TY - JOUR
T1 - Parallel intestinal and liver injury during early cholestasis in the rat
T2 - Modulation by bile salts and antioxidants
AU - Portincasa, Piero
AU - Grattagliano, Ignazio
AU - Testini, Mario
AU - Caruso, Maria Lucia
AU - Wang, David Q H
AU - Moschetta, Antonio
AU - Calamita, Giuseppe
AU - Vacca, Michele
AU - Valentini, Anna Maria
AU - Renna, Giuseppe
AU - Lissidini, Germana
AU - Palasciano, Giuseppe
N1 - Funding Information:
This research was supported in part by the FIRB National Grant (Fondo per gli Investimenti della Ricerca di Base) from Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), Roma and Fondi Progetto Ateneo 2004/2005, University of Bari Medical School. P.P. was a recipient of the Short Term Mobility Grant 2005 (Harvard Medical School, Boston, MA) from the Centro Nazionale delle Ricerche (CNR, Roma, Italy). The authors are indebted to Michele Persichella, Rosa De Venuto, Paola De Benedictis, Claudia Curci and Laura Castellano for skillful technical assistance.
PY - 2007/5/1
Y1 - 2007/5/1
N2 - 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.
AB - 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.
KW - Bile duct ligation
KW - Bile salts
KW - Extrahepatic cholestasis
KW - Glutathione
KW - Intestinal mucosa
KW - Mitochondria
KW - Protein sulfhydryls
KW - Protein-glutathione mixed disulfides
KW - Ussing chamber
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U2 - 10.1016/j.freeradbiomed.2007.01.039
DO - 10.1016/j.freeradbiomed.2007.01.039
M3 - Article
C2 - 17395011
AN - SCOPUS:33947609744
SN - 0891-5849
VL - 42
SP - 1381
EP - 1391
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 9
ER -