Renal systems biology of patients with systemic inflammatory response syndrome

A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular weight proteins and acute phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and n-acetylaspartate were inversely correlated with the majority of significantly down-regulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness

Immune Responsiveness of Monkeys Exposed Chronically to Cigarette Smoke

Eleven adult male stumptailed monkeys (Macaca arctoides) were chronically exposed to either a low dose (human equivalent of 1 pack/day) or a high dose (human equivalent of 3 packs/day) of high-tar, high-nicotine University of Kentucky reference cigarette smoke for 4-8 years. Several parameters of their immunological response were compared to six nonsmoked control animals. The results from these experiments suggest that cigarette smoking does not significantly affect the response of spleen cells to the mitogens phytohemagglutinin or lipopolysaccharide. However, spleen cells from animals subjected to the heavy dose of cigarette smoke demonstrated a significant reduction in their natural killer cell-mediated lytic activity and a decreased response to concanavalin A. These results suggest that cigarette smoking may have a differential effect on lymphocyte subpopulations, and that the effects on the immune response are related to the dose of cigarette smoke

Immunosuppressive and Anti-Inflammatory Effects of Nicotine Administered by Patch in an Animal Model

To study the immunological effects of nicotine, there are several rodent models for chronic nicotine administration. These models include subcutaneously implanted miniosmotic pumps, nicotine-spiked drinking water, and self-administration via jugular cannulae. Administration of nicotine via these routes affects the immune system. Smokers frequently use nicotine patches to quit smoking, and the immunological effects of nicotine patches are largely unknown. To determine whether the nicotine patch affects the immune system, nicotine patches were affixed daily onto the backs of Lewis rats for 3 to 4 weeks. The patches efficiently raised the levels of nicotine and cotinine in serum and strongly inhibited the antibody-forming cell response of spleen cells to sheep red blood cells. The nicotine patch also suppressed the concanavalin A-induced T-cell proliferation and mobilization of intracellular Ca(2+) by spleen cells, as well as the fever response of animals to subcutaneous administration of turpentine. Moreover, immunosuppression was associated with chronic activation of protein tyrosine kinase and phospholipase C-γ1 activities. Thus, in this animal model of nicotine administration, the nicotine patch efficiently raises the levels of nicotine and cotinine in serum and impairs both the immune and inflammatory responses

A novel cytokine profile associated with cancer metastasis to mediastinal and hilar lymph nodes identified using fine needle aspiration biopsy - A pilot study.

Cancer metastasis to the lymph nodes is indicative of a poor prognosis. An endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) biopsy is increasingly being used to sample paratracheal lymph nodes for simultaneous cancer diagnosis and staging. In this prospective, single-center study, we collected dedicated EBUS-FNA biopsies from 27 patients with enlarged paratracheal and hilar lymph nodes. Cytokines were assayed using Bio-Plex Pro human cancer biomarker panels (34 cytokines), in a Bio-Rad 200 suspension array system. A mean cytokine value was taken from each subject with more than 1 lymph node station EBUS-FNA biopsies. Malignant and benign histologic diagnoses were established in 16 and 12 patients, respectively. An initial analysis using the Kruskal-Wallis test with Sidak correction for multiple comparisons, showed significant elevation of sVEGFR-1, IL-6, VEGF-A, Angiopoeintin-2, uPA, sHER-2/neu and PLGF in malignant lymph node samples compared to benign samples. The univariate logistic regression analyses revealed that 6 cytokines were significant predictors and 1 cytokine (PLGF) was marginally significant for discrimination between benign and malignant samples. The prediction power of these cytokines as biomarkers were very high according to the area under the ROC curve. Multiple logistic regression for subsets of the seven cytokine combined; provided an almost complete discrimination between benign and malignant samples (AUC=0.989). For screening and diagnostic purposes, we presented the optimal discrimination cut-off for each cytokine: sVEGFR-1 (2124.5pg/mL), IL-6 (40.2pg/mL), VEGF-A (1060.1pg/mL), Angiopoeintin-2 (913.7pg/mL), uPA (248.1pg/mL), sHER-2/neu (5010pg/mL) and PLGF (93.4pg/mL). For the very first time, a novel cytokine profile associated with cancer metastasis to the paratracheal lymph nodes were reported