Promoting tobacco through the international language of dance music: British American Tobacco and the Ministry of Sound.

BACKGROUND: Tobacco companies target young adults through marketing strategies that use bars and nightclubs to promote smoking. As restrictions increasingly limit promotions, music marketing has become an important vehicle for tobacco companies to shape brand image, generate brand recognition and promote tobacco. METHODS: Analysis of previously secret tobacco industry documents from British American Tobacco, available at http://legacy.library.ucsf.edu. RESULTS: In 1995, British American Tobacco (BAT) initiated a partnership with London's Ministry of Sound (MOS) nightclub to promote Lucky Strike cigarettes to establish relevance and credibility among young adults in the UK. In 1997, BAT extended their MOS partnership to China and Taiwan to promote State Express 555. BAT sought to transfer values associated with the MOS lifestyle brand to its cigarettes. The BAT/MOS partnership illustrates the broad appeal of international brands across different regions of the world. CONCLUSION: Transnational tobacco companies like BAT are not only striving to stay contemporary with young adults through culturally relevant activities such as those provided by MOS but they are also looking to export their strategies to regions across the world. Partnerships like this BAT/MOS one skirt marketing restrictions recommended by the World Health Organization's Framework Convention on Tobacco Control. The global scope and success of the MOS program emphasizes the challenge for national regulations to restrict such promotions.

The role of SGK and CFTR in acute adaptation to seawater in Fundulus heteroclitus.

Killifish are euryhaline teleosts that adapt to increased salinity by up regulating CFTR mediated Cl(-) secretion in the gill and opercular membrane. Although many studies have examined the mechanisms responsible for long term (days) adaptation to increased salinity, little is known about the mechanisms responsible for acute (hours) adaptation. Thus, studies were conducted to test the hypotheses that the acute homeostatic regulation of NaCl balance in killifish involves a translocation of CFTR to the plasma membrane and that this effect is mediated by serum-and glucocorticoid-inducible kinase (SGK1). Cell surface biotinyation and Ussing chamber studies revealed that freshwater to seawater transfer rapidly (1 hour) increased CFTR Cl(-) secretion and the abundance of CFTR in the plasma membrane of opercular membranes. Q-RT-PCR and Western blot studies demonstrated that the increase in plasma membrane CFTR was preceded by an increase in SGK1 mRNA and protein levels. Seawater rapidly (1 hr) increases cortisol and plasma tonicity, potent stimuli of SGK1 expression, yet RU486, a glucocorticoid receptor antagonist, did not block the increase in SGK1 expression. Thus, in killifish SGK1 does not appear to be regulated by the glucocorticoid receptor. Since SGK1 has been shown to increase the plasma membrane abundance of CFTR in Xenopus oocytes, these observations suggest that acute adaptation (hours) to increased salinity in killifish involves translocation of CFTR from an intracellular pool to the plasma membrane, and that this effect may be mediated by SGK1.

MRP2 and acquired tolerance to inorganic arsenic in the kidney of killifish (Fundulus heteroclitus).

We used proximal tubules isolated from the killifish, Fundulus heteroclitus, to examine the effect of environmentally relevant, sublethal levels of arsenic on the function and expression of MRP2, an ABC transporter that transports xenobiotics into urine, including arsenic-glutathione conjugates. Exposure of fish to arsenic as sodium arsenite (4-14 days) increased both MRP2 expression in the apical membrane of proximal tubules and MRP2-mediated transport activity. The level of MRP2 mRNA was not affected, suggesting a posttranslational mechanism of action. Acute exposure of proximal tubules isolated from control fish to 75-375 ppb arsenic decreased mitochondrial function (inner membrane electrical potential). However, in tubules from fish that were preexposed to arsenic (4-14 days), no such effect on mitochondrial function was observed. Thus, chronic in vivo exposure to arsenic induces mechanisms that protect proximal tubules during subsequent arsenic exposure. Upregulation of MRP2 expression and activity is one likely contributing factor.

Role of glucocorticoid receptor in acclimation of killifish (Fundulus heteroclitus) to seawater and effects of arsenic.

Killifish are euryhaline teleosts that adapt to rapid changes in the salinity of the seawater. It is generally accepted that acclimation to seawater is mediated by cortisol activation of the glucocorticoid receptor (GR), which stimulates CFTR mRNA expression and CFTR-mediated Cl- secretion by the gill. Because there is no direct evidence in killifish that the GR stimulates CFTR gene expression, quantitative PCR studies were conducted to test the hypothesis that cortisol activation of GR upregulates CFTR mRNA expression and that this response is required for acclimation to seawater. Inhibition of the GR by RU-486 prevented killifish from acclimating to increased salinity and blocked the increase in CFTR mRNA. In contrast, inhibition of the mineralocorticoid receptor by spironolactone had no effect on acclimation to seawater. Thus acclimation to increased salinity in killifish requires signaling via the GR and includes an increase in CFTR gene expression. Because arsenic, a toxic metalloid that naturally occurs in the aquatic environment, has been shown to disrupt GR transcriptional regulation in avian and mammalian systems, studies were also conducted to determine whether arsenic disrupts cortisol-mediated activation of CFTR gene expression in this in vivo fish model and thereby blocks the ability of killifish to acclimate to increased salinity. Arsenic prevented acclimation to seawater and decreased CFTR protein abundance. However, arsenic did not disrupt the GR-induced increase in CFTR mRNA. Thus arsenic blocks acclimation to seawater in killifish by a mechanism that does not disrupt GR-mediated induction of CFTR gene expression.

Arsenic inhibits CFTR-mediated chloride secretion by killifish (Fundulus heteroclitus) opercular membrane.

Killifish are euryhaline teleosts that normally experience rapid changes in the salinity of the swim water. Acclimation to seawater is mediated by cortisol, which by activating glucocorticoid receptors, upregulates CFTR mediated Cl- secretion in the gill and operculum. Arsenic, a toxic metalloid that naturally occurs in the aquatic environment, has been shown to disrupt glucocorticoid hormone-mediated regulation of genes. Because little is known about the effects of environmentally relevant levels of arsenic on ion channels and salt homeostasis, studies were conducted to examine the effects of arsenic on the ability of killifish to acclimate to increased salinity. Arsenic in the swim water or administered by intraperitoneal injection prevented acclimation. To determine if arsenic blocked acclimation by inhibiting CFTR mediated Cl- secretion (Isc), opercular membranes were isolated and mounted in Ussing chambers and the effects of arsenic on Isc were measured. Arsenic (24 hr exposure) reduced Isc in opercular membranes isolated from salt water acclimated killifish. In addition, arsenic acutely (5-10 minutes) and reversibly inhibited Isc with an IC50 = 4.1 microM (305 ppb) when applied to the apical (seawater) side of the operculum, but not when added to the basolateral side of the operculum. Arsenic (4 microM for 60 minutes) also reduced mitochondrial respiration. Thus, environmentally relevant levels of arsenic block acclimation to seawater in killifish by reversibly inhibiting CFTR-mediated Cl- secretion by the opercular membrane, in part by inhibiting mitochondrial respiration.

Pseudomonas aeruginosa inhibits endocytic recycling of CFTR in polarized human airway epithelial cells.

The most common mutation in the CFTR gene in individuals with cystic fibrosis (CF), DeltaF508, leads to the absence of CFTR Cl(-) channels in the apical plasma membrane, which in turn results in impairment of mucociliary clearance, the first line of defense against inhaled bacteria. Pseudomonas aeruginosa is particularly successful at colonizing and chronically infecting the lungs and is responsible for the majority of morbidity and mortality in patients with CF. Rescue of DeltaF508-CFTR by reduced temperature or chemical means reveals that the protein is at least partially functional as a Cl(-) channel. Thus current research efforts have focused on identification of drugs that restore the presence of CFTR in the apical membrane to alleviate the symptoms of CF. Because little is known about the effects of P. aeruginosa on CFTR in the apical membrane, whether P. aeruginosa will affect the efficacy of new drugs designed to restore the plasma membrane expression of CFTR is unknown. Accordingly, the objective of the present study was to determine whether P. aeruginosa affects CFTR-mediated Cl(-) secretion in polarized human airway epithelial cells. We report herein that a cell-free filtrate of P. aeruginosa reduced CFTR-mediated transepithelial Cl(-) secretion by inhibiting the endocytic recycling of CFTR and thus the number of WT-CFTR and DeltaF508-CFTR Cl(-) channels in the apical membrane in polarized human airway epithelial cells. These data suggest that chronic infection with P. aeruginosa may interfere with therapeutic strategies aimed at increasing the apical membrane expression of DeltaF508-CFTR.