title: Suppression of the HPA axis during extrahepatic biliary obstruction induces cholangiocyte proliferation in the rat.
abstract: Cholestatic patients often present with clinical features suggestive of adrenal insufficiency. In the bile duct-ligated (BDL) model of cholestasis, the hypothalamic-pituitary-adrenal (HPA) axis is suppressed. The consequences of this suppression on cholangiocyte proliferation are unknown. We evaluated 1) HPA axis activity in various rat models of cholestasis and 2) effects of HPA axis modulation on cholangiocyte proliferation. Expression of regulatory molecules of the HPA axis was determined after BDL, partial BDL, and α-naphthylisothiocyanate (ANIT) intoxication. The HPA axis was suppressed by inhibition of hypothalamic corticotropin-releasing hormone (CRH) expression by central administration of CRH-specific Vivo-morpholinos or by adrenalectomy. After BDL, the HPA axis was reactivated by 1) central administration of CRH, 2) systemic ACTH treatment, or 3) treatment with cortisol or corticosterone for 7 days postsurgery. There was decreased expression of 1) hypothalamic CRH, 2) pituitary ACTH, and 3) key glucocorticoid synthesis enzymes in the adrenal glands. Serum corticosterone and cortisol remained low after BDL (but not partial BDL) compared with sham surgery and after 2 wk of ANIT feeding. Experimental suppression of the HPA axis increased cholangiocyte proliferation, shown by increased cytokeratin-19- and proliferating cell nuclear antigen-positive cholangiocytes. Conversely, restoration of HPA axis activity inhibited BDL-induced cholangiocyte proliferation. Suppression of the HPA axis is an early event following BDL and induces cholangiocyte proliferation. Knowledge of the role of the HPA axis during cholestasis may lead to development of innovative treatment paradigms for chronic liver disease.
authors: Department of Internal Medicine, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
authors: Matthew
authors: M
authors: Quinn
authors: Yoshiyuki
authors: Y
authors: Ueno
authors: Hae Yong
authors: HY
authors: Pae
authors: Li
authors: L
authors: Huang
authors: Gabriel
authors: G
authors: Frampton
authors: Cheryl
authors: C
authors: Galindo
authors: Heather
authors: H
authors: Francis
authors: Darijana
authors: D
authors: Horvat
authors: Matthew
authors: M
authors: McMillin
authors: Sharon
authors: S
authors: Demorrow
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity; D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000494:pharmacology; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D049109:Cell Proliferation; D001651:Cholestasis, Extrahepatic / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000097:blood / Q000494:pharmacology; D006854:Hydrocortisone / Q000097:blood / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D060172:Morpholinos / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D060172:Morpholinos; D015058:1-Naphthylisothiocyanate; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D006854:Hydrocortisone