The cells of the renal medulla produce large amounts of prostaglandin E 2 (PGE 2 ) via cyclooxygenases (COX)-1 and -2. PGE 2 is well known to play a critical role in salt and water balance and maintenance of medullary blood flow. Since renal medullary PGE 2 production increases in antidiuresis, and since COX inhibition is associated with damage to the renal medulla during water deprivation, PGE 2 may promote the adaptation of renal papillary cells to high interstitial solute concentrations. To address this question, MDCK cells were exposed to a gradual tonicity increase in the presence or absence of 20 μM PGE 2 prior to analysis of (i) cell survival, (ii) expression of osmoprotective genes (AR, BGT1, SMIT, HSP70 and COX-2), (iii) subcellular TonEBP/NFAT5 abundance, (iv) TonEBP/NFAT5 transcriptional activity and (v) aldose reductase promoter activity. Cell survival and apoptotic indices after raising the medium tonicity improved markedly in the presence of PGE 2 . PGE 2 significantly increased tonicity-mediated up-regulation of AR, SMIT and HSP70 mRNAs. However, neither nuclear abundance nor TonEBP/NFAT5-driven reporter activity were elevated by PGE 2 , but aldose reductase promoter activity was significantly increased by PGE 2 . Interestingly, tonicity-induced COX-2 expression and activity was also stimulated by PGE 2 , suggesting the existence of a positive feedback loop. These results demonstrate that the major medullary prostanoid, PGE 2 , stimulates the expression of osmoprotective genes and favours the adaptation of medullary cells to increasing interstitial tonicities, an effect that is not explained directly by the presence of TonEs in the promoter region of the respective target genes. These findings may be relevant in the pathophysiology of medullary damage associated with analgesic drugs.

(COX-2)-derived PGE2 is critical for the integrity and function of renal medullary cells during antidiuresis. The present study extended our previous finding that tonicity-induced COX-2 expression is further stimulated by the major COX-2 product PGE2 and investigated the underlying signaling pathways and the functional relevance of this phenomenon. Hyperosmolality stimulated COX-2 expression and activity in Madin-Darby canine kidney (MDCK) cells, a response that was further increased by PGE2-cAMP signaling, suggesting the existence of a positive feedback loop. This effect was diminished by AH-6809, an EP2 antagonist, and by the PKA inhibitor H-89, but not by AH-23848, an EP4 antagonist. The effect of PGE2 was mimicked by forskolin and dibutyryl-cAMP, suggesting that the stimulatory effect of PGE2 on COX-2 is mediated by a cAMP-PKAdependent mechanism. Accordingly, cAMP-responsive element (CRE)-driven reporter activity paralleled the effects of PGE2, AH-6809, AH-23848, H-89, forskolin, and dibutyryl-cAMP on COX-2 expression. In addition, the stimulatory effect of PGE2 on tonicity-induced COX-2 expression was blunted in cells transfected with dominantnegative CRE binding (CREB) protein, as was the case in a COX-2 promoter reporter construct in which a putative CRE was deleted. Furthermore, PGE2 resulted in PKA-dependent phosphorylation of the pro-apoptotic protein Bad at Ser155, a mechanism that is known to inactivate Bad, which coincided with reduced caspase-3 activity during osmotic stress. Conversely, pharmacological interruption of the PGE 2-EP2-cAMP-PKA pathway abolished Ser155 phosphorylation of Bad and blunted the protective effect of PGE 2 on cell survival during osmotic stress. These observations indicate the existence of a positive feedback loop of PGE 2 on COX-2 expression during osmotic stress, an effect that apparently is mediated by EP2-cAMP-PKA signaling, and that contributes to cell survival under hypertonic conditions. cyooxygenase-2; prostaglandin E 2; osmoadaptation; apoptosis; survival factor THE INTERSTITIAL ENVIRONMENT of the renal medulla is characterized by extremely high interstitial osmolalities and low oxygen tension (34). Nevertheless, medulla-resident cells not only have the ability to survive in this hostile environment but also to function normally. This feature is of integral importance for maintaining the kidneys' function in regulating systemic electrolyte and fluid homeostasis.A characteristic feature of renal medullary cells is their high capacity for production of prostaglandins (PG) (4). PGs are autacoids acting close to their site of formation and contribute essentially to the regulation of tubular solute and water reabsorption and adjusting medullary blood flow to metabolic requirements (12,32,34). Moreover, PGs promote the adaptation of renal medullary cells to high extracellular osmolalities by virtue of enhancing the expression of osmoprotective genes (29,35,37). The formation of PGs depends on the sequential action of cytosolic phospholipase A 2 (cPLA 2 ), which releases ...

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Perihilär betonte, deutliche, eckige Zeichnungsvermehrung im Röntgenthorax, vereinbar mit atypischen In ltraten. Patient mit AtemnotSo weit kann es ohne HIV-Therapie kommen! _ Ein 57-jähriger Elektriker, der ursprünglich aus Nigeria stammt, aber seit 15 Jahren in Deutschland lebt, stellte sich in der Notaufnahme der Klinik vor. Seit etwa einer Woche litt er unter Kra losigkeit, Atemnot bei Anstrengung, trockenem, zum Teil blutig tingiertem Husten und Fieber bis 38,5°C. Er berichtete davon, häu g zu frösteln und sich besonders warm anziehen zu müssen.Bei der körperlichen Untersuchung zeigten sich ein Puls von 104/min, eine Atemfrequenz von 18/min in Ruhe, ein Blutdruck von 134/100 mmHg und eine Körpertemperatur von 38,0° C. Bei einer Körpergröße von 170 cm wog der Patient 66 kg. Die Auskultation und Perkussion der Lunge ergab normale Befunde. Beim Blick in den Mund el ein Mundsoor auf. Nach Vorerkrankungen gefragt, berichtete der Mann von einer seit zehn Jahren bekannten HIV-Infektion. Seit 2012 habe er keine antiretrovirale erapie (ART) mehr genommen -er habe sie nicht gut vertragen und glaube, dass sie ihm schade.Das Labor ergab einen pO 2 -Wert von 60,3 mmHg, einen pCO 2 -Wert von 31,8 mmHg und einen pH-Wert von 7,45. Die Konzentration von LDH im Serum lag bei 316 U/l, die von CRP bei 6,7 mg/dl. Das Gesamteiweiß lag bei 8,6 g/dl. Im Rönt-genthorax zeigte sich perihilär betont eine deutliche eckige Zeichnungsvermehrung, vereinbar mit (atypischen) In ltraten.In der Zusammenschau ergibt sich die zwingende Verdachtsdiagnose einer Pneumozystis-jirovecii-Pneumonie (PjP)

This report concerns a young man who attempted suicide by ingesting a cocktail with a lethal dose of chloroquine phosphate and large amounts of diazepam. On presentation, the patient was drowsy, unresponsive and in cardiogenic shock with severely impaired left ventricular function. Active charcoal and vasopressors were administered, and despite his intoxication with diazepam, a high-dose diazepam treatment was initiated in the hospital. It is concluded that diazepam in the cocktail played a vital role in the survival of this patient. With a rise in numbers, every emergency and intensive care physician should be familiar with chloroquine poisoning.