title: Down-regulation of common NFκB-iNOS pathway by chronic Thalidomide treatment improves Hepatopulmonary Syndrome and Muscle Wasting in rats with Biliary Cirrhosis.
abstract: Thalidomide can modulate the TNFα-NFκB and iNOS pathway, which involve in the pathogenesis of hepatopulmonary syndrome (HPS) and muscle wasting in cirrhosis. In bile duct ligated-cirrhotic rats, the increased circulating CD16+(inflammatory) monocytes and its intracellular TNFα, NFκB, monocyte chemotactic protein (MCP-1) and iNOS levels were associated with increased circulating MCP-1/soluable intercellular cell adehesion molecule-1 (sICAM-1), pulmonary TNFα/NOx, up-regulated M1 polarization, exacerbated angiogenesis and hypoxemia (increased AaPO2) in bronchoalveolar lavage (BAL) fluid and pulmonary homogenates. Meanwhile, a significant correlation was noted between circulating CD16+monocyte/M1 (%) macrophages in BAL; M1 (%) macrophages in BAL/pulmonary iNOS mRNA expression; pulmonary iNOS mRNA expression/relative pulmonary MVD; pulmonary NOx level/AaPO2; circulating CD16+monocyte/M1 (%) macrophages in muscle homogenates; 3-nitrotyrosine (representative of peroxynitrite) concentration/M1 (%) macrophages in muscle homogenates. The in vitro data demonstrated an iNOS-dependent inhibition of thalidomide on the TNFα-stimulated angiogenesis and myogenesis in human pulmonary artery endothelial cells (HPAECs) and C2C12 myoblasts. Significantly, the co-culture of CD16+monocyte from different rats with HPAECs, or co-culture of supernatant of above mixed cultures with HPAECs or C2C12 myoblasts stimulated angiogenesis, migration and myogenesis. Our findings demonstrate that TNFα inhibitor thalidomide markedly diminishes the severity of experimental HPS and muscle wasting by down-regulation of common peripheral and local NFκB-iNOS pathway.
authors.affiliation: Division of Allergy and Immunology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Chiayi Branch, Taichung Veterans General Hospital, No. 600, Sec. 2, Shixian Rd., West District, Chiayi City, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, No. 155, Sec. 2, Linong St., Taipei, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Li
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.
authors.forename: Pei-Chang
authors.initials: PC
authors.lastname: Lee
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.
authors.forename: Kuei-Chuan
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Division of Allergy and Immunology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.
authors.forename: Chang-Youh
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, No. 155, Sec. 2, Linong St., Taipei, Taiwan.|Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.|Division of General Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.|Division of Infection Diseases, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.
authors.forename: Shiang-Fen
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.|Institute of Traditional Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, No. 155, Sec. 2, Linong St., Taipei, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.|Genomics Research Center, Academia Sinica, 128 Sec. 2, Academia Rd., Nankang, Taipei City, Taiwan.
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Hou
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.|Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.|Cheng Hsin General Hospital, No. 45, Cheng Hsin St., Beitou District, Taipei.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020065:Hepatopulmonary Syndrome / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018932:Chemokine CCL2; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat