The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from cas pase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-beta-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways.

Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n = 123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF -308GA, IL1 beta -31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC-AUC = 0.68), use of APACHE II score and two genetic parameters (TNF -308 and IL1 beta -31) enabled more accurate prediction of ICU mortality (ROC-AUC = 0.80). Significant association of two genetic polymorphisms, TNF -308 and IL1 beta -31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients. (C) 2010 Elsevier Ltd All rights reserved.

Background and purpose: Injurious ventilation with high peak inspiratory pressure (PIP) is known to cause systemic inflammatory response through cytokine production. This study was performed to examine whether body temperature could regulate cytokine production in ventilator-induced lung injury (VILI) model. Methods: After performing anesthesia, tracheostomy, and catheter insertion, rats were ventilated with 17 cm, H(2)O of PIP in the low-pressure (LP) group or 35 cm H(2)O in the high-pressure (HP) group. Then, each group was divided into three subgroups; hyperthermia (39 degrees C), normothermia (37 degrees C), and hypothermia (34 degrees C) group. Six groups were observed for 6 h. Results: Plasma levels of pro-inflammatory cytokines, TNF-a and IL-6 at 1 h after the start of observation were highest in 39 degrees C-HP group and were lowest in 34 degrees C-HP group. Furthermore, sustained high plasma levels of IL-6 were observed only in 39 degrees C-HP group. In contrast, plasma levels of anti-inflammatory cytokine, IL-10 at 1 h were highest in 34 degrees C-HP group, and lowest in 39 degrees C-HP group. Conclusion: The body temperature significantly affects cytokine production in a model of VILI. Body temperature control may be a potentially effective therapeutic modality to regulate cytokine production in VILI. (C) 2009 Elsevier Ltd. All rights reserved.

Objectives: To investigate the usefulness of analysis of single nucleotide polymorphism (SNP) using a newly developed DNA chip assay involving single base extension(SBE) and subsequent hybridization in cytokine-related genes in critical care patients. Design and methods: Genotyping was performed in 76 ICU patients admitted to the ICU. First, the DNA samples from 58 patients were subjected to PCR and SBE conditioning for DNA. Second, another 18 patients were subjected to genotyping for SNPs in IL-6 -596G/A, -572C/G, -174G/C, TNF-alpha -308G/A, -238G/A, IL-1 beta -511C/T and -31T/C by both TaqMan and DNA chip method, and by DNA direct sequencing prospectively. Results: First, PCR and SBE condition were established with initial sample sets, which were consistent with results by TaqMan method. Second, no difference was observed between two assay methods in prospective validation set. Conclusions: The genotyping assay using the new chip was developed and its usefulness was confirmed. (C) 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.