Soluble N-ethylmaleimide-sensitive factors attachment protein receptors (SNAREs), initially found to mediate membrane fusion, have now been shown to also bind and regulate a number of membrane ion channels in neurones and neuroendocrine cells. We recently reported that the SNARE protein SNAP-25 regulates Ca(2+)- activated (K(Ca)) and delays rectifier K(+) channels (K(V)) in oesophageal smooth muscle cells. This raised the possibility that cognate and other SNARE proteins could also be present in the oesophageal smooth muscle cell to regulate these and other functions. Circular muscle tissue sections and single freshly isolated muscle cells from the oesophageal body circular and longitudinal layers, and from lower oesophageal sphincter clasp and sling regions were studied. The subcellular location of SNAP-23, SNAP-25, syntaxins 1 to 4, and vesicle-associated membrane protein (VAMP)-2 were explored using a laser scanning confocal imaging system. Feline oesophageal smooth muscle of all regions examined demonstrated the presence of SNAP-23, SNAP-25, syntaxins 1 to 4, and VAMP-2 on the plasma membrane. The intensity of these syntaxins and SNAP-25/-23 proteins varied between the different muscle groups of the oesophagus. In some regions, some SNARE proteins were also noted in the muscle cell cytoplasm. No differential expression was found for VAMP-2. The differential expression of SNAP-25 and its regulation of K(+) channels indicate the important role of SNAP-25 in regulating the distinct membrane excitability and contractility along the smooth muscle of the oesophagus. This is further contributed by its interactions with the cognate syntaxins, which are also differentially expressed in the muscle groups of the oesophageal body and lower oesophageal sphincter (LOS). These SNARE proteins probably have other functions in the smooth muscle cell, such as regulating vesicular transport processes.
Ductopenia is often regarded as a chronic process where ≥50% of portal
tracts lack bile ducts, which is also known as vanishing bile duct
syndrome (VBDS). One etiology is drug-induced liver injury. Cloxacillin,
an anti-staphylococcal penicillin, typically causes “bland”
cholestasis. We present the first case of cloxacillin-induced acute
ductopenia or VBDS and a review of published cloxacillin-induced liver
injuries. A 66-year-old woman with no prior liver disease, but known
penicillin allergy, was treated for post-carotid angioplasty
staphylococcal infection with 6 weeks of cloxacillin. She presented with
a two-week history of weakness and jaundice. Laboratory work-up showed
elevated liver enzymes, hyperbilirubinemia, and eosinophilia. She
required ICU transfer for hypotension and was started empirically on
prednisone. Liver biopsy revealed severe centrilobular cholestasis, mild
necroinflammation, and ductopenia with epithelial injury, but no
ductular reaction. Two-months later, she was discharged on
hydrocortisone and ursodiol with persistently elevated alkaline
phosphatase and bilirubin. She was considered for liver transplantation
but died of liver failure four months later. Four additional articles
were found with histopathologic descriptions of cloxacillin-related
liver injury. These included portal inflammation, cholestasis and mild
necroinflammation. Clinical features were reported in two cases; both
had mild symptoms with cholestatic liver enzymes and hyperbilirubinemia.
Both patients recovered completely within 10-60 days.
Cloxacillin-induced cholestasis can be secondary to acute ductopenia,
which can result in worse clinical outcomes than previously described
“bland” cholestasis. Liver biopsy is recommended to identify cases
with acute VBDS.
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