title: 4-Chloro-DL-phenylalanine protects against monocrotaline‑induced pulmonary vascular remodeling and lung inflammation.
abstract: 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.
authors: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, P.R. China.
authors: Yang
authors: Y
authors: Bai
authors: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, P.R. China.
authors: Han-Ming
authors: HM
authors: Wang
authors: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, P.R. China.
authors: Ming
authors: M
authors: Liu
authors: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, P.R. China.
authors: Yun
authors: Y
authors: Wang
authors: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, P.R. China.
authors: Guo-Chao
authors: GC
authors: Lian
authors: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, P.R. China.
authors: Xin-Hua
authors: XH
authors: Zhang
authors: National Key Subject, Institute of Respiratory Diseases, China Medical University, Shenyang, P.R. China.
authors: Jian
authors: J
authors: Kang
authors: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, P.R. China.
authors: Huai-Liang
authors: HL
authors: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D065627:Familial Primary Pulmonary Hypertension; D010134:Fenclonine / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016686:Monocrotaline / Q000009:adverse effects*; D010649:Phenylalanine; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy*; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016601:RNA-Binding Proteins; C482440:Sert1 protein, rat; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D010649:Phenylalanine; D016686:Monocrotaline; D014365:Tryptophan Hydroxylase; C504570:tph1 protein, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D010134:Fenclonine