Meconium ileus (MI) is often the first manifestation of cystic fibrosis (CF) and occurs in approximately 20% of patients diagnosed with CF. This article reviews the pathophysiology of MI and its clinical presentation. It focuses on the medical and surgical management emphasizing the importance of nutrition and a multidisciplinary approach to improve both short-term and long-term outcomes for CF patients with MI.

Extracellular ATP represents an important autocrine/paracrine signaling molecule within the liver. The mechanisms responsible for ATP release are unknown, and alternative pathways have been proposed, including either conductive ATP movement through channels or exocytosis of ATP-enriched vesicles, although direct evidence from liver cells has been lacking. Utilizing dynamic imaging modalities (confocal and total internal reflection fluorescence microscopy and luminescence detection utilizing a high sensitivity CCD camera) at different scales, including confluent cell populations, single cells, and the intracellular submembrane space, we have demonstrated in a model liver cell line that (i) ATP release is not uniform but reflects point source release by a defined subset of cells; (ii) ATP within cells is localized to discrete zones of high intensity that are ϳ1 m in diameter, suggesting a vesicular localization; (iii) these vesicles originate from a bafilomycin A 1 -sensitive pool, are depleted by hypotonic exposure, and are not rapidly replenished from recycling of endocytic vesicles; and (iv) exocytosis of vesicles in response to cell volume changes depends upon a complex series of signaling events that requires intact microtubules as well as phosphoinositide 3-kinase and protein kinase C. Collectively, these findings are most consistent with an essential role for exocytosis in regulated release of ATP and initiation of purinergic signaling in liver cells.Extracellular ATP functions within liver as a key autocrine/ paracrine signaling molecule. The purinergic signaling cascade is initiated by release of ATP from intracellular stores, but the mechanisms involved are poorly understood. However, P2 receptors are expressed on all liver cell types, and once outside of the cell ATP has multiple effects, including (i) coordination within the liver lobule of cell-to-cell [Ca 2ϩ ] i signaling (1), (ii) maintenance of cell volume within a narrow physiological range (2), and (iii) coupling of the separate hepatocyte and cholangiocyte contributions to bile formation and stimulation of biliary secretion (3). Specifically, cellular ATP release leads to increased concentrations of ATP in bile sufficient to activate P2 receptors in the apical membrane of targeted cholangiocytes, resulting in a robust secretory response through activation of Cl Ϫ channels in the apical membrane. Moreover, multiple signals including intracellular calcium, cAMP and bile acids appear to coordinate ATP release, which has been recognized recently as a final common pathway responsible for biliary secretion (3-5). Accordingly, definition of the mechanisms involved in ATP release represents a key focus for efforts to modulate liver function and the volume and composition of bile.Previous studies indicate that increases in cell volume serve as a potent stimulus for physiologic ATP release in many epithelia and in liver cells increase extracellular nucleotide concentrations 5-10-fold (6). Two broad models for ATP release by nonexcitatory cells have been...

Adenosine triphosphate (ATP) is released from cholangiocytes into bile and is a potent secretogogue by increasing intracellular Ca 21 and stimulating fluid and electrolyte secretion via binding purinergic (P2) receptors on the apical membrane. Although morphological differences exist between small and large cholangiocytes (lining small and large bile ducts, respectively), the role of P2 signaling has not been previously evaluated along the intrahepatic biliary epithelium. The aim of these studies therefore was to characterize ATP release and P2-signaling pathways in small (MSC) and large (MLC) mouse cholangiocytes. The findings reveal that both MSCs and MLCs express P2 receptors, including P2X4 and P2Y2. Exposure to extracellular nucleotides (ATP, uridine triphosphate, or 2 0 ,3 0 -O-[4-benzoyl-benzoyl]-ATP) caused a rapid increase in intracellular Ca 21 concentration and in transepithelial secretion (I sc ) in both cell types, which was inhibited by the Cl 2 channel blockers 5-nitro-2-(-3-phenylpropylamino)-benzoic acid (NPPB) or niflumic acid. In response to mechanical stimulation (flow/shear or cell swelling secondary to hypotonic exposure), both MSCs and MLCs exhibited a significant increase in the rate of exocytosis, which was paralleled by an increase in ATP release. Mechanosensitive ATP release was two-fold greater in MSCs compared to MLCs. ATP release was significantly inhibited by disruption of vesicular trafficking by monensin in both cell types. Conclusion: These findings suggest the existence of a P2 signaling axis along intrahepatic biliary ducts with the ''upstream'' MSCs releasing ATP, which can serve as a paracrine signaling molecule to ''downstream'' MLCs stimulating Ca 21 -dependent secretion. Additionally, in MSCs, which do not express the cystic fibrosis transmembrane conductance regulator, Ca 21 -activated Cl 2 efflux in response to extracellular nucleotides represents the first secretory pathway clearly identified in these cholangiocytes derived from the small intrahepatic ducts.

ATP in bile is a potent secretogogue, stimulating biliary epithelial cell (BEC) secretion through binding apical purinergic receptors. In response to mechanosensitive stimuli, BECs release ATP into bile, although the cellular basis of ATP release is unknown. The aims of this study in human and mouse BECs were to determine whether ATP release occurs via exocytosis of ATP-enriched vesicles and to elucidate the potential role of the vesicular nucleotide transporter SLC17A9 in purinergic signaling. Dynamic, multiscale, live cell imaging (confocal and total internal reflection fluorescence microscopy and a luminescence detection system with a high sensitivity charge-coupled device camera) was utilized to detect vesicular ATP release from cell populations, single cells, and the submembrane space of a single cell. In response to increases in cell volume, BECs release ATP, which was dependent on intact microtubules and vesicular trafficking pathways. ATP release occurred as stochastic point source bursts of luminescence consistent with exocytic events. Parallel studies identified ATP-enriched vesicles ranging in size from 0.4 to 1 m that underwent fusion and release in response to increases in cell volume in a protein kinase C-dependent manner. Present in all models, SLC17A9 contributed to ATP vesicle formation and regulated ATP release. The findings are consistent with the existence of an SLC17A9-dependent ATPenriched vesicular pool in biliary epithelium that undergoes regulated exocytosis to initiate purinergic signaling.Purinergic signaling has emerged as a dominant pathway regulating biliary secretion and bile formation. Released into bile by both hepatocytes and biliary epithelial cells (known as cholangiocytes) in response to mechanosensitive stimuli (cell swelling and flow/shear stress) (1-3), extracellular ATP activates P2 receptors in the apical membrane of targeted cholangiocytes, resulting in increases in [Ca 2ϩ ] i , activation of K ϩ (4, 5) and Cl Ϫ (6, 7) channels, and a robust secretory response (8). Recent studies suggest that even the classical model of biliary epithelial cell secretion wherein secretin stimulates Cl Ϫ secretion via increases in cAMP is mediated by a pathway regulated by ATP release and autocrine/paracrine stimulation of P2 receptors on the apical cholangiocyte membrane (9, 10). The cellular mechanism of biliary epithelial ATP release has not been identified. Two potential pathways exist: transporter/ channel-mediated or exocytosis of ATP-containing vesicles. Cholangiocytes express several ATP-binding cassette proteins, such as MDR-1 and the cystic fibrosis transmembrane conductance regulator (CFTR) 2 (11, 12), implicated in ATP release. However, the effect of MDR-1 on ATP release can be disassociated from p-glycoprotein-related substrate transport, suggesting that MDR-1 per se is not likely to function as an ATP channel (13). Similarly, despite provocative data that CFTR functions as a regulator of ATP release, many cells exhibit ATP release in the absence of apparent CFTR express...

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