Departments of
1 Internal Medicine and
2 Medical Physiology, 5 Division of Research and Education, Scott & White Clinic and The Texas A&M University System Health Science Center, College of Medicine, ...and 3 Central Texas Veterans Health Care System, Temple, Texas 76504; 4 Division of Gastroenterology, Tohoku University School of Med, Aobaku, Sendai 980-8574, Japan; and 6 Division of Gastroenterology, University of Rome, "La Sapienza," Rome 00185, Italy
Submitted 25 October 2002
; accepted in final form 10 March 2003
Tumor necrosis factor (TNF)- plays a critical role in epithelial
cell injury. However, the role of TNF- in mediating cholangiocyte
injury under physiological or pathophysiological conditions is unknown. Thus
we assessed the effects of TNF- alone or following sensitization by
actinomycin D on cell apoptosis, proliferation, and basal and
secretin-stimulated ductal secretion in cholangiocytes from normal or bile
duct-ligated (BDL) rats. Cholangiocytes from normal or BDL rats were highly
resistant to TNF- alone. However, presensitization by actinomycin D
increased apoptosis in cholangiocytes following BDL and was associated with an
inhibition of proliferation and secretin-stimulated ductal secretion. Thus
TNF- mediates cholangiocyte injury and altered ductal secretion
following bile duct ligation. These observations suggest that cholestasis may
enhance susceptibility to cytokine-mediated cholangiocyte injury.
bile flow; intrahepatic biliary epithelium; proliferation; secretin
Address for reprint requests and other correspondence: T. Patel, Division of
Gastroenterology, Scott & White Clinic, Texas A&M Univ. System Health
Science Center College of Medicine, 2401 South 31st St., Temple, TX 76502
(E-mail:
tpatel{at}medicine.tamu.edu ).
Cholestatic liver diseases represent a major public health concern leading to liver transplantation or mortality. The role of sensory innervation and neuropeptides in the regulation of liver ...physiology and cholestatic liver disease pathogenesis has not been studied thoroughly. In our study, we demonstrated that α-CGRP-positive sensory innervation plays a key role in the regulation of cholangiocyte proliferation and biliary mass during cholestasis induced by extrahepatic bile duct obstruction (BDL). We have shown that cholestasis induces proliferation of cholangiocytes with a dramatic increase in biliary mass, which was associated with concomitant increases circulating levels of CGRP. In vitro, α- and β-CGRP stimulated increased intracellular cAMP levels, activation of PKA and phosphorylation of CREB (Ser-133). Finally, we demonstrated that cholangiocyte proliferation induced by cholestasis was partially ablated in a knockout mouse model lacking the sensory neuropeptide α-CGRP. These findings indicate that sensory innervation of the liver plays a predominant role in the regulation of cholangiocyte proliferation and the pathogenesis of cholestatic liver diseases.
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