Translocated LPS Might Cause Endotoxin Tolerance in Circulating Monocytes of Cystic Fibrosis Patients

Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene codes of a chloride channel. The lungs of CF patients are chronically infected by several pathogens but bacteraemia have rarely been reported in this pathology. Besides that, circulating monocytes in CF patients exhibit a patent Endotoxin Tolerance (ET) state since they show a significant reduction of the inflammatory response to bacterial stimulus. Despite a previous description of this phenomenon, the direct cause of ET in CF patients remains unknown. In this study we have researched the possible role of microbial/endotoxin translocation from a localized infection to the bloodstream as a potential cause of ET induction in CF patients. Plasma analysis of fourteen CF patients revealed high levels of LPS compared to healthy volunteers and patients who suffer from Chronic Obstructive Pulmonary Disease. Experiments in vitro showed that endotoxin concentrations found in plasma of CF patients were enough to induce an ET phenotype in monocytes from healthy controls. In agreement with clinical data, we failed to detect bacterial DNA in CF plasma. Our results suggest that soluble endotoxin present in bloodstream of CF patients causes endotoxin tolerance in their circulating monocytes

Position-dependent expression of GADD45 alpha in rat brain tumours

Although the complex and multifactorial process of tumour growth has been extensively studied for decades, our understanding of the fundamental relationship between tumour growth dynamics and genetic expression profile remains incomplete. Recent studies of tumour dynamics indicate that gene expression in solid tumours would depend on the distance from the centre of the tumour. Since tumour proliferative activity is mainly localised to its external zone, and taking into account that generation and expansion of genetic mutations depend on the number of cell divisions, important differences in gene expression between central and peripheral sections of the same tumour are to be expected. Here, we have studied variations in the genetic expression profile between peripheral and internal samples of the same brain tumour. We have carried out microarray analysis of mRNA expression, and found a differential profile of genetic expression between the two cell subsets. In particular, one major nuclear protein that regulates cell responses to DNA-damaging and stress signals, GADD45 alpha, was expressed at much lower levels in the peripheral zone, as compared to tumour core samples. These differences in GADD45 alpha mRNA transcription levels have been confirmed by quantitative analysis via real time PCR, and protein levels of GADD45 alpha also exhibit the same pattern of differential expression. Our findings suggest that GADD45 alpha might play a major role in the regulation of brain tumour invasive potential