Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium.

Rat and human biliary epithelium is morphologically and functionally heterogeneous. As no information exists on the heterogeneity of the murine intrahepatic biliary epithelium, and with increased usage of transgenic mouse models to study liver disease pathogenesis, we sought to evaluate the morphological, secretory, and proliferative phenotypes of small and large bile ducts and purified cholangiocytes in normal and cholestatic mouse models. For morphometry, normal and bile duct ligation (BDL) mouse livers (C57/BL6) were dissected into blocks of 2-4 microm(2), embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Sizes of bile ducts and cholangiocytes were evaluated by using SigmaScan to measure the diameters of bile ducts and cholangiocytes. In small and large normal and BDL cholangiocytes, we evaluated the expression of cholangiocyte-specific markers, keratin-19 (KRT19), secretin receptor (SR), cystic fibrosis transmembrane conductance regulator (CFTR), and chloride bicarbonate anion exchanger 2 (Cl(-)/HCO(3)(-) AE2) by immunofluorescence and western blot; and intracellular cyclic adenosine 3',5'-monophosphate (cAMP) levels and chloride efflux in response to secretin (100 nM). To evaluate cholangiocyte proliferative responses after BDL, small and large cholangiocytes were isolated from BDL mice. The proliferation status was determined by analysis of the cell cycle by fluorescence-activated cell sorting, and bile duct mass was determined by the number of KRT19-positive bile ducts in liver sections. In situ morphometry established that the biliary epithelium of mice is morphologically heterogeneous, with smaller cholangiocytes lining smaller bile ducts and larger cholangiocytes lining larger ducts. Both small and large cholangiocytes express KRT19 and only large cholangiocytes from normal and BDL mice express SR, CFTR, and Cl(-)/HCO(3)(-) exchanger and respond to secretin with increased cAMP levels and chloride efflux. Following BDL, only large mouse cholangiocytes proliferate. We conclude that similar to rats, mouse intrahepatic biliary epithelium is morphologically and functionally heterogeneous. The mouse is therefore a suitable model for defining the heterogeneity of the biliary tree.

The AMA proposal to mandate nicotine reduction in cigarettes: a simulation of the population health impacts.

BACKGROUND: The American Medical Association (AMA) has advocated gradually reducing the nicotine content of cigarettes to decrease smoking prevalence. Some experts have voiced concerns that smokers may "compensate" by smoking more cigarettes or inhaling more deeply. Further, a black market may emerge, perpetuating cigarette availability. Thus, it is unclear whether a federal mandate would result in a net increase or decrease in population health. The purpose of this research is to estimate the long-term health gains or losses that are likely to accrue to the US population if the nicotine content of cigarettes is gradually reduced to trace levels over a 6-year period. METHODS: To estimate health impacts, we created the Tobacco Policy Model, a computer simulation model. The model simulates the US population as they age and change their smoking behavior over time. Secondary data for model parameters were obtained from publicly available sources. Population health impacts were measured as the change in cumulative quality-adjusted life-years (QALYs) in the US population over 50 years. RESULTS: Following a mandate to reduce nicotine, smoking prevalence is likely to decline from 23% to 5% of the population. Accordingly, a cumulative gain of 157 million QALYs is expected over 50 years. CONCLUSIONS: Despite any mortality increases due to compensatory smoking or the emergence of a black market, implementation of the AMA proposal would likely prevent the addiction of scores of new smokers and result in important gains to the nation's health. This research should prove useful to Congress as they contemplate giving the FDA the authority to regulate tobacco.