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-pituitaryadrenal (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 ␣-naphthylisothiocyanate (ANIT) intoxication. The HPA axis was suppressed by inhibition of hypothalamic corticotropinreleasing 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.corticotropin-releasing hormone; glucocorticoids; biliary epithelium; adrenocorticotropic hormone CHOLANGIOCYTES ARE EPITHELIAL cells that line the intra-and extrahepatic bile ducts. They are constitutively mitotically dormant but possess marked proliferative capacity (2), which is apparent during experimental conditions, such as cholestasis induced by bile duct ligation (BDL) or ␣-naphthylisothiocyanate (ANIT) intoxication (1), as well as in human cholangiopathies (2). In humans, cholangiocyte proliferation occurs in extrahepatic biliary obstruction, in the course of chronic cholestatic liver diseases (e.g., primary sclerosing cholangitis, primary biliary cirrhosis, liver allograft rejection, and graft-vs.-host disease) (2), and in many forms of liver injury (e.g., in response to alcohol, toxin, or drugs) (2, 43).The hypothalamic-pituitary-adrenal (HPA) axis describes a complex set of positive-and negative-feedback influences between the hypothalamus, pituitary gland, and adrenal gland (25). These feedforward and feedback mechanisms work in a neuroendocrine manner to modulate a number of physiological processes, such as immunity (32), digestion (30), and the body's response to stress (30). In addition, the HPA axis has been shown to have an influence on human psychology (7, 53).The mechanism by which the HPA axis rem...

Gulf war illness-related chemicals increase CD11b/c+ monocyte infiltration into the liver and aggravate hepatic cholestasis in a rodent model

“…In parallel, we determined the expression of proteins of interest by IHC of paraffin sections of livers by using the VectaStain ABC systems from Vector Labs (Burlingame, CA), as described before 28 . Quantitative determinations were performed by image analysis using ImageJ software.…”

The HPA axis response to critical illness: New study results with diagnostic and therapeutic implications

“…In addition low plasma ACTH and high plasma cortisol levels have been documented during cholestasis (Zietz et al, 2001). Also, it has been shown in a bile-ligated model of cholestasis in the rat that the HPA axis is suppressed at the level of ACTH as well as CRH expression (Quinn et al, 2012). The association between increased bile acids and reduced cortisol metabolizing enzyme expression during critical illness is only suggestive of a possible causal role and should be further investigated in experimental models.…”

Lessons Learned From Vivo-Morpholinos: How to Avoid Vivo-Morpholino Toxicity

“…Fifteen of these studies used a mouse model (2,4,11,13,14,16,21,23-30), with the remaining studies using rats (17-19), newts (22), chicken embryos (7), zebrafish (3,5,6), and amphibians (8,10,20). In the mouse model, it has been shown that intravenous (IV) and intraperitoneal (IP) administration of vivo-morpholinos were equally efficacious, and recent studies have shown success with direct injection in target tissue (17-19). To this point, no toxicity of vivo-morpholinos has been reported in any published study.…”