title: Downregulation of osteopontin is associated with fluoxetine amelioration of monocrotaline-induced pulmonary inflammation and vascular remodelling.
abstract: 1. Osteopontin (OPN) has emerged as a key factor in inflammatory activation and cardiovascular remodelling. The aim of the present study was to investigate the involvement of OPN in fluoxetine amelioration of monocrotaline (MCT)-induced pulmonary inflammation and vascular remodelling in rats. 2. Wistar rats were divided into control, MCT and two fluoxetine-treated groups. Pulmonary arterial hypertension (PAH) was induced by a single injection of MCT (60 mg/kg, i.p.). Fluoxetine (2 and 10 mg/kg) was administered via the intragastric route once a day for 21 days. On Day 22, pulmonary haemodynamic measurements were undertaken, followed by ELISA, western blotting and immunohistochemistry. 3. Monocrotaline caused pulmonary inflammation and vascular remodelling and significantly enhanced OPN expression in the plasma, lungs and pulmonary arteries. Fluoxetine decreased pulmonary arterial pressure and ameliorated pulmonary inflammation and pulmonary vascular remodelling. At 10 mg/kg, fluoxetine significantly inhibited MCT-induced increases in the expression of serotonin transporter (SERT) and phosphorylated extracellular signal-regulated kinase 1/2 and downregulated the expression of OPN, macrophage inflammatory protein-1β and matrix metalloproteinase 2/tissue inhibitor of metalloproteinase 2. Although 2 mg/kg fluoxetine tended to ameliorate some MCT-induced changes in the lung, the differences did not always reach statistical significance. Linear regression analysis showed that there was a positive correlation between plasma OPN concentrations and mean pulmonary arterial pressure, as well as percentage medial wall thickness and percentage wall area in the pulmonary artery. 4. In conclusion, the amelioration by fluoxetine of MCT-induced pulmonary inflammation and vascular remodelling is associated with downregulation of OPN expression in rats.
authors.affiliation: Department of Clinical Pharmacology, China Medical University, Shenyang, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Han
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.forename: Huai-Liang
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008168:Lung / Q000098:blood supply*; D008171:Lung Diseases / Q000139:chemically induced*; D016686:Monocrotaline / Q000633:toxicity*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D011920:Rats, Inbred WF; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D005473:Fluoxetine; D016686:Monocrotaline; D053495:Osteopontin; D017367:Selective Serotonin Reuptake Inhibitors