Chronic nicotine exposure stimulates biliary growth and fibrosis in normal rats

Abstract

Background: Epidemiological studies have indicated smoking to be a risk factor for the progression of liver diseases. Nicotine is the chief addictive substance in cigarette smoke and has powerful biological properties throughout the body. Nicotine has been implicated in a number of disease processes, including increased cell proliferation and fibrosis in several organ systems. Aims: The aim of this study was to evaluate the effects of chronic administration of nicotine on biliary proliferation and fibrosis in normal rats. Methods: In vivo, rats were treated with nicotine by osmotic minipumps for two weeks. Proliferation, α7-nicotinic receptor (α7-nAChR) and profibrotic expression were evaluated in liver tissue, cholangiocytes and a polarized cholangiocyte cell line (NRIC). Nicotine-dependent activation of the Ca2+/IP3/ERK 1/2 intracellular signaling pathway was also evaluated in NRIC. Results: Cholangiocytes express α7-nAChR. Chronic administration of nicotine to normal rats stimulated biliary proliferation and profibrotic gene and protein expression such as alpha-smooth muscle actin (α-SMA) and fibronectin 1 (FN-1). Activation of α7-nAChR stimulated Ca2+/ERK1/2-dependent cholangiocyte proliferation. Conclusion: Chronic exposure to nicotine contributes to biliary fibrosis by activation of cholangiocyte proliferation and expression of profibrotic genes. Modulation of α7-nAChR signaling axis may be useful for the management of biliary proliferation and fibrosis during cholangiopathies.

Regulators of Cholangiocyte Proliferation

“…In a recent study, Jensen et al demonstrated that cholangiocytes express the α7 nicotinic acetylcholine receptor (α7-nAChR) 119 . Chronic stimulation of this receptor with nicotine in rats using osmotic minipumps for 2 weeks stimulated ERK1/2-dependent cholangiocyte proliferation and expression of fibrotic genes, such as fibronectin-1 and α-smooth muscle actin 119 .…”

“…In a recent study, Jensen et al demonstrated that cholangiocytes express the α7 nicotinic acetylcholine receptor (α7-nAChR) 119 . Chronic stimulation of this receptor with nicotine in rats using osmotic minipumps for 2 weeks stimulated ERK1/2-dependent cholangiocyte proliferation and expression of fibrotic genes, such as fibronectin-1 and α-smooth muscle actin 119 . Further stud ies are needed to determine how chronic nicotine exposure correlates with cholestatic liver injury and cholangiopathies, but these results demonstrate that environmental exposures may also contribute to cholangiocyte proliferation and fibrosis.…”

Effects of Smoking on Pegylated Interferon alpha 2a and First Generation Protease Inhibitor-based Antiviral Therapy in Naïve Patients Infected with Hepatitis C Virus Genotype 1

“…Fibrosis progression and advanced fibrosis are negative predictors for SVR [20,21]. Although smoking is associated with an increased risk of liver cirrhosis independent of alcohol intake, APRI was comparable between S and NS, suggesting that smoking had no substantial impact on fibrosis in our cohort [13][14][15]. Nevertheless, APRI score > 1.5 was a highly significant negative predictor for SVR in DT.…”

“…Tobacco and nicotine induce fibrogenic changes and smoking is associated with an increased risk of liver cirrhosis independent of alcohol intake [13][14][15][16]. In HCV positive patients, smoking leads to a significantly higher risk for the development of HCC [17][18][19].…”

Nicotine Alters the Proteome of Two Human Pancreatic Duct Cell Lines

“…Nicotine is readily absorbed by the lungs as well as other, more distal organs via systemic circulation [9]. Nicotine interacts with a population of nicotinic acetylcholine receptors (nAChR), with varying affinities and downstream effectors [10] and as such is as a contributing factor to myocardial [11, 12] , atrial [13], pulmonary [14, 15] and biliary fibrosis [16] diseases. The binding of nicotine to cell surface receptors transduces extracellular signals to the intracellular space resulting in ion transport and/or initiation of phosphorylation cascades and other signaling pathways [17-19].…”