Suppression of the HPA axis during extrahepatic biliary obstruction induces cholangiocyte proliferation in the rat

BACKGROUND: 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. AIMS: We evaluated (i) HPA axis activity in various rat models of cholestasis and (ii) the effects of HPA axis modulation on cholangiocyte proliferation. METHODS: The 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 inhibiting hypothalamic corticotropin releasing hormone (CRH) expression by central administration of CRH-specific Vivo-morpholinos, or by adrenalectomy. Cholangiocyte proliferation was assessed. Following BDL, the HPA axis was reactivated by (i) central administration of CRH; (ii) systemic adrenocorticotropin hormone (ACTH) treatment; or (iii) treatment with cortisol or corticosterone for 7 days post-surgery. Cholangiocyte proliferation was assessed. RESULTS: 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 to sham and after 2 weeks of ANIT feeding. The experimental suppression of the HPA axis increased cholangiocyte proliferation shown by increased CK-19 and PCNA positive cholangiocytes. Conversely, restoring HPA axis activity inhibited BDL-induced cholangiocyte proliferation. CONCLUSION: 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 the development of innovative treatment paradigms for chronic liver disease.