alpha-melanocyte-stimulating hormone gene transfer attenuates inflammation after bile duct ligation in the rat.
Cholestasis occurs in a wide variety of human liver diseases, and hepatocellular injury is an invariant feature of cholestasis causing liver dysfunction and inflammation, promoting fibrogenesis, and ultimately leading to liver failure. alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent anti-inflammatory agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation. The aim of this study was to investigate whether the gene transfer of alpha-MSH could attenuate hepatic inflammation after bile duct ligation in the rat. Studies were performed in bile duct-ligated (BDL) rats. Hydrodynamic-based gene transfection with alpha-MSH plasmid via rapid tail vein injection was performed 30 min after ligation of bile duct. The endpoints were studied as markers of inflammation 7 days after bile duct ligation. alpha-MSH expression in liver via a single administration of naked plasmid was demonstrated. Liver inflammation index, including neutrophil infiltration and serum alanine aminotransferase, were significantly reduced in alpha-MSH gene transfer rats. Markers for liver inflammation, including expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and inducible NO synthase (iNOS) mRNA, as assessed by real-time PCR, were also attenuated by alpha-MSH gene therapy. Expression of iNOS protein in liver diminished after alpha-MSH gene transfer. Consistent with these data, hepatic stellate cells (HSC) and Kupffer cells were markedly inhibited in alpha-MSH gene-treated rats. Our findings show that gene transfer of alpha-MSH could attenuate hepatic inflammation after bile duct ligation in the rat.
Wang
Chien-Che
CC
Department of Surgery, PoJen General Hospital, Taipei, Taiwan.
Lin
Jia-Wei
JW
Lee
Liang-Ming
LM
Lin
Chien-Min
CM
Chiu
Wen-Ta
WT
Pai
Hsin-Te
HT
Hung
Kuo-Sheng
KS
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001651:Cholestasis, Extrahepatic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003135:Common Bile Duct / Q000601:surgery; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000097:blood; D007728:Kupffer Cells / Q000378:metabolism; D008026:Ligation; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000097:blood; D010957:Plasmids; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D000521:alpha-MSH; D052247:Nitric Oxide Synthase Type II; D000410:Alanine Transaminase