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...

1. Suppressing apoptosis and downregulating K(+) channels in pulmonary artery smooth muscle cells (PASMC) have been implicated in the development of pulmonary vascular medial hypertrophy and pulmonary arterial hypertension (PAH). Previous studies have shown that selective serotonin re-uptake inhibitors (SSRIs) protected against PAH. The aim of the present study was to investigate the involvement of Kv1.5 channels and apoptosis in the protective effect of the SSRI fluoxetine against PAH. 2. Monocrotaline (MCT) was used to establish PAH in Wistar rats. Fluoxetine (2 and 10 mg/kg per day) was administered by gavage once a day for 3 weeks. Three weeks after the induction of PAH by MCT, pulmonary haemodynamic measurements and pulmonary artery morphological assessments were undertaken, along with detection of apoptosis and Kv1.5. 3. Fluoxetine (2 and 10 mg/kg per day) decreased pulmonary artery pressure, reduced the right ventricular index and inhibited the increase in medial wall thickness of pulmonary arteries in established PAH. Fluoxetine (10 mg/kg per day) reduced the expression of Bcl-2 and Bcl-xL protein, increased the expression of cleaved caspase 3 protein and enhanced the expression of Kv1.5 protein and mRNA in pulmonary arteries. Furthermore, fluoxetine (10 mg/kg per day) significantly suppressed proliferation and enhanced apoptosis of PASMC in MCT-induced PAH. 4. In conclusion, fluoxetine protects against MCT-induced PAH by suppressing PASMC proliferation, inducing PASMC apoptosis and upregulating Kv1.5 channels.

The present study was performed to investigate the effects of 4-chloro-DL-phenylalanine (PCPA), a tryptophan hydroxylase (Tph) inhibitor (TphI), on pulmonary vascular remodeling and lung inflammation in monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Animal models of PAH were established using Sprague-Dawley (SD) rats by a single intraperitoneal injection of MCT (60 mg/kg). PCPA (50 or 100 mg/kg/day) was administered to the rats with PAH. On day 22, hemodynamic measurements and morphological observations of the lung tissues were performed. The levels of Tph-1 and serotonin transporter (SERT) in the lungs were analyzed by immunohistochemistry and western blot analysis. The expression of matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 and inflammatory cytokines were assayed by western blot analysis. The activity of MMP-2 and MMP-9 was evaluated by gelatin zymography (GZ). MCT markedly promoted PAH, increased the right ventricular hypertrophy index, pulmonary vascular remodeling, lung inflammation and mortality, which was associated with the increased expression of Tph-1, SERT, MMP-2/-9, TIMP-1/-2 and inflammatory cytokines. PCPA markedly attenuated MCT-induced pulmonary vascular remodeling and lung inflammation, inhibited the expression of Tph-1 and SERT and suppressed the expression of MMP-2/-9, TIMP-1/-2, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1). These findings suggest that the amelioration of MCT-induced pulmonary vascular remodeling and lung inflammation by PCPA is associated with the downregulation of Tph-1, SERT, MMP/TIMP and inflammatory cytokine expression in rats.

The Mann-Kendall test, composite analysis, and 68 high-quality meteorological stations were used to explore the spatiotemporal variations and causes of precipitation extremes over the Yellow River basin (YRB) during the period of 1960-2011. Results showed that (a) the YRB is characterized by decreases of most precipitation indices, excluding the simple daily intensity index, which has increasing trends in most locations, suggesting that the intensity of rainfall and the probability of occurrence of droughts have increased during the last decades. (b) Trends of extreme precipitation show mixed patterns in the lower reach of the YRB, where droughtflood disasters have increased. The increases in heavy rainfall and decreases in consecutive wet days in recent years over the northwestern portions of the YRB indicate that the intensity and frequency of above-normal precipitation have been trending upward in domains. In the centralsouth YRB, the maximum 1-day precipitation (RX1day) and precipitation on extremely wet days (R99p) have significantly increased, whereas the number of consecutive dry days has declined; these trends suggest that the intensity of precipitation extremes has increased in those regions, although the frequency of extreme and total rainfall has decreased. (c) The spatial distributions of seasonal trends in RX1day and maximum 5-day precipitation (RX5day) exhibited less spatial coherence, and winter is becoming the wettest season regionwide, particularly over the central-south YRB. (d) There were multiple and overlapping cycles of variability for most precipitation indices, indicating variations of time and frequency. (e) Elevation is intimately correlated with precipitation indices, and a weakening East Asian summer monsoon during 1986-2011 compared to that in 1960-1985 may have played an important role in the declines in most indices over the YRB. Therefore, the combined effects from local and teleconnection forcing factors have collectively influenced the variations in precipitation extremes across the YRB. This study may provide valuable evidence for the effective management of water resources and the conduct of agricultural activities at the basin scale.

1. Serotonin (5-HT), as a type of mitogen for smooth muscle cells, plays an important role in the development of pulmonary hypertension. It is known that selective serotonin re-uptake inhibitors (SSRI) inhibit 5-HT internalization. Therefore, the aim of the present study was to investigate the protective effect and mechanism of the SSRI sertraline against pulmonary hypertension. 2. Monocrotaline (MCT)-induced chronic 'inflammatory' pulmonary hypertension in Wistar rats was established. Pulmonary haemodynamic measurement and lung tissue morphological investigations were undertaken. Serotonin transporter (SERT) mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR). 3. The results showed that pulmonary artery pressure (PAP) was significantly increased by MCT treatment from 12.6 +/- 2.1 to 20.1 +/- 3.4 mmHg (P < 0.01 vs control) and sertraline attenuated the MCT-induced increase in PAP from 20.1 +/- 3.4 to 16.4 +/- 1.8 mmHg (P < 0.05 vs MCT). The right ventricular index was increased in the MCT-treated group from 0.32 +/- 0.04 to 0.51 +/- 0.09 (P < 0.01 vs control) and was reduced to 0.42 +/- 0.04 by sertraline (P < 0.05 vs MCT). The degree of muscularization of the pulmonary artery in the MCT-treated group was significantly higher than control (P < 0.01) and was decreased by sertraline (P < 0.01 vs MCT). The RT-PCR assay showed that MCT increased SERT mRNA expression from 0.86 +/- 0.08 to 0.99 +/- 0.06 (P < 0.05 vs control), which was attenuated by sertraline (0.82 +/- 0.09; P < 0.05 vs MCT). 4. In conclusion, the SSRI sertraline protects against MCT-induced pulmonary hypertension by decreasing PAP, right ventricular index and pulmonary artery remodelling, which may be related to a reduction in SERT mRNA.