11-β Hydroxysteroid Dehydrogenase Type 2 in Human Adult and Fetal Lung and Its Regulation by Sex Steroids

Garbrecht, Mark R.; Klein, Jonathan M.; McCarthy, Troy; Schmidt, Thomas J.; Krozowski, Zygmunt; Snyder, Jeanne M.

doi:10.1203/pdr.0b013e3180676cf3

Cited by 17 publications

(13 citation statements)

References 41 publications

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“…11β‐Hydroxysteroid dehydrogenase‐2 ‘protects’ tissues from cortisol by converting it to inactive cortisone. Like 11β‐HSD‐1, 11β‐HSD‐2 is present in Type II alveolar epithelial cells in the fetal lungs . Proinflammatory stimuli downregulate 11β‐HSD‐2, thereby increasing tissue cortisol availability …”

Section: Potential Mediators Of Inflammation‐induced Lung Maturationmentioning

confidence: 99%

Effects of intrauterine infection or inflammation on fetal lung development

Westover

Moss

2012

Clin Exp Pharma Physio

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1. Intrauterine infection or inflammation is common in cases of preterm birth. Preterm infants are at risk of acute respiratory distress as a result of lung immaturity; evidence of exposure to infection and/or inflammation before birth is associated with a reduced risk of neonatal respiratory distress syndrome (RDS). Experimentally induced intrauterine inflammation or infection in sheep causes a precocious increase in pulmonary surfactant in the preterm lungs that improves preterm lung function, consistent with the reduced risk of RDS in human infants exposed to infection and/or inflammation before birth. 2. The effects of intrauterine inflammation on fetal lung development appear to result from direct action of proinflammatory stimuli within the lungs rather than by systemic signals, such as the classical glucocorticoid-mediated lung maturation pathway. However, paracrine and/or autocrine production and/or metabolism of glucocorticoids in fetal lung tissue may occur as a result of inflammation-induced changes in the expression of 11β-hydroxysteroid dehydrogenase (types 1 and 2). 3. Likely candidates that mediate inflammation-induced surfactant production by the preterm lung include prostaglandin E₂ and/or other arachidonic acid metabolites. Intrauterine inflammation induces the expression of enzymes responsible for prostaglandin production in fetal lung tissue. Inhibition of prostaglandin production prevents, at least in part, the effects of inflammation on fetal lungs. 4. Our experiments are identifying mechanisms of surfactant production by the preterm lungs that may be exploited as novel therapies for preventing respiratory distress in preterm infants. Elucidation of the effects of inflammation on the fetal lungs and other organs will allow more refined approaches to the care of preterm infants exposed to inflammation in utero.

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Section: Potential Mediators Of Inflammation‐induced Lung Maturationmentioning

confidence: 99%

Effects of intrauterine infection or inflammation on fetal lung development

Westover

Moss

2012

Clin Exp Pharma Physio

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“…Lung epithelial cells contain both mineralocorticoid and glucocorticoid receptors (93)(94)(95), but since circulating levels of aldosterone are usually low compared with glucocorticoids, it is likely that the major steroids regulating lung ENaC are glucocorticoids. However, alveolar type II cells do contain 11-b-hydoxysteroid dehydrogenase 2 (11b-HSD2) (96,97), which is often considered a hallmark of aldosterone target cells (98), and there are some reports of an effect of aldosterone concentrations on alveolar fluid reabsorption (99) and ENaC activity in type 2 cells (100). Regardless, both aldosterone and glucocorticoids regulate sodium absorption by similar shortand long-term processes: an initial phase that increases transport four-to sixfold in the first 2 to 6 hours, and a late phase that requires 12 to 48 hours and increases transport another three-to fourfold (reviewed in Reference 101).…”

Section: Regulation Of Nedd4-2 Activity and Enac Degradation Ratementioning

confidence: 99%

Regulation of Epithelial Sodium Channel Trafficking by Ubiquitination

Eaton¹,

Malik²,

Bao³

et al. 2010

Proceedings of the American Thoracic Society

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Amiloride-sensitive epithelial sodium (Na(+)) channels (ENaC) play a crucial role in Na(+) transport and fluid reabsorption in the kidney, lung, and colon. The magnitude of ENaC-mediated Na(+) transport in epithelial cells depends on the average open probability of the channels and the number of channels on the apical surface of epithelial cells. The number of channels in the apical membrane, in turn, depends upon a balance between the rate of ENaC insertion and the rate of removal from the apical membrane. ENaC is made up of three homologous subunits, alpha, beta, and gamma. The C-terminal domain of all three subunits is intracellular and contains a proline rich motif (PPxY). Mutations or deletion of this PPxY motif in the beta and gamma subunits prevent the binding of one isoform of a specific ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein (Nedd4-2) to the channel in vitro and in transfected cell systems, thereby impeding ubiquitin conjugation of the channel subunits. Ubiquitin conjugation would seem to imply that ENaC turnover is determined by the ubiquitin-proteasome system, but when MDCK cells are transfected with ENaC, ubiquitin conjugation apparently leads to lysosomal degradation. However, in untransfected epithelial cells (A6) expressing endogenous ENaC, ENaC appears to be degraded by the ubiquitin-proteasome system. Nonetheless, in both transfected and untransfected cells, the rate of ENaC degradation is apparently controlled by the rate of Nedd4-2-mediated ENaC ubiquitination. Controlling the rate of degradation is apparently important enough to have multiple, redundant pathways to control Nedd4-2 and ENaC ubiquitination.

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“…In our experiments, as well as those conducted by others (Z. Krozowski, unpublished observations), the HSD2-specific antibody (HUH23) utilized in this study variably yields HSD2-specific bands that correlate to monomers, dimers, and trimers. Using this antibody, we have previously detected these bands in cultured lung epithelial cells (NCI-H441), cultured colon epithelial cells (CaCo-2), and in human adult and fetal lung tissues [7, 10]. Furthermore, HSD2 has been previously shown to exist in dimer form under oxidizing conditions [11].…”

Section: Discussionmentioning

confidence: 99%

Expression and Regulation of 11-β Hydroxysteroid Dehydrogenase Type 2 Enzyme Activity in the Glucocorticoid-Sensitive CEM-C7 Human Leukemic Cell Line

Garbrecht

Schmidt

2013

ISRN Oncology

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Glucocorticoids are commonly used in the first-line treatment of hematological malignancies, such as acute lymphoblastic leukemia, due to the ability of these steroids to activate pro-apoptotic pathways in human lymphocytes. The goal of the current study was to examine the gene expression and enzyme activity of the microsomal enzyme, 11-β hydroxysteroid dehydrogenase type 2 (HSD11B2, HSD2), which is responsible for the oxidation of bioactive glucocorticoids to their inert metabolites. Using the glucocorticoid-sensitive human leukemic cell line, CEM-C7, we were able to detect the expression of HSD2 at the level of mRNA (via RT-PCR), protein (via immunohistochemistry and immunoblotting), and enzyme activity (via conversion of tritiated cortisol to cortisone). Furthermore, we observed that HSD2 enzyme activity is down regulated in CEM-C7 cells that were pretreated with the synthetic glucocorticoid, dexamethasone (100 nM, <15 hours), and that this down regulation of enzyme activity is blocked by the administration of the glucocorticoid receptor antagonist, RU-486. Taken collectively, these data raise the possibility that the effectiveness of glucocorticoids in the treatment of human leukemias may be influenced by: (1) the ability of these neoplastic cells to metabolize glucocorticoids via HSD2 and (2) the ability of these steroids to regulate the expression of this key enzyme.

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11-β Hydroxysteroid Dehydrogenase Type 2 in Human Adult and Fetal Lung and Its Regulation by Sex Steroids

Cited by 17 publications

References 41 publications

Effects of intrauterine infection or inflammation on fetal lung development

Effects of intrauterine infection or inflammation on fetal lung development

Regulation of Epithelial Sodium Channel Trafficking by Ubiquitination

Expression and Regulation of 11-β Hydroxysteroid Dehydrogenase Type 2 Enzyme Activity in the Glucocorticoid-Sensitive CEM-C7 Human Leukemic Cell Line

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