Aim: To investigate the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine on extracellular matrix (ECM) remodeling of the pulmonary artery and inflammation of the lungs in pulmonary arterial hypertension (PAH) induced by monocrotaline in rats. Methods: MCT-induced chronic PAH was established in Wistar rats. After treatment with fluoxetine for 3 weeks, pulmonary hemodynamic measurement and morphological investigation of lung tissues were undertaken. The main components of the ECM, elastin and collagen, were detected using Van Gieson stain and Orcein stain, respectively, or using Victoria-ponceau's double stain. The ECM proteolytic enzymes matrix metalloproteinase (MMP)-2 and MMP-9, and the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, were detected by Western blot. Inflammation of lung tissue was assayed using lung morphology and inflammatory cytokine expression. Results: Fluoxetine (2 and 10 mg/kg) significantly inhibited MCT-induced PAH, attenuated pulmonary arterial muscularization and ECM remodeling, and decreased MMP/TIMP expression. Fluoxetine also suppressed inflammatory responses in lung tissue and inhibited the expression of the inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein (MCP-1) and intercellular adhesion molecule-1 (ICAM-1). Conclusion: Fluoxetine inhibited MCT-induced ECM remodeling of the pulmonary artery and inflammation of lung tissue. These effects were related to its inhibition on MMPs/TIMPs and cytokine productions.Keywords: extracellular matrix; inflammation; pulmonary arterial hypertension; selective serotonin reuptake inhibitor Acta Pharmacologica Sinica (2011) 32: 217-222; doi: 10.1038/aps.2010 published online 10 Jan 2011 Original Article * To whom correspondence should be addressed. [11,12] . It was reported that the plasma concentration in serotonin was significantly increased in PAH patients [13] . We have previously reported that serotonin induced PASMCs mitogenesis in vitro, and serotonin selective reuptake inhibitor (SSRI) fluoxetine inhibited serotonininduced PASMCs proliferation via blocking SERT [14] . We have also found that SSRI fluoxetine and sertraline protected against pulmonary vascular remodeling by inhibiting pulmonary vascular muscularization in monocrotaline (MCT)-induced pulmonary hypertensive rats [15,16] . However, whether SSRI has a protective effect against ECM remodeling in the pulmonary artery remains unknown.Inflammatory mechanisms play an important role in the development of PAH. It has been demonstrated that lymphocytes and macrophages were present in the vicinity of remodeled pulmonary vessels and that cytokines such as interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) were increased in PAH patients [17][18][19][20] . We have also reported previously that chronic lung inflammation existed in MCT-induced PAH rats [21] . However, several studies have shown that...

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