Publications

Here, we investigate how Candida albicans, the most prevalent human fungal pathogen, protects itself from nitric oxide (*NO), an antimicrobial compound produced by the innate immune system. We show that exposure of C. albicans to *NO elicits a reproducible and specific transcriptional response as determined by genome-wide microarray analysis. Many genes are transiently induced or repressed by *NO, whereas a set of nine genes remain at elevated levels during *NO exposure. The most highly induced gene in this latter category is YHB1, a flavohemoglobin that detoxifies *NO in C. albicans and other microbes. We show that C. albicans strains deleted for YHB1 have two phenotypes in vitro; they are hypersensitive to *NO and they are hyperfilamentous. In a mouse model of disseminated candidiasis, a YHB1 deleted C. albicans strain shows moderately attenuated virulence, but the virulence defect is not suppressed by deletion of the host NOS2 gene. These results suggest that *NO production is not a prime determinant of virulence in the mouse tail vein model of candidiasis and that the attenuated virulence of a yhb1delta/yhb1delta strain is attributable to a defect other than its reduced ability to detoxify *NO.

BACKGROUND/AIMS

CXC chemokines function as survival factors for several types of cells. In this study, we investigated whether CXC chemokines promote survival of liver cells following an apoptotic stimulus in vivo.

METHODS

Apoptosis was induced in mouse liver by treatment with galactosamine and endotoxin (Gal/ET). The influence of CXC chemokines was investigated by comparing Gal/ET responses in wild-type (WT) mice to those in mice with a transgene encoding the CXC chemokine interleukin-8 (IL-8 TG).

RESULTS

IL-8 TG mice displayed less apoptosis and better survival after Gal/ET treatment than did WT mice (60% fewer TUNEL-positive cells at 6 h; 36% better survival at 24 h). Gal/ET toxicity was also preventable in WT mice by pre-treatment with IL-8. Notably, IL-8 was not protective against hepatic apoptosis due to anti-Fas or concanavalin A. In Gal/ET-treated mice, IL-8 promoted liver cell survival by interfering with the mitochondrial pathway of apoptosis. Survival was not attributable to activation of NF-kappaB or up-regulation of anti-apoptotic proteins, but coincided instead with activation of Akt and phosphorylation of the pro-apoptotic protein Bad.

CONCLUSIONS

IL-8 protects liver cells from Gal/ET-mediated apoptosis by signaling through phosphatidylinositol-3 kinase (PI-3K). This is in keeping with the reported mechanism of chemokine-related survival in other tissues.

Recent studies have highlighted the relation between erectile dysfunction (ED) and cardiovascular disease. In particular, the role of endothelial dysfunction and nitric oxide in ED and atherosclerotic disease has been elucidated. Given the large number of men receiving medical treatment for ED, concerns regarding the risk for sexual activity triggering acute cardiovascular events and potential risks of adverse or unanticipated drug interactions need to be addressed. A risk stratification algorithm was developed by the First Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. Patients were assigned to 3 categories: low, intermediate (including those requiring further evaluation), and high risk. This consensus study from the Second Princeton Consensus Conference corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED. The panel reviewed recent safety and drug interaction data for 3 phosphodiesterase (PDE)-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. Increasing evidence supports the role of lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease. Special management recommendations for patients taking PDE-5 inhibitors who present at the emergency department and other emergency medical situations are described. Finally, further research on the role of PDE-5 inhibition in treating patients with other medical or cardiovascular disorders is recommended.