-Husseini
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University-School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Dayanjan S
authors.initials: DS
authors.lastname: Wijesinghe
authors.affiliation: Pulmonary and Critical care Medicine Division, Victoria Johnson Center for Lung Research, Richmond, Virginia, United States of America.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Farkas
authors.affiliation: Pulmonary and Critical care Medicine Division, Victoria Johnson Center for Lung Research, Richmond, Virginia, United States of America.
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.affiliation: Pulmonary and Critical care Medicine Division, Victoria Johnson Center for Lung Research, Richmond, Virginia, United States of America.
authors.forename: Jennifer I
authors.initials: JI
authors.lastname: Drake
authors.affiliation: Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Van Tassel
authors.affiliation: Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University-School of Medicine, Richmond, Virginia, United States of America; Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia, United States of America; The Massey Cancer Center, Richmond, Virginia, United States of America; Virginia Commonwealth University Reanimation Engineering Science Center (VCURES), Richmond, Virginia, United States of America.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
authors.affiliation: Pulmonary and Critical care Medicine Division, Victoria Johnson Center for Lung Research, Richmond, Virginia, United States of America.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004049:Diethylcarbamazine / Q000494:pharmacology*; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000860:Hypoxia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007249:Inflammation; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D011460:Prostaglandins F / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016278:Ventricular Function, Right / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D011460:Prostaglandins F; D011720:Pyrazoles; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D013929:Thromboxane B2; D017998:Leukotriene D4; D015237:Dinoprost; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015232:Dinoprostone; D004049:Diethylcarbamazine; C100006:prostaglandin F1