The journal of cardiothoracic trauma最新文献

Background: Genetic variation contributes to risk and outcomes of sepsis. We sought to determine whether variation in inflammation related genes is associated with severity of sepsis in trauma patients.

Methods: A cohort of severely injured Caucasian patients was studied and genotyped for candidate single nucleotide polymorphisms (SNPs). These were toll-like receptor 4 (TLR4) A896G, tumor necrosis factor-alpha G-308A, interleukin-6 G-174C, interleukin-1beta C-31T, and cluster of differentiation marker 14C-159T. SNP genotypes among patients with sepsis and complicated sepsis were analyzed by chi2 and logistic regression. Six haplotype-tagging SNPs in the TLR4 gene were subsequently examined to analyze their influence on TLR4 A896G SNPs relationship to sepsis severity.

Results: We enrolled 598 patients. Complicated sepsis developed in 147 (25%). Adjusting for independent risk factors, carriage of the variant TLR4 896 G allele was associated with decreased risk of complicated sepsis (odds ratio = 0.3, 95% confidence interval, 0.1-0.7, p = 0.008). Furthermore, two haplotypes seemed to better characterize this risk than the variant TLR4 896G allele. The variant TLR4 896G allele is linked to one common haplotype, which seems to confer a considerably reduced risk of complicated sepsis. (aOR = 0.2 95% confidence interval, 0.05-0.7, p = 0.01).

Conclusions: Variation within TLR4 gene is associated with severity of posttraumatic sepsis. This risk may not be solely related to TLR4 A896G SNP. It is likely that other, uncharacterized variations in the TLR4 gene contribute to sepsis severity. A thorough evaluation of variability within the TLR4 gene is needed to characterize sepsis risk.

Background: Burn injury can result in loss of intestinal barrier function, leading to systemic inflammatory response syndrome and multiorgan failure. Myosin light chain kinase (MLCK), a tight junction protein involved in the regulation of barrier function, increases intestinal epithelial permeability when activated. Prior studies have shown that tumor necrosis factor (TNF)-alpha activates MLCK, in part through a nuclear factor (NF)-kappa B-dependent pathway. We have previously shown that pentoxifylline (PTX) decreases both TNF-alpha synthesis and NF-kappaB activation in models of shock. Therefore, we postulate that PTX will attenuate activation of the tight junction protein MLCK, which may decrease intestinal tight junction permeability after severe burn.

Methods: Male balb/c mice undergoing a severe burn were randomized to resuscitation with normal saline (NS) or NS + PTX (12.5 mg/kg). Intestinal TNF-alpha levels were evaluated using enzyme linked immunosorbent assay. Gut extracts were obtained to assess MLCK, phosphorylated IKK, IkappaB-alpha, and NF-kappaB p65 levels by immunoblotting.

Results: Burn injury increased intestinal MLCK protein levels threefold in animals resuscitated with NS, whereas those receiving PTX had MLCK levels similar to control (p < 0.01). Treatment with PTX attenuated burn-induced intestinal permeability. PTX decreased cytoplasmic IKK, IkappaB-alpha phosphorylation, and nuclear NF-kappaB p65 translocation to sham levels (p < 0.05 vs. NS).

Conclusion: Treatment with PTX attenuates activation of the tight junction protein MLCK, likely through its ability to decrease local TNF-alpha synthesis and NF-kappaB activation after burn. PTX may have therapeutic utility by decreasing intestinal barrier breakdown after burn.