Combinatorial therapy with acetylation and methylation modifiers attenuates lung vascular hyperpermeability in endotoxemia-induced mouse inflammatory lung injury.

Impairment of tissue fluid homeostasis and migration of inflammatory cells across the vascular endothelial barrier are crucial factors in the pathogenesis of acute lung injury (ALI). The goal for treatment of ALI is to target pathways that lead to profound dysregulation of the lung endothelial barrier. Although studies have shown that chemical epigenetic modifiers can limit lung inflammation in experimental ALI models, studies to date have not examined efficacy of a combination of DNA methyl transferase inhibitor 5-Aza 2-deoxycytidine and histone deacetylase inhibitor trichostatin A (herein referred to as Aza+TSA) after endotoxemia-induced mouse lung injury. We tested the hypothesis that treatment with Aza+TSA after lipopolysaccharide induction of ALI through epigenetic modification of lung endothelial cells prevents inflammatory lung injury. Combinatorial treatment with Aza+TSA mitigated the increased endothelial permeability response after lipopolysaccharide challenge. In addition, we observed reduced lung inflammation and lung injury. Aza+TSA also significantly reduced mortality in the ALI model. The protection was ascribed to inhibition of the eNOS-Cav1-MLC2 signaling pathway and enhanced acetylation of histone markers on the vascular endothelial-cadherin promoter. In summary, these data show for the first time the efficacy of combinatorial Aza+TSA therapy in preventing ALI in lipopolysaccharide-induced endotoxemia and raise the possibility of an essential role of DNA methyl transferase and histone deacetylase in the mechanism of ALI.

A novel approach for removing an intra-renal migrated Memokath™ stent.

INTRODUCTION: The use of metallic stents in managing benign and malignant ureteric strictures is gaining increasing popularity in urology and has been shown to be a safe and effective alternative to the commonly used double J stents. PRESENTATION OF CASE: We present here the case of a 54 year old female with a symptomatic benign ureteric narrowing at the pelvi-ureteric junction of her left kidney who was successfully managed with a metallic Memokath™ stent inserted at the site of the stricture. She went on to develop a rare complication of proximal migration of the stent into the kidney necessitating removal. DISCUSSION: Our study systematically reviews the published evidence for the clinical effectiveness of metallic ureteric stents in stricture management and details a novel and safe approach that was successfully used to remove the intra-renal migrated stent in an antegrade percutaneous fashion. CONCLUSION: Our report highlights a rare complication of metallic ureteric stents and a novel approach to their removal. This has significant importance for the urologist managing an awkwardly positioned stent lying within the kidney and hence difficult to manipulate via the previously published retrograde approaches.