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Objective: lnterleukin-6 (IL-6) is a pivotal cytokine in both innate and adaptive immunity. Several polymorphisms in the IL-6 promoter have been reported in Western populations. However, little is known about their occurrence in the Chinese population. The functionality of IL-6 promoter polymorphisms remains controversial. Design: Genetic, functional, and association studies. Setting: National key laboratory of trauma and departments of traumatic surgery in two teaching hospitals. Subjects: A total of 348 healthy blood donors and 105 patients with major trauma. Interventions: None. Measurements and Main Results: Identification of polymorphisms in the lL-6 promoter was performed using sequencing and restriction fragment length polymorphism methods. Their functionality was assessed by observation of transcription activity, IL-6 production, and their clinical relevance in 105 patients with major trauma. Only one variant (C-572G) was identified in IL-6 promoter in Chinese Han population. This polymorphism was associated with IL-6 production by peripheral leukocytes in response to ex vivo lipopolysaccharide stimulation in an allele-dose-dependent effect. The C→G variation at position -572 could reduce transcriptional activity of the IL-6 promoter as shown in both U-937 and K562 cell lines. Moreover, the -572 polymorphism was associated with lower risk of sepsis in major trauma patients. Conclusions: The -572 polymorphism, a unique variation in the IL-6 promoter in the Chinese Han population, may be used as a relevant risk estimate for sepsis in trauma patients.

Subarachnoid hemorrhage results in significant long-lasting neurologic sequelae. Here, we investigated whether human albumin improves long-term outcomes in experimental subarachnoid hemorrhage and whether neurovascular remodeling is involved in the protection of albumin.Laboratory investigation.Hospital research laboratory.Male Sprague-Dawley rats.Rats underwent subarachnoid hemorrhage by endovascular perforation. Albumin of either 0.63 or 1.25 g/kg was injected IV immediately after the surgery. Modified Garcia test, beam-walking test, novel object recognition, and Morris water maze were employed to determine the behavioral deficits. The effects of albumin on early neurovascular dysfunction and chronic synaptic plasticity were also studied.Both doses of albumin significantly improved the sensorimotor scores (F = 31.277; p = 0.001) and cognitive performance (F = 7.982; p = 0.001 in novel object recognition test; and F = 3.431; p = 0.026 in the latency analysis of Morris water maze test) for at least 40 days after subarachnoid hemorrhage. There were remarkable microvasculature hypoperfusion, intracranial pressure rise, early vasoconstriction, neural apoptosis, and degeneration in subarachnoid hemorrhage rats, with albumin significantly attenuating such neurovascular dysfunction. Furthermore, albumin markedly prevented blood-brain barrier disruption, as indicated by less blood-brain barrier leakage, preserved blood-brain barrier-related proteins, and dampened gelatinase activities. The expressions of key synaptic elements were up-regulated with albumin supplementation in both acute and chronic phases. Accordingly, a higher dendritic spine density was observed in the prefrontal and hippocampal areas of albumin-treated subarachnoid hemorrhage animals.Albumin at low-to-moderate doses markedly improves long-term neurobehavioral sequelae after subarachnoid hemorrhage, which may involve an integrated process of neurovascular remodeling.

Several polymorphisms in the CD14 promoter have been reported to be associated with various inflammatory diseases. However, conflicting results have been shown in association studies in different populations. This study aimed to investigate the possible functional significance of both the G-1145A and T-159C polymorphisms in the CD14 promoter and their association with organ dysfunction and sepsis in adult trauma patients.Genetic, functional, and association studies.National Key Laboratory of Trauma and Departments of Traumatic Surgery in two teaching hospitals.Three hundred twenty-five healthy volunteers and 105 patients with major trauma.None.Among the five single nucleotide polymorphisms identified within CD14 promoter in a Chinese Han population, two single nucleotide polymorphisms (G-1145A and T-159C) were selected according to bioinformatics analysis. Promoter activity of polymorphisms was determined using the reporter gene assay. Plasma sCD14 and tumor necrosis factor-alpha levels were measured by enzyme-linked immunosorbent assay. Both single nucleotide polymorphisms significantly reduced transcriptional activity of the promoter, and were significantly associated with a decrease of inducible sCD14 and tumor necrosis factor-alpha production in an allele-dose effect. Moreover, trauma patients carrying the -1145 A or -159 C allele appeared to have a decreased risk of multiple organ dysfunction and sepsis. In addition, both polymorphisms had a marked synergistic effect.The CD14/-1145 and -159 polymorphisms are functional variants, which may function in a synergistic fashion, and could be used as biological risk predictors of multiorgan dysfunction and sepsis in trauma patients.