创伤后细胞因子和炎症介质的变化及其意义

创伤后全身炎症反应综合征,代偿性抗炎反应综合征是引起多器官功能障碍综合征的发病基础.了解促炎介质与抗炎介质在创伤后免疫功能障碍及脓毒症发生发展中的作用有助于指导治疗,改善预后.     

细胞损伤中腺苷代谢通路与促炎因子调控的研究进展

细胞损伤释放出大量三磷酸腺苷(adenosine triphophate,ATP),激活炎症细胞产生多种炎症因子,从而引发瀑布式炎症反应及血栓形成,加重损伤程度。腺苷(adenosine,Ado)代谢通路由Ado合成酶CD39-CD73、核苷转运体(nucleoside transporters,NTs)及代谢关键酶—腺苷脱氨酶(adenosine deaminase,ADA)、腺苷激酶(adenosine kinase,ADK)组成,能将促炎因子ATP转化为抗炎介质Ado,如同炎症反应的"开关",调节促炎与抗炎平衡,影响损伤的转归。本文就近年来腺苷代谢通路在细胞损伤中的进展进行综述。     

迷走神经及其递质乙酰胆碱抗炎研究进展

外界刺激(如细菌、创伤、烧伤等)引起致炎因子释放并导致炎症反应,有利于消灭细菌、清除坏死组织、促进修复及伤口的愈合.同时,为了防止过度炎症,机体本身亦产生内源性的抗炎因子和抗炎反应,如果致炎反应和抗炎反应达到平衡则机体处于稳态[1].若致炎因子大量释放,则引起过度炎症反应.相反,抗炎因子大量释放,可导致免疫抑制.以往的研究较多关注体液因素或细胞因子的自分泌和旁分泌对抗炎或促炎介质释放的影响,近年来"神经-内分泌"抗炎通路逐渐成为研究热点,其中迷走神经及其递质乙酰胆碱具有重要的作用.现将近年来这方面的研究进展综述如下.     

炎性介质与SIRS、CARS、MODS和CBP治疗

近年来研究证明机体的炎症细胞被各种损伤过度激活后产生大量的炎性介质,导致机体炎症反应失控是发生全身性炎症反应综合征(SIRS)、代偿性抗炎反应综合征(CARS)和多器官功能障碍综合征(MODS)的重要环节,而早期控制炎症反应,阻断其发展或有效清除循环中的炎性介质可能是防治SIRS和MODS的关键。因此,近年来研究连续性血液净化(CBP)对机体炎性介质的清除也成为一个热点。     

全身炎症反应综合征的免疫状态和干预措施

全身炎症反应综合征是由感染和非感染因素引起的促炎症因子与抗炎症因子失去平衡,继而导致初期免疫功能亢进,后期免疫功能抑制。连续性血液净化既可排除炎症介质,又可调节免疫状态。     

兴奋胆碱能抗炎通路干预炎症与缺血引起的器官损害

胆碱能抗炎通路是指中枢神经系统通过胆碱能神经及其递质调节或对抗全身炎症反应的通路。其抗炎机制是通过兴奋胆碱能N受体α7亚基(α7nAChR)、阻断核因子-κB(NF—κB)途径活化,进而抑制促炎细胞因子/趋化因子的产生和释放,阻止T细胞的分化和成熟以及抑制中性粒细胞和单个核     

免疫应答在重症急性胰腺炎相关感染中的作用

目的总结免疫应答在重症急性胰腺炎(SAP)并发感染中的作用及研究进展,为给予SAP适当的免疫靶向治疗提供依据。方法对近年来免疫应答在SAP并发感染中作用的研究进展进行综述。结果 SAP早期胰腺损伤导致免疫激活,一方面炎症细胞大量聚集并释放炎性因子而引发级联炎症反应,另一方面机体代偿性地释放抗炎因子来对抗级联炎症反应过程中产生的炎症因子,随后抗炎因子释放而引起代偿性抗炎反应综合征,此时机体呈免疫抑制状态,从而使感染发生率明显增加。结论代偿性抗炎反应综合征是SAP发生感染的主要原因之一。目前,SAP的治疗以补液、禁食、肠外营养等对症支持治疗为主。若能针对SAP发生感染的免疫机制进行相对应的免疫治疗,即早期给予适当的免疫抑制治疗同时动态监测机体免疫系统状态,当机体免疫状态趋于抑制时适当的免疫刺激疗法将有可能降低SAP的病死率并改善其预后。     

全身炎症反应综合征的免疫状态和干预措施

全身炎症反应综合征是由感染和非感染因素引起的促炎症因子与抗炎症因子失去平衡，继而导致初期免疫功能亢进，后期免疫功能抑制。连续性血液净化既可排除炎症介质，又可调节免疫状态。     

急性胰腺炎中全身炎症反应综合征与抗炎症反应综合征

急性胰腺炎是一种常见的急重症,被公认为是炎症紊乱的过程.早期暴发性的促炎细胞因子释放引起全身炎症反应综合征,导致多器官功能障碍综合征引起死亡.后期由于大量的抗炎细胞因子,引发抗炎症反映综合征,机体免疫功能受到抑制,诱发感染,进而形成毒血症.因此,重新建立SIRS/CARS的平衡对急性胰腺炎患者发病过程及转归有着重要的临床意义.本文就急性胰腺炎引起的SIRS、CARS有关参与冈子及机制做一综述.     

炎性介质与SIRS、CARS、MODS和CBP治疗

近年来研究证明机体的炎症细胞被各种损伤过度激活后产生大量的炎性介质，导致机体炎症反应失控是发生全身性炎症反应综合征(SIRS)、代偿性抗炎反应综合征(CARS)和多器官功能障碍综合征(MODS)的重要环节，而早期控制炎症反应，阻断其发展或有效清除循环中的炎性介质可能是防治SIRS和MODS的关键。因此，近年来研究连续性血液净化(CBP)对机体炎性介质的清除也成为一个热点。     

Cytokine storm in acute pancreatitis

Efforts to unravel the events in the evolution of tissue damage in acute pancreatitis have shown a number of inflammatory mediators to be involved. The pathways of damage are similar, whatever the etiology of pancreatitis, with three phases of progression: local acinar injury, systemic response, and generalized sepsis. The proinflammatory response is countered by an anti-inflammatory response, and an imbalance between these two systems leads to localized tissue destruction and distant organ damage. Cytokines lie at the heart of the problem and are involved in all aspects of the cascade leading to systemic inflammatory response syndrome and multiple organ dysfunction syndrome. This review discusses the present knowledge about the role of various mediators in this process, their genetic control, and the effects of their modulation. The major proinflammatory mediators are tumor necrosis factor, interleukins 1, 6, and 8, platelet activation factor, and the chemokines. The major anti-inflammatory factors include interleukin 10, and interleukin 1 receptor antagonist. Emerging knowledge of new mediators as well as future strategy of damage control is discussed. Received: February 19, 2002 / Accepted: March 8, 2002 Offprint requests to: A.N. Kingsnorth     

Pathophysiology of polytrauma

Immediate and early trauma deaths are determined by primary brain injuries, or significant blood loss (haemorrhagic shock), while late mortality is caused by secondary brain injuries and host defence failure. First hits (hypoxia, hypotension, organ and soft tissue injuries, fractures), as well as second hits (e.g. ischaemia/reperfusion injuries, compartment syndromes, operative interventions, infections), induce a host defence response. This is characterized by local and systemic release of pro-inflammatory cytokines, arachidonic acid metabolites, proteins of the contact phase and coagulation systems, complement factors and acute phase proteins, as well as hormonal mediators: it is defined as systemic inflammatory response syndrome (SIRS), according to clinical parameters. However, in parallel, anti-inflammatory mediators are produced (compensatory anti-inflammatory response syndrome (CARS). An imbalance of these dual immune responses seems to be responsible for organ dysfunction and increased susceptibility to infections. Endothelial cell damage, accumulation of leukocytes, disseminated intravascular coagulation (DIC) and microcirculatory disturbances lead finally to apoptosis and necrosis of parenchymal cells, with the development of multiple organ dysfunction syndrome (MODS), or multiple organ failure (MOF). Whereas most clinical trials with anti-inflammatory, anti-coagulant, or antioxidant strategies failed, the implementation of pre- and in-hospital trauma protocols and the principle of damage control procedures have reduced post-traumatic complications. However, the development of immunomonitoring will help in the selection of patients at risk of post-traumatic complications and, thereby, the choice of the most appropriate treatment protocols for severely injured patients.     

The impact of inflammation on metabolic regulation in chronic kidney disease: a review.

Chronically uremic patients are characterized by a low-grade systemic inflammation that reflects the consequences of an unbalanced production of proinflammatory and anti-inflammatory cytokines and contributes to the progression of atherosclerotic vascular disease and malnutrition. The causes of inflammation in end-stage kidney disease have been studied in details. Nonetheless, the degree of activation of the systemic inflammatory response shows great interindividual variability that cannot be explained by renal disease or dialysis. The amount of cytokine that is produced on a definite stimulus varies among individuals. Single nucleotide polymorphisms in the promoter or coding regions of cytokine genes lead to high or low productions of these mediators and may genetically explain this heterogeneity. The "low-producer" genotypes for the anti-inflammatory cytokine interleukin-10 are more permissive for a greater level of systemic inflammation and for increased cardiovascular morbidity and mortality in patients on hemodialysis. Potential pharmacologic and nutritional approaches for treatment of systemic inflammation have been identified in recent years. In addition, physical exercise training may reduce the systemic inflammatory response. Definition of the relationships between different cytokine gene polymorphisms and systemic inflammation in chronically uremic patients will improve efficacy of targeted anti-inflammatory treatments.     

Inflammatory cytokines and cell response in surgery

The systemic inflammatory response as mediated by the cytokine network is undoubtedly complex. While inflammatory cytokines are indispensable in wound healing and the restoration of homeostasis, it is often the excessive activity of either proinflammatory or anti-inflammatory cytokines that causes injury to the host or renders the host immunocompromised, respectively. Central to the functional biology of cytokines in surgical injury and infections are the responses of immune cells to such insults. It is clear that immunocytes are the source of cytokine production, and these products possess important autocrine, as well as systemic activities. The ability to alter immunocyte function through extracellular hormonal influences or by manipulating intracellular signaling mechanisms are potential strategies for regulating the inflammatory cytokine response during injury.     

Immune response in asymptomatic smokers

BACKGROUND: It has been demonstrated that cigarette smoking affects the immune system. Impairment of alveolar mononuclear cell function, described previously, may contribute to the higher rate of postoperative respiratory infections. However, increased susceptibility of smokers to infections of other origin (e.g. wound-related) implies that tobacco effect is not restricted to the respiratory immune competent cells. The present study was designed to investigate the systemic effect of tobacco smoking as it exerted on blood-derived immune cells. We measured systemic cytotoxic activity of natural killer cells, production of pro- and anti-inflammatory cytokines by blood mononuclear cells and their proliferation in response to mitogens. To minimize the immunosuppressive effect of other smoke-related factors, the smokers with chronic obstructive pulmonary disease (COPD) were excluded from this study. METHODS: Peripheral blood mononuclear cells (PBMC) from 24 chronic asymptomatic smokers, and 28 controls, age and gender matched, were isolated and incubated in vitro with lipopolysaccharide (LPS) or phytohemagglutinin (PHA) to induce secretion of IL-1beta, IL-1ra, IL-6, IL-10, TNFalpha and IL-2, respectively, from mononuclear cells. The level of the cytokines in the supernatants was measured using ELISA kits. The proliferative response to the mitogens PHA and concanavalin A (ConA) was evaluated by 3H-thymidine incorporation and NK cell cytotoxicity by 51Cr release assay. RESULTS: Mononuclear cells from smokers showed increased production of the pro-inflammatory cytokines IL-1beta, IL-6 and TNFalpha and enhanced proliferative response to mitogens as compared to non-smoking population. The secretion of IL-2 and the anti-inflammatory cytokines IL-1ra and IL-10 was similar in both groups. NK cell cytotoxic activity was suppressed in the smokers. CONCLUSION: Cigarette smokers without chronic obstructive pulmonary disease (COPD) exhibit impaired NK cytotoxic activity in peripheral blood and unbalanced systemic production of pro- and anti-inflammatory cytokines. These changes may serve as predisposing factors for respiratory and systemic infections in the postoperative period and should alert an anesthetist during perioperative management.     

Cytokine Levels (IL-4, IL-6, IL-8 and TGFβ) as Potential Biomarkers of Systemic Inflammatory Response in Trauma Patients

Purpose

Much research is now being conducted in order to understand the role of cytokines in the development of the inflammatory response following trauma. The purpose of this study was to evaluate whether serum levels of certain cytokines, measured immediately after initial injury, can be used as potential biomarkers for predicting the development and the degree of severity of the systemic inflammatory response (SIRS) in patients with moderate and severe trauma.

Methods

We conducted a prospective study with 71 individuals of whom 13 (18.3 %) were healthy controls and 58 (81.7 %) were traumatized orthopaedic patients who were categorized into two groups: 31 (43.6 %) with moderate injuries and 27 (38.1 %) patients with severe orthopaedic trauma. Thirty cc of heparinized blood were drawn from each individual within a few hours after the injury. Serum levels of pro-inflammatory, regulatory and anti-inflammatory cytokines were measured in each individual participant.

Results

High levels of pro-inflammatory cytokines IL-1β,-6,-8,-12, tumour necrosis factor alpha and interferon gamma were found in all injured patients compared to healthy controls. Only IL-6 and IL-8 were significantly higher in the injured patients. Levels of the regulatory cytokines, transformed growth factor beta (TGF-β) and IL-10 were higher in the injured patients, but significant only for TGF-β. Levels of IL-4 were significantly lower in the injured groups as compared to the controls.

Conclusions

Secretion of large amounts of pro-inflammatory cytokines and decreased level of anti-inflammatory cytokines during the acute phase of trauma may lead to the development of systemic inflammatory response syndrome (SIRS) in unstable polytraumatized patients. SIRS may result in life threatening conditions as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). High levels of IL-6, IL-8, TGFβ and low levels of IL-4 were found to be reliable markers for the existence of immune reactivity in trauma patients. More research is needed to study pattern of cytokine levels along the acute period of injury, after surgical interventions and during recovery.     

Intrarenal Administration of Molsidomine, a Molecule Releasing Nitric Oxide, Reduces Renal Ischemia-Reperfusion Injury in Rats

Ischemia reperfusion (I-R)-induced renal damage is reduced by systemic administration of the NO-dependent vasodilator molsidomine. The aim of this study was to estimate the effect of direct intrarenal molsidomine administration on renal dysfunction and inflammatory reaction after experimental I-R in rats, in order to assess only renal NO effects and to obviate its systemic hemodynamic action. Ischemia was induced by renal pedicle ligation (60 min) followed by reperfusion and contralateral nephrectomy. Molsidomine (4 mg/kg) was infused into the renal artery 15 min before reperfusion and its effects were compared with those of the NO-independent vasodilator hydralazine (2 mg/kg). Survival rates after 7 days were 100% in the sham-operated group and 75% in the I-R rats. Molsidomine treatment almost completely prevented the I-R-induced renal dysfunction, and survival reached 100%. Molsidomine prevented an I-R-induced increase in superoxide anion and reduced plasma levels of pro-inflammatory cytokines (TNF-alpha, IL-1beta and IFN-gamma), whereas it enhanced anti-inflammatory cytokines (IL-6 and IL-10). Inflammatory cell infiltration and cell-adhesion molecules (ICAM-1, PECAM-1, VCAM-1 and P-selectin) were lower in the molsidomine-treated kidneys than in the untreated animals. All these protective effects were not observed after hydralazine administration. In conclusion, intrarenal administration of molsidomine before reperfusion improved renal function and decreased inflammatory responses after I-R.     

IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly

It has been increasingly apparent that wasting and cardiovascular disease (CVD) is associated with a persistent systemic inflammatory response in end-stage renal disease (ESRD) patients. The reasons for the increased risk of inflammation in ESRD patients appear to be complex, including non-dialysis as well as dialysis-related factors. The combination of an impaired immune response coupled with persistent immune stimulation may have a role in the low-grade systemic inflammation and altered cytokine balance that characterizes the uremic state and which may translate into increased risk for vascular disease. The accelerated atherosclerotic process of ESRD may involve several interrelated processes, such as oxidative stress, endothelial dysfunction, and vascular calcification, in a milieu of constant low-grade inflammation with impaired function of neutrophils and T cells, as well as a dysregulated cytokine network. Although a large number of pro- and anti-inflammatory cytokines are of importance, available data suggest that the anti-inflammatory cytokine interleukin (IL)-10 and the mainly proinflammatory cytokines IL-6 and tumor necrosis factor-alpha (TNF-alpha) may play important roles in the development of Th imbalance, CVD and wasting in the uremic milieu. Given the strong association between proinflammatory cytokines and complications common in ESRD, such as vascular calcification and wasting, the potential role of both general and targeted anticytokine treatment strategies in ESRD patients needs further evaluation.     

Pro-inflammatory and anti-inflammatory cytokine increases after spinal instrumentation surgery

We investigated the effects of instrumentation on postoperative inflammatory reaction and identified standard changes in serum cytokine concentrations after spinal surgery. Pro-inflammatory cytokines [interleukin (IL)-6 and IL-8] and anti-inflammatory cytokines [IL-10, IL-1 receptor antagonist (ra), and soluble tumor necrosis factor receptors (sTNF-R) I and II] were assayed in serum from seven patients with lumbar spinal posterior decompression, six with spinal decompression and posterolateral fusion without instrumentation and seven with spinal decompression and posterolateral fusion with instrumentation. All cytokines after spinal instrumentation increased significantly more than in other groups on postoperative days 0 and 1. Seven days after SI, IL-6, -8, and -10 had normalized, but IL-1ra and sTNF-RI and sTNF-RII remained elevated. Both pro-inflammatory and anti-inflammatory cytokines were enhanced by implants in the acute phase, whereas only anti-inflammatory cytokines were enhanced by instruments in the subacute phase.     

Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation.

Tissue damage by proinflammatory cytokines is attenuated at both systemic and cellular levels by counter anti-inflammatory factors such as corticosteroids. Target cell responses to corticosteroids are dependent on several factors including prereceptor regulation via local steroidogenic enzymes. In particular, two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), by interconverting hormonally active cortisol (F) to inactive cortisone (E), regulate the peripheral action of corticosteroids 11beta-HSD1 by converting E to F and 11beta-HSD2 by inactivating F to E. In different in vitro and in vivo systems both 11beta-HSD isozymes have been shown to be expressed in osteoblasts (OBs). Using the MG-63 human osteosarcoma cell-line and primary cultures of human OBs, we have studied the regulation of osteoblastic 11beta-HSD isozyme expression and activity by cytokines and hormones with established roles in bone physiology. In MG-63 cells, interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) potently inhibited 11beta-HSD2 activity (cortisol-cortisone conversion) and messenger RNA (mRNA) levels in a dose-dependent manner while stimulating reciprocal expression of 11beta-HSD1 mRNA and activity (cortisone-cortisol conversion). A similar rise in 11beta-HSD1 reductase activity also was observed in primary cultures of OBs treated with 10 ng/ml TNF-alpha. Pretreatment of MG-63 cells with 0.1 ng/ml IL-1beta resulted in increased cellular sensitivity to physiological glucocorticoids as shown by induction of serum and glucocorticoid-inducible kinase (SGK; relative increase with 50 nM F but no IL-1beta pretreatment 1.12 +/- 0.34; with pretreatment 2.63 +/- 0.50; p < 0.01). These results highlight a novel mechanism within bone cells whereby inflammatory cytokines cause an autocrine switch in intracellular corticosteroid metabolism by disabling glucocorticoid inactivation (11beta-HSD2) while inducing glucocorticoid activation (11beta-HSD1). Therefore, it can be postulated that some of the effects of proinflammatory cytokines within bone (e.g., periarticular erosions in inflammatory arthritis) are mediated by this mechanism.