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LIVER AND BILIARY TRACT

Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells

¹Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, and ²Laboratory of Neurophysiology, University of Barcelona School of Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and ³Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York

Submitted 28 November 2005 ; accepted in final form 6 June 2006

Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through ₁-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca²⁺ concentration ([Ca²⁺]_i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-₁(I) expression were assessed by [³H]thymidine incorporation and quantitative PCR, respectively. NF-B activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed _1A-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed _1A-adrenoceptors. NE induced multiple rapid [Ca²⁺]_i oscillations (Ca²⁺ spikes). Prazosin (₁-blocker) completely prevented NE-induced Ca²⁺ spikes, whereas propranolol (nonspecific -blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-₁(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-B activation. BAY 11-7082, a specific NF-B inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-B and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC.

portal hypertension; collagen; inflammation; catecholamines; liver fibrosis

This article has been cited by other articles:

				S. L. Friedman Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver Physiol Rev, January 1, 2008; 88(1): 125 - 172. [Abstract] [Full Text] [PDF]