Cytokine serum level during severe sepsis in human IL-6 as a marker of severity.

Forty critically ill surgical patients with documented infections were studied during their stay in an intensive care unit. Among these patients, 19 developed septic shock and 16 died, 9 of them from septic shock. Interleukin 1 beta (IL-1 beta), tumor necrosis factor (TNF alpha), and interleukin 6 (IL-6) were measured each day and every 1 or 2 hours when septic shock occurred. Although IL-1 beta was never found, TNF alpha was most often observed in the serum at a level under 100 pg/mL except during septic shock. During these acute episodes TNF alpha level reached several hundred pg/mL, but only for a few hours. In contrast, IL-6 was always increased in the serum of acutely ill patients (peak to 500,000 pg/mL). There was a direct correlation between IL-6 peak serum level and TNF alpha peak serum level during septic shock and between IL-6 serum level and temperature or C-reactive protein serum level. Moreover, IL-6 correlated well with APACHE II score, and the mortality rate increased significantly in the group of patients who presented with IL-6 serum level above 1000 pg/mL. Thus, IL-6 appears to be a good marker of severity during bacterial infection.     

颅脑损伤早期血清炎性细胞因子的变化与预后关系分析

目的：探讨颅脑损伤患者早期血清中肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）和白细胞介素8（IL-8）变化与预后之间的关系及其临床意义。方法选取2012年3月至2014年3月期间,在本院住院的急性颅脑损伤患者80例作为观察组,并按照格拉斯哥昏迷评分标准（GCS）分为两组,其中颅脑损伤中重型（3~12分）40例,轻型（13-15分）40例;同时选择本院同期健康体检志愿者共80例为正常对照组;分别采用放射免疫法及酶联免疫吸附试验（ELISA）测定各组血清中TNF-α、IL-6和IL-8的含量水平,并且分析血清中TNF-α、IL-6和IL-8的含量与颅脑损伤程度的关系。结果住院后第1天颅脑损伤组血清中TNF-α、IL-6和IL-8水平均显著高于正常对照组（P＜0.05）;且发现所有时间点中重度组的炎症因子TNF-α、IL-6和IL-8水平均显著性高于轻度组（P＜0.05）;所有患者入院1个月后,按照格拉斯哥评分（GOS）评定患者,预后良好30例,预后不良60例,对比两组炎症因子水平,发现预后不两组患者TNF-α、IL-6和IL-8水平均显著高于预后良好组（P＜0.05）。结论血清中TNF-α、IL-6和IL-8水平可作为判断颅脑损伤严重程度的指标,其联合检测敏感性和特异性均较高,对颅脑损伤的早期诊断及预后判断意义重大。     

Comparison of systemic cytokine levels in patients with acute respiratory distress syndrome, severe pneumonia, and controls

BACKGROUND: The inflammatory response has been widely investigated in patients with acute respiratory distress syndrome (ARDS) and pneumonia. Studies investigating the diagnostic values of serum cytokine levels have yielded conflicting results and only little information is available for the differential diagnosis between ARDS and pneumonia. METHODS: Clinical and physiological data, serum concentrations of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, and quantitative cultures of lower respiratory tract specimens were obtained from 46 patients with ARDS and 20 with severe pneumonia within 24 hours of the onset of the disease and from 10 control subjects with no inflammatory lung disease. Cytokine concentrations were compared between groups and determinants in addition to the diagnosis were tested. RESULTS: Serum TNF-alpha levels were significantly higher in ARDS patients (67 (57) pg/ml) than in patients with severe pneumonia (35 (20) pg/ml; p = 0.031) or controls (17 (8) pg/ml; p = 0.007). For IL-1beta and IL-6 the observed differences were not statistically significant between patients with ARDS (IL-1beta: 34 (65) pg/ml; IL-6: 712 (1058) pg/ml), those with severe pneumonia (IL-1beta: 3 (4) pg/ml, p = 0.071; IL-6: 834 (1165) pg/ml, p = 1.0), and controls (IL-1beta: 6 (11) pg/ml, p = 0.359; IL-6: 94 (110) pg/ml, p = 0.262). TNF-alpha (standardised coefficient beta = 0.410, p<0.001) and IL-1beta (standardised coefficient beta = 0.311, p = 0.006) were most strongly associated with the degree of lung injury, even when the diagnostic group was included in the statistical model. CONCLUSIONS: Serum TNF-alpha levels were higher in patients with ARDS than in those with severe pneumonia or in control subjects. Multivariate results suggest that the levels of systemic TNF-alpha and IL-1beta reflect the severity of the lung injury rather than the diagnosis.     

Early IL-6 plasma concentrations correlate with severity of brain injury and pneumonia in brain-injured patients

BACKGROUND: Brain injury as well as early inflammatory and endocrine responses were found to be indicators for infectious complications in patients with multiple injuries. In this context, brain-derived inflammatory response as well as centrally triggered neuroendocrine activation and systemic immunodepression seem to be of major importance. Therefore, we hypothesize that a circulating index of inflammatory or endocrine function measured soon after brain injury (in patients with admission Glasgow Coma Scale [GCS] score of 4-7) would discriminate severe from moderate injury as indexed by GCS status on postinjury day 7. METHODS: In a retrospective study, 25 patients with either acute traumatic brain injury or cerebral hemorrhage and an initial GCS score of 4 to 7 were examined. Blood samples were obtained at different time points, and different immune variables and neuroendocrine hormones were determined. According to the GCS score on day 7, patients were divided into two groups (GCS score > or = 8, moderate brain injury; and GCS score < 8, severe brain injury or patients who died within the first week) for comparison of variables. Concluding from the results of this retrospective analysis, in a prospective study patients (n = 26) were divided into two groups according to their interleukin (IL)-6 plasma concentrations on day 1 (IL-6 > or = 100 pg/mL and IL 6 < 100 pg/mL). After 7 days, the GCS score, the infection rate, and the mortality were compared between these two groups. RESULTS: In the retrospective study, we could show that severe brain injury (as assessed by GCS score and mortality on day 7) was associated with high plasma levels of pro- and anti-inflammatory cytokines, acute phase proteins, and neuroendocrine hormones within 2 to 6 hours after the acute event. Among the investigated variables, elevated IL-6 plasma concentrations were stable up to 1 day after the acute event with a high predictive value with regard to the short-term prognosis and incidence of infectious complications within the first week. Because of this stability during the first 24 hours, we selected IL-6 for further studies. In the prospective study with a calculated cut-off IL-6 plasma concentration of 100 pg/mL on day 1, the predictive value of this parameter regarding the severity of the brain injury was fully confirmed (positive predictive value, 0.94; this value represents the observed pretest probability of 0.62). All patients who died (n = 5) or developed infectious complications within the first week (n = 8) showed plasma IL-6 levels > or = 100 pg/mL on day 1. CONCLUSION: The IL-6 plasma level 1 day after the acute event with a cut-off of 100 pg/mL (Immulite) seems to be a predictor for short-term prognosis and infectious complications in brain-injured patients.     

Interleukin-1 beta stimulates human mesangial cells to synthesize and release interleukins-6 and -8.

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF) have been reported to stimulate human mesangial cells (HMC) to proliferate and synthesize eicosanoids. We have examined whether they also induce HMC to release cytokines. In this study we show that both IL-1 and TNF stimulate HMC to release IL-6 and IL-8. Cycling and quiescent HMC were stimulated with various concentrations of either recombinant IL-1 beta or TNF for 1 to 24 hours. IL-1 beta at doses as low as 6 pg/ml stimulated mesangial cells to synthesize mRNA for both IL-6 and IL-8 as assessed by Northern analysis; mRNA for tubulin remained constant, which demonstrated a specific increase in mRNA. Secretion of IL-6 and IL-8 into the culture medium increased (4.5 to 18 ng/ml and 4 to 40 ng/ml, respectively) measured by ELISAs. TNF had similar effects but only in high concentrations (greater than 100 ng/ml). IL-1 beta did not stimulate cells to proliferate, as measured by 3H thymidine incorporation. TNF caused proliferation but only in concentrations over 100 ng/ml. We conclude that IL-1 beta is a potent stimulator of human mesangial cell production of IL-6 and IL-8, both of which may influence injury in nephritis. TNF also stimulates mesangial cells but only in pharmacological doses.     

Effects of acetate dialysate on transforming growth factor beta 1, interleukin, and beta 2-microglobulin plasma levels.

To evaluate potential adverse effects of acetate use in hemodialysis (HD), we measured plasma interleukin (IL-1 alpha, IL-1 beta, IL-6), TNF alpha, TGF beta 1, and beta 2-microglobulin levels with ELISA assays in normal (N = 9), CRF (N = 6), CAPD (N = 7) and HD (N = 8) subjects and compared the effects of acetate (Ac) and acetate-free (Ac-free) dialysate. TGF beta 1 was the only cytokine consistently detected. Compared to normals (median 57, range 53 to 68 pg/ml, one undetected; N = 8), TGF beta 1 was higher in the CRF (75, 70 to 97 pg/ml, one undetected) and CAPD (75.5, 66 to 116 pg/ml, N = 6) groups (P less than 0.05), and was somewhat higher in the HD (68, 52 to 88 pg/ml) group (P less than 0.10). Acutely, TGF beta 1 pre-HD (70, 63 to 88 pg/ml) increased above normals post AcHD [79.5, 65 to 140 pg/ml uncorrected for ultrafiltration (UF)] and was higher after AcHD versus Ac-free HD both uncorrected (79.5, 65 to 140 pg/ml vs. 70, 52 to 86 pg/ml) and corrected for UF (68, 51 to 115 pg/ml vs. 57, 43 to 69 pg/ml; P less than 0.05). beta 2-microglobulin was not different after AcHD (81.2 +/- 8.0 mg/ml) versus Ac-free HD (72.5 +/- 6.9 mg/ml). Significantly lower serum inorganic phosphorus was also found four hours post-AcHD compared to four hours post-Ac-free HD (0.87 mmol +/- 0.10 SEM vs. 1.05 mmol +/- 0.07 SEM; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

细胞因子在心脏移植急性排斥反应中的表达及其作用机理

目的观察同种大鼠心脏移植急性排斥反应中,局部细胞因子网络的变化及其机理.方法健康雄性Wistar大鼠(受体)和SD大鼠各48只,将接受移植心脏的Wistar大鼠分4组,每组12只.A组对照组;B组抗白介素2单克隆抗体(IL-2Mab)组;C组环孢菌素A(CsA)组;D组IL-2Mab加CsA组.4组大鼠分别静脉给予生理盐水、抗白介素2单克隆抗体及口服CsA、静脉给予抗白介素2单克隆抗体加口服CsA,采用改良的移植术式建立移植模型.常规监测排斥反应发生情况.应用RT-PCR的方法于术后第1、3、5、7、9、11、14天动态检测移植物局部细胞因子IL-1β、IL-2、CD25、IL-4、IL-5、IL-6、IL-10、TNFα、IFNγ的表达水平.结果移植心脏存活时间,A组为(8.3±1.7)d;B组为(29.2±7.1)d;C组为(26.4±5.7)d;D组为(55.0±11.6)d.B、C、D组移植心脏存活时间显著延长,与A组相比,差异有极显著性意义(P＜0.01).存活时间较长的移植心脏的淋巴细胞浸润和心肌坏死的程度比存活时间较短的心脏明显减轻.IL-1β的表达在各组均较高;IL-4、IL-5、IL-6、IL-10的表达水平在移植心脏存活时间较长的组较高;而IL-2、CD25、IFN-γ、TNFα的表达则相对较低;4组相比差异有显著性意义(P＜0.05).结论细胞因子网络在心脏移植排斥反应中发生了相应的变化,并与干预的因素及移植物存活时间有密切的关系.IL-2Mab、CsA联合用药促使TH1类细胞因子向TH2类细胞因子整体偏离,这种免疫偏离使移植心脏存活时间显著延长.     

Cerebrovascular cytokine responses during coronary artery bypass surgery: specific production of interleukin-8 and its attenuation by hypothermic cardiopulmonary bypass.

Brain dysfunction after cardiopulmonary bypass (CPB) is common, and it has been hypothesized that this injury might be due partly to activation of inflammatory processes in the brain. We measured juguloarterial gradients for interleukin-1beta, interleukin-6, and interleukin-8 (IL-8) as indices of local proinflammatory cytokine production in the brain and studied the effect of temperature during CPB on these changes. Twelve patients undergoing coronary artery bypass graft surgery (normothermic CPB n = 6, hypothermic CPB n = 6) were studied. Cytokine levels were measured in paired arterial and jugular bulb samples obtained before, during, and after CPB. Although systemic levels of all three cytokines increased during and after CPB, increases in juguloarterial cytokine gradients were observed only for IL-8. Juguloarterial IL-8 gradients started to increase 1 h post-CPB and were significantly elevated 6 h post-CPB (P < 0.05). At this time point, the median (interquartile range) juguloarterial IL-8 gradients were significantly larger in the normothermic CPB group (25.81 [24.49-39.51] pg/mL) compared with the hypothermic CPB group (6.69 [-0.04 to 15.47] pg/mL; P < 0.05). These data imply specific and significant IL-8 production in the cerebrovascular bed during CPB and suggest that these changes may be suppressed by hypothermia during CPB. IMPLICATIONS: Using juguloarterial gradients to measure cerebrovascular cytokine production is novel in the setting of cardiopulmonary bypass and implicates the cerebral activation of inflammatory processes, which may contribute to brain dysfunction. Hypothermia during cardiopulmonary bypass may significantly attenuate this response.     

Changes of interleukin-1 β, tumor necrosis factor α and interleukin-6 in brain and plasma after brain injury in rats

Objective: To study the changes of interleukin-1 β(IL-1β), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) levels in brain and plasma after brain injury and to assess the relationship between the cytokine levels and injury severity in rats. Methods. A total of 51 male Wistar rats, weighing 280-340g, were anesthetized with chloral hydrate(400 mg/kg body weight) through intraperitoneal injection and fixed on a stereotaxic instrument. Severe brain injury was created in 16 rats (severe injury group) and moderate brain injury in 18 rats (moderate injury group) by a fluid percussion model, and cytokine levels of IL-1β, TNFα and IL-6 were measured with biological assay. And sham operation was made on the other 17 rats (control group). Results: In the control group, the levels of IL-1β,TNFα and IL-6 were hardly detected in the cortex of the rats, but in the ipsilateral cortex of the rats in both injury groups, they increased obviously at 8 hours after injury.The increasing degree of these cytokines had no significant difference between the two injury groups. The levels of IL-6 in the plasma of all the rats increased slightly, whereas the levels of IL-1β and TNFα were undetectable. Conc|usions: The increase of IL-1β, TNFα and IL-6 levels is closely related to brain injury. The increased cytokine levels in the central nervous system are not parallel to those in the peripheral blood. It suggests that inflammatory cytokines play important roles in the secondary neural damage after brain injury.     

Decreased IL-6 secretion by fibroblasts following repeated doses of TNF alpha or IL-1 alpha: post-transcriptional gene regulation

Tumor necrosis factor-alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) are pluripotent cytokines mediating the host response to sepsis, injury, and cancer. Animals can be protected from the lethal effects of TNF alpha by repeated administration of sublethal doses, but the mechanism of this effect is not known. Human foreskin fibroblasts (FS4 cells), which rapidly elaborate interleukin-6 (IL-6) when stimulated with TNF alpha or IL-1 alpha, were grown in culture as confluent monolayers and their secretion of IL-6 was quantitated using the murine B9-hybridoma bioassay against an external reference of human recombinant IL-6 (Genetics Institute). When FS4 cells were incubated with human recombinant TNF alpha (50 ng/ml; Cetus) or recombinant IL-1 alpha (30 pg/ml; Genzyme) a rapid increase in IL-6 production was measured over control, rising to IL-6 levels of 71.7 +/- 5.9 units/ml with TNF alpha and 54.0 +/- 1.2 units/ml with IL-1 alpha after 7.5 hr incubation. FS4 cells which were exposed to cytokine, rinsed, and then reexposed to cytokine 24 hr later produced significantly less IL-6 [38.1 +/- 2.8 units/ml with second exposure to TNF alpha (P less than 0.05), and 18.3 +/- 1.9 units/ml with second exposure to IL-1 alpha (P less than 0.01)]. Successive daily exposure to TNF alpha or IL-1 alpha caused a further stepwise diminution of IL-6 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

血液灌流对尿毒症患者血清IL-1β、CRP和TNF-α水平的影响

目的观察血液灌流对维持性血液透析尿毒症患者血清中IL-1β、CRP和TNF-α的影响,以期为临床工作提供理论支持。方法收集93例尿毒症患者,随机分为观察组（51例）与对照组（42例）,对照组应用常规治疗和血液透析,观察组在常规治疗基础上加用血液灌流治疗,观察二组治疗前、治疗后血清中IL-1β、CRP和TNF-α的改变。结果尿毒症患者血清中IL-1β、CRP和TNF-α的表达增高,观察组与对照组治疗后血清中IL-1β、CRP和TNF-α的表达均下降,但是观察组下降值明显高于对照组。结论尿毒症患者应用血液透析和血液灌流进行治疗,能明显降低血清中IL-1β、CRP和TNF-α的表达,改善炎性微循环,临床中可以积极应用。     

Inhibition of cytokine synthesis by peritoneal dialysate persists throughout the CAPD cycle.

The current study focused on the effect of continuous ambulatory peritoneal dialysis (CAPD) dialysate obtained following different intraperitoneal dwell periods on the release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha) from mononuclear leukocytes (PBMC). Aliquots of 5 x 10(6)/ml healthy peripheral PBMC were exposed to fresh or spent CAPD dialysate (10-240 min of intra-peritoneal dwell) and stimulated with Escherichia coli endotoxin (10 micrograms/ml, 2h). IL-6 and TNF alpha in cell supernatants were determined by specific enzyme immunoassays. Control PBMC in physiological buffer released 361 +/- 70 pg/ml IL-6 and 717 +/- 147 pg/ml TNF alpha (mean +/- SEM, n = 8), whereas exposure to fresh dialysis fluids severely suppressed cytokine release from PBMC (less than 30 pg/ml IL-6 and less than 15 pg/ml TNF alpha). A significant inhibition of IL-6 and TNF alpha release was also observed in PBMC exposed to spent dialysate. The inhibitory capacity of the spent fluids was pronounced with increasing intra-peritoneal dwell time (10 min: 183 +/- 45 pg/ml IL-6 and 538 +/- 109 pg/ml TNF alpha; 240 min: 26 +/- 5 pg/ml IL-6 and 105 +/- 30 pg/ml TNF alpha; mean +/- SEM, n = 16). These data indicate that the impairment of cell responsiveness following exposure of PBMC to peritoneal dialysate is not restricted to the unused fluids, but is also observed following intra-peritoneal equilibration. Moreover, our findings suggest the presence of cytokine inhibitory factors in the peritoneal dialysate of CAPD patients which appear to accumulate in the peritoneal effluent during the CAPD cycle.     

清胰汤对大鼠重症急性胰腺炎时急性肺损伤治疗作用的观察

目的 :探讨中药清胰汤在治疗重症急性胰腺炎 (SAP)时对急性肺损伤 (ALI)的保护机制 ,为临床用药提供确切的理论依据。 方法 :Wistar大鼠制备大鼠重症急性胰腺炎肺损伤模型 ,随机分成 3组 :假手术对照组 (SHAM) ,SAP模型组 (SAP) ,SAP +清胰汤治疗组 (QYT)。分别于造模后 2 4h测定动脉血气、血清淀粉酶的含量、血清内毒素及血清和肺组织匀浆中的TNF、IL - 6、MDA、SOD的含量、肺湿重 /干重比值以及肺组织病理学改变。 结果 :①SAP模型组内毒素、TNF、IL - 6、氧自由基、肺湿重 /干重比值均较SHAM组明显升高 (P <0 0 1)。动脉血气显示肺损伤严重 ,肺组织病理学形态改变加重。②QYT组各检测指标均较SAP组明显改善 (P <0 0 5 )。 结论 :清胰汤通过保护肠屏障 ,减少了细菌移位 ,降低血清中内毒素水平 ,防止过氧化损伤 ,纠正机体致炎和抗炎系统失衡等多方面机制而对肺脏起到全面保护作用。     

Mechanical Ventilation with Lower Tidal Volumes and Positive End-expiratory Pressure Prevents Pulmonary Inflammation in Patients without Preexisting Lung Injury

Background: Mechanical ventilation with high tidal volumes aggravates lung injury in patients with acute lung injury or acute respiratory distress syndrome. The authors sought to determine the effects of short-term mechanical ventilation on local inflammatory responses in patients without preexisting lung injury.

Methods: Patients scheduled to undergo an elective surgical procedure (lasting >=5 h) were randomly assigned to mechanical ventilation with either higher tidal volumes of 12 ml/kg ideal body weight and no positive end-expiratory pressure (PEEP) or lower tidal volumes of 6 ml/kg and 10 cm H2O PEEP. After induction of anesthesia and 5 h thereafter, bronchoalveolar lavage fluid and/or blood was investigated for polymorphonuclear cell influx, changes in levels of inflammatory markers, and nucleosomes.

Results: Mechanical ventilation with lower tidal volumes and PEEP (n = 21) attenuated the increase of pulmonary levels of interleukin (IL)-8, myeloperoxidase, and elastase as seen with higher tidal volumes and no PEEP (n = 19). Only for myeloperoxidase, a difference was found between the two ventilation strategies after 5 h of mechanical ventilation (P < 0.01). Levels of tumor necrosis factor [alpha], IL-1[alpha], IL-1[beta], IL-6, macrophage inflammatory protein 1[alpha], and macrophage inflammatory protein 1[beta] in the bronchoalveolar lavage fluid were not affected by mechanical ventilation. Plasma levels of IL-6 and IL-8 increased with mechanical ventilation, but there were no differences between the two ventilation groups.     

Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra

Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1alpha (IL-1alpha) and IL-1beta in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1alpha, IL-1beta, and IL-1ra in brain microdialysates (100-kDa membrane) in 15 TBI patients. We also analyzed energy-related molecules (glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate ratio) in these brain microdialysates. Mean of mean (+/-SD) in vitro microdialysis percentage recoveries (extraction efficiencies) were IL-1alpha 19.7+/-7.6%, IL-1beta 23.9+/-10.5%, and IL-1ra 20.9+/-6.3%. In the patients' brain microdialysates, mean of mean cytokine concentrations (not corrected for percentage recovery) were IL-1alpha 5.6+/-14.8 pg/mL, IL-1beta 10.4+/-14.7 pg/mL, and IL-1ra 2796+/-2918 pg/mL. IL-1ra was consistently much higher than IL-1alpha and IL-1beta. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1beta and increasing IL-1ra (Spearman r=0.59, p=0.028). There was also a significant relationship between increasing IL-1ra and decreasing intracranial pressure (Spearman r=-0.57, p=0.041). High concentrations of IL-1ra, and also high IL-1ra/IL-1beta ratio, were associated with better outcome (Mann Whitney, p=0.018 and p=0.0201, respectively), within these 15 patients. It is unclear whether these IL-1ra concentrations are sufficient to antagonize the effects of IL-1beta in vivo. This study demonstrates feasibility of our microdialysis methodology in recovering IL-1 family cytokines for assessing their inter-relationships in the injured human brain, and suggests a neuroprotective role for IL-1ra. It remains to be seen whether exogenous IL-1ra or other agents can be used to manipulate cytokine levels in the brain, for potential therapeutic effect.     

Absence of early proinflammatory cytokine expression in experimental intracerebral hemorrhage

OBJECTIVE: We sought to analyze the regional concentrations of proinflammatory cytokines in the acute period of intracerebral hemorrhage (ICH) and to test the hypothesis that ICH is associated with the expression of proinflammatory cytokines in the acute period. Although the expression of cytokines and their role in neuronal injury and inflammation is well characterized in cerebral ischemia and head injury, no information exists regarding expression of cytokines in ICH. METHODS: We introduced ICH in eight anesthetized mongrel dogs by autologous blood injection (6 ml) under arterial pressure in the deep white matter adjacent to the left basal ganglia. Samples of arterial blood and cerebrospinal fluid were collected, and tissue extracts were prepared from different regions of the brain for immunoassay of tumor necrosis factor alpha, interleukin (IL)-1beta, and IL-6 concentrations in animals with and without ICH. RESULTS: The tumor necrosis factor a levels (+/- standard error) in the cerebrospinal fluid 1 hour after ICH did not differ significantly between the ICH group and the control group (7.1 +/- 1.3 pg/ml versus 10.8 +/- 2.3 pg/ml, P = 0.22). Levels in the perihematoma region in the ICH group (96.6 +/- 3.1 pg/ml) were not significantly different from those in the control group (93.4 +/- 6.7 pg/ml, P = 0.7). IL-6 levels (+/- standard error) in the perihematoma region in the ICH group (116.3 +/- 13.3 pg/ml) did not differ significantly from those in corresponding regions in the control group (122.3 +/- 12.8 pg/ml, P = 0.7). IL-1beta levels were below 5 pg/ml in serum, cerebrospinal fluid, and extracts of different brain regions. CONCLUSION: The early pathophysiology of ICH does not involve significant expression of tumor necrosis factor a either in the perihematoma region or other regions of the brain. The observation suggests that the pathophysiology of ICH in the acute period is different from both cerebral ischemia and traumatic brain injury.     

The effect of traumatic brain injury upon the concentration and expression of interleukin-1beta and interleukin-10 in the rat

BACKGROUND: Using a model of traumatic brain injury (TBI) in the rat, this study was undertaken to characterize the short-term biochemical changes of IL-1beta, IL-10, and tumor necrosis factor TNF-alpha to determine whether injury in the brain elicits a systemic cytokine response. METHODS: Sprague-Dawley rats were subjected to a TBI using a weight-drop model and then killed at various time points after injury. Samples of blood, brain, and liver were recovered and analyzed for concentrations of IL-1beta, IL-10, and TNF-alpha as well as IL-1beta and IL-10 mRNA expression in liver and brain. RESULTS: In brain, IL-1beta increased in the first hour after injury, peaked at 8 hours, and declined during the final 16 hours. IL-10 quickly increased during the first 4 hours and then gradually rose over the last 20 hours. Analysis of liver showed no upregulation of these markers and plasma IL-1beta and IL-10 were unchanged compared with controls. Although not upregulated in brain, TNF-alpha showed a statistically significant (p < 0.05) rise in plasma from 14 +/- 16 pg/mL at 20 minutes to 91 +/- 28 pg/mL at 24 hours. CONCLUSION: Using a model of TBI, we have demonstrated that there is a rise in both IL-1beta and IL-10 in the injured rat brain within the first 24 hours after injury without a corresponding rise in either plasma or liver. Therefore, it appears as if two strong indicators of brain injury severity are expressed and possibly carry out their actions solely in the brain.     

TNF Alpha−308 Genotype and Renin–Angiotensin System in Hemodialysis Patients: An Effect on Inflammatory Cytokine Levels?

BACKGROUND: Renin-angiotensin system (RAS) was suggested to modulate inflammatory cytokine production. Angiotensin II was consistently shown to increase production of tumor necrosis factor alpha (TNF-alpha). However, inflammatory cytokines and RAS were modulated by genetic polymorphisms such as TNF-alpha-308 G > A and angiotensin-converting enzyme (ACE) I/D gene polymorphisms. The aim of this study was to investigate the effects of ACE and TNF-alpha genotypes on inflammatory cytokines in hemodialysis (HD) patients. METHODS: ACE I/D and TNF-alpha-308 G > A genotypes, pre- and postdialysis plasma renin activity (PRA), serum ACE, interleukin-1 beta (IL-1beta), and TNF-alpha levels were determined in 22 HD patients. RESULTS: Predialysis serum ACE activity is correlated with TNF-alpha (r = 0.63; P = 0.01), and PRA was correlated with IL-1beta levels (r = 0.49; P = 0.02). Pre/postdialysis IL-1beta and TNF-alpha were similar in DD and II/ID ACE genotypes. Predialysis TNF-alpha and IL-1beta (32.4 +/- 5; 35.1 +/- 4.2 vs. 28.1 +/- 3.7; 26.5 +/- 6.2 pg/mL; P < 0.05) and postdialysis TNF-alpha levels (30.4 +/- 1.4 vs. 28.4 +/- 0.82 pg/mL; P < 0.05) were significantly higher in TNF1/2 than TNF1/1 patients. CONCLUSION: ACE and TNF-alpha-308 G > A (1/2) gene polymorphisms may contribute to modulation of proinflammatory cytokine production and hence chronic inflammation in HD patients.