Parallel intestinal and liver injury during early cholestasis in the rat: modulation by bile salts and antioxidants.
Whereas long-term cholestasis results in intestinal alterations and increased permeability to hepatotoxins, the effect of short-term cholestasis is less known and was investigated in bile duct ligated (BDL) rats. In the intestinal mucosa, at Day 7 BDL, total glutathione and protein sulfhydryl contents had decreased, oxidized glutathione levels increased (P<0.05 vs baseline), and a reduced epithelium thickness with dissolving crypt phenomena was observed in 40% of rats. At Day 10, total protein content, glutathione-related enzyme activities, and the transmural electrophysiological activity had decreased (-50%); by contrast, oxidized proteins doubled (P<0.05), and histological changes were extended to 70% of rats. In vitro exposure to taurodeoxycholate at micellar concentrations determined dysepithelization in normal gut but dissolving crypt phenomena and necrosis in cholestatic bowels. In the liver, ongoing cholestasis was associated with early oxidative changes especially in mitochondria, where protein sulfhydryls were decreased and negatively correlated with glutathione-protein mixed disulfides (r=-0.807, P<0.001). Daily oral administration of tauroursodeoxycholate, a hydrophilic bile salt, and glutathione to BDL rats improved intestinal histology, function, and redox state. In conclusion, short-term cholestasis results in distinctive functional, oxidative, and morphological changes of intestinal mucosa, determined increased vulnerability to toxic injury, and parallel hepatic oxidative damage.
Portincasa
Piero
P
Clinica Medica A. Murri, Department of Internal Medicine and Public Medicine, University of Bari Medical School, Policlinico, 70124 Bari, Italy. p.portincasa@semeiotica.uniba.it
Grattagliano
Ignazio
I
Testini
Mario
M
Caruso
Maria Lucia
ML
Wang
David Q-H
DQ
Moschetta
Antonio
A
Calamita
Giuseppe
G
Vacca
Michele
M
Valentini
Anna Maria
AM
Renna
Giuseppe
G
Lissidini
Germana
G
Palasciano
Giuseppe
G
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001647:Bile Acids and Salts / Q000627:therapeutic use*; D001652:Bile Ducts / Q000502:physiology; D002779:Cholestasis / Q000150:complications*; D004195:Disease Models, Animal; D019803:Glutathione Disulfide / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000293:injuries*; D008099:Liver / Q000187:drug effects* / Q000293:injuries; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D001647:Bile Acids and Salts; D019803:Glutathione Disulfide