Die Bedeutung der Zytokine in der posttraumatischen Entzündungsreaktion

Alterations in the immune response after multiple trauma, posttraumatic sepsis and surgery are recognized as physiological reactions of the organism to restore homeostasis. The level of these immunological changes correlates with the degree of tissue damage as well as with the severity of haemorrhage and ischaemia. Cytokines are known to be integral components of this immune response. The local release of pro- and antiinflammatory cytokines after severe trauma indicates their potential to induce systemic immunological alterations. It appears that the balance or imbalance of these different cytokines partly controls the clinical course in these patients. Overproduction of either proinflammatory cytokines or antiinflammatory mediators may result in organ dysfunction. Whereas predominance of the proinflammatory response leads to the systemic inflammatory response syndrome (SIRS), the antiinflammatory reaction may result in immune suppression with an enhanced risk of infectious complications. Systemic inflammation, as well as immune suppression, are thought to play a decisive role in the development of multiple organ dysfunction syndrome (MODS). The major proinflammatory cytokines involved in the response to trauma and surgery include tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-8. These cytokines, which are predominantly produced by monocytes and macrophages, mediate a variety of frequently overlapping effects, and their actions can be additive. TNF-α and IL-1β are early regulators of the immune response and both induce the release of secondary cytokines, such as IL-6 and IL-8. IL-10 is an antiinflammatory cytokine which reduces the synthesis of proinflammatory mediators. Other important antiinflammatory mediators are soluble TNF receptors and the IL-1 receptor antagonist, which interfere with the effects of TNF-α and IL-1β. Early evaluation of the prognosis of polytraumatized patients and assessment of their clinical status is known to be difficult. Therefore, in several clinical studies, cytokine levels during the posttraumatic course have been determined with the aim of finding predictive markers of patient outcome. The purpose of this review was to highlight our current knowledge on the interaction of posttraumatic immune reactivity and the development of complications. A better understanding of these mechanisms might lead to the introduction of preventive and therapeutic strategies into clinical practice.     

Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part III: leucocyte activation: a new feature for platelet concentrates?

Platelet-rich fibrin (PRF) belongs to a new generation of platelet concentrates, with simplified processing and without biochemical blood handling. In this third article, we investigate the immune features of this biomaterial. During PRF processing, leucocytes could also secrete cytokines in reaction to the hemostatic and inflammatory phenomena artificially induced in the centrifuged tube. We therefore undertook to quantify 5 significant cell mediators within platelet poor plasma supernatant and PRF clot exudate serum: 3 proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), an antiinflammatory cytokine (IL-4), and a key growth promoter of angiogenesis (VEGF). Our data are correlated with that obtained in plasma (nonactivated blood) and in sera (activated blood). These initial analyses revealed that PRF could be an immune regulation node with inflammation retrocontrol abilities. This concept could explain the reduction of postoperative infections when PRF is used as surgical additive.     

Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure.

OBJECTIVE: This study investigates the course of serum cytokine levels in patients with multiple trauma, patients with a ruptured abdominal aortic aneurysm (AAA), and patients undergoing elective AAA repair and the relationship of these cytokines to the development of adult respiratory distress syndrome (ARDS) and multiple organ failure (MOF). SUMMARY BACKGROUND DATA: Severe tissue trauma, hemorrhagic shock, and ischemia-reperfusion injury are pathophysiologic mechanisms that may result in an excessive uncontrolled activation of inflammatory cells and mediators. This inflammatory response is thought to play a key role in the development of (remote) cell and organ dysfunction, which is the basis of ARDS and MOF. METHODS: The study concerns 28 patients with multiple trauma, 20 patients admitted in shock because of a ruptured AAA, and 18 patients undergoing elective AAA repair. Arterial blood was serially sampled from admission (or at the start of elective operation) to day 13 in the intensive care unit, and the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6 were determined. RESULTS: Twenty-two patients died, 15 within 48 hours and 7 after several weeks, as a result of ARDS/MOF. At hospital admission and after 6 hours, these nonsurvivors had significantly higher plasma TNF-alpha and IL-1 beta levels than did the survivors. At the same measuring points, TNF-alpha and IL-1 beta were significantly more elevated in patients with ruptured AAA than in traumatized patients. However, IL-6 was significantly higher in the traumatized patients. In 10 patients, ARDS/MOF developed, and 41 had an uncomplicated course in this respect. Those with ARDS/MOF exhibited significantly different cytokine patterns in the early postinjury phase. TNF-alpha and IL-1 beta levels were higher mainly on the first day of admission; IL-6 concentrations were significantly elevated in patients with ARDS/MOF from the second day onward. The latter cytokine showed a good correlation with the daily MOF score during the whole 2-week observation period. CONCLUSIONS: In the early postinjury phase, higher concentrations of these cytokines are associated, not only with an increased mortality rate, but also with an increased risk for subsequent ARDS and MOF. These data therefore support the concept that these syndromes are caused by an overwhelming autodestructive inflammatory response.     

VATS lobectomy reduces cytokine responses compared with conventional surgery

BACKGROUND: Video-assisted thoracic surgery (VATS) lobectomy for early lung cancer has been shown to be technically feasible. Comparative studies on laparoscopic versus open procedures indicate that laparoscopy may reduce inflammatory reactions as reflected by the lesser release of cytokines. We investigated the cytokine responses following VATS and conventional lobectomy for clinical stage I lung cancer. METHODS: Thirty-six patients with clinical stage I nonsmall cell lung cancer were studied. 18 patients underwent VATS lobectomy and the other 18 by conventional thoracotomy. There were no differences between the two groups with respect to age, gender, pulmonary function, smoking history, comorbidity, tumor size, and pathology. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-8, and an antiinflammatory cytokine IL-10 were measured before surgery, at the end of the procedure, and 4, 8, 24, and 48 hours thereafter in all patients. RESULTS: There was no mortality or major complication in either group. Analgesic requirement was significantly less in the VATS group. Although the release of TNF-alpha and IL-1beta were minimal after surgery in both groups, the levels of IL-6, IL-8, and IL-10 were elevated. IL-6 and IL-8 levels were significantly lower in the VATS group at the end of surgery than in the open group. In addition, reduced release of IL-10 was also observed in the VATS group shortly after surgery. CONCLUSIONS: VATS lobectomy is associated with reduced postoperative release of both proinflammatory and antiinflammatory cytokines compared with the open approach. The clinical significance of these findings remains to be fully elucidated.     

Pain and the immune system: friend or foe?

When tissue is destroyed, pain arises. Tissue destruction as well as wound healing are associated with an inflammatory reaction. This leads to activation of nociceptors ("pain receptors") which can cross-communicate with the inflammatory infiltrate. The following review will concentrate on pain-exaggerating (hyperalgesic) and pain-ameliorating (analgesic) mediators which arise from immune cells or the circulation during the inflammation. In the early stages of inflammation endogenous hyperalgesic mediators are produced, including the proinflammatory cytokines IL-1, IL-6 and TNF-alpha, nerve growth factor as well as bradykinin and prostaglandins. Simultaneously, analgesic mechanisms are activated. Opioid peptides such as endorphins, enkephalins and dynorphins are produced by immune cells and can be released locally in the inflamed tissue on stimulation with IL-1 or corticotropin releasing factor. Analgesia is elicited by binding of the opioid peptides to receptors on peripheral sensory neurons. During the course of an inflammatory process, peripheral opioid-mediated analgesia increases. In parallel, antiinflammatory cytokines such as IL-4, IL-10, IL-13 and IL-1ra are produced and reduce hyperalgesic effects of the proinflammatory cytokines initially produced. Inflammatory pain, therefore, is the result of an interplay between hyperalgesic and analgesic mediators. Drugs such as immunosuppressants influencing this interplay may also impair endogenous hyperalgesic and analgesic mechanisms.     

Is circulating endotoxin the trigger for the systemic inflammatory response syndrome seen after injury?

OBJECTIVE: Patients with severe traumatic or burn injury and a mouse model of burn injury were studied early after injury to determine the relation of plasma endotoxin (lipopolysaccharide [LPS]) to the production of proinflammatory cytokines and subsequent resistance to infection. SUMMARY BACKGROUND DATA: Elevated levels of plasma LPS have been reported in patients after serious injury. It has been suggested that circulating LPS may be a trigger for increased proinflammatory cytokine production and may play a role in the septic syndromes seen in a substantial portion of such patients. Yet, despite multiple reports of leakage of LPS from the gut and bacterial translocation after injury in animal models, there is little direct evidence linking circulating LPS with production of inflammatory mediators. METHODS: The authors studied serial samples of peripheral blood from 10 patients with 25% to 50% surface area burns and 8 trauma patients (injury Severity Score, 25-57). Patients were compared with 18 healthy volunteers. The study was focused on the first 10 days after injury before the onset of sepsis or the systemic inflammatory response syndrome. Plasma samples were assayed for LPS, and adherent cells from the blood were studied for basal and LPS-stimulated production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6). The correlation of increased plasma LPS with TNF-alpha production was studied as was the association of increased plasma LPS and increased TNF-alpha production with subsequent septic complications. We also studied a mouse model of 25% burn injury. Burn mice were compared with sham burn control subjects. Plasma samples were assayed at serial intervals for LPS, and adherent cells from the spleens were studied for basal- and LPS-stimulated production of TNF-alpha, IL-1 beta, and IL-6. Expression of the messenger RNAs for IL-1 beta and TNF-alpha also was measured. The relation of increased TNF-alpha production with mortality from a septic challenge, cecal ligation and puncture (CLP), was determined. Finally, the effect of administration of LPS to normal mice on subsequent mortality after CLP and on TNF-alpha production was studied. RESULTS: Elevated plasma LPS (> 1 pg/mL) was seen in 11 of the 18 patients within 10 days of injury and in no normal control subjects. In this period, patients as compared with control subjects showed increased stimulated production of TNF-alpha, IL-1 beta, and IL-6. Increased TNF-alpha production was not correlated with elevated plasma LPS in the same patients. Neither increased plasma LPS nor increased TNF-alpha production early after injury was correlated with subsequent development of systemic inflammatory response syndrome or sepsis in the patients. Burn mice, as compared with sham burn control subjects, showed elevated plasma LPS levels chiefly in the first 3 days after injury. Increased stimulated production of proinflammatory cytokines by adherent splenocytes from the burn mice also was seen at multiple intervals after injury and did not correlate with mortality from CLP. Increased production of TNF-alpha and IL-1 beta was associated with increased expression of messenger RNAs for these cytokines. Finally, two doses of 1 ng LPS administered 24 hours apart to normal mice had no effect on mortality from CLP performed 7 days later nor on the production of TNF-alpha at the time of CLP. CONCLUSIONS: These findings call into question the idea that circulating LPS is the trigger for increased proinflammatory cytokine production, systemic inflammatory response syndrome, and septic complications in injured patients.     

Perioperative immunologic changes in colorectal cancer patients

The aim of the study was to investigate the perioperative immunological profile in colon cancer patients and possible correlations with disease. To investigate the changes in immune mediators profile induced by tumor resection, we assessed the serum levels of cytokines (IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha), chemokines (MIP-1alpha, MCP-1, ENA-78) and growth factors (VEGF, bFGF) in colon cancer patients before, during and after surgery and compared the results with those measured for a group of healthy controls. We have used XMap profiling technology (Luminex) that allows simultaneous measurement of multiple parameters in small volumes of samples. Circulating levels of proinflammatory cytokines IL-1, IL-6, IL-8 and antiinflamatory cytokine IL-10 were elevated in cancer patients with respect to healthy controls. Before surgery, serum levels of MCP-1 and MIP-1alpha positively correlated with the levels of proinflammatory cytokines. During surgery, an increase in serum concentration of all determined mediators was noticed, with positive correlation between TNF-alpha, IL-8, MCP-1 and MIP-1alpha. Interestingly, these correlations were no more noticed one week after operation. Postoperatively, cytokines levels decreased as compared to those noticed before surgery, but still higher than in control group. These preliminary results suggest that both tumor and surgical act may influence immune mediators' network.     

Downregulation of T helper type 1 immune response and altered pro-inflammatory and anti-inflammatory T cell cytokine balance following conventional but not laparoscopic surgery

BACKGROUND: The clinical advantages of laparoscopic procedures result from a minimized surgical trauma. The present study was performed to investigate immunosupression following laparoscopic operations as compared with open surgery. Our analysis focused on the T cell secretion of cytokines that regulate the critical balance of either T helper type-1 (Th1)- and Th2-mediated immune responses on pro- and antiinflammatory activities. METHODS: In a prospective study, immunological data of 26 patients submitted to laparoscopic cholecystectomy (LCE) and 17 patients undergoing conventional cholecystectomy (CCE) for symptomatic cholecystolithiasis were compared. Patients with acute cholecystitis and patients developing postoperative complications or receiving immunosuppressive medication were excluded. Production of interferon (IFN)-gamma, interleukin (IL)-2, IL-4, tumor necrosis factor (TNF)-alpha, and IL-10 by isolated T cells stimulated by cross-linking of CD3 and CD28 was evaluated preoperatively as well as on postoperative days 1 and 6 or 7. Cytokines were measured by immunoenzymometric assay. RESULTS: IFN-gamma, TNF-alpha, and IL-2 production by T cells decreased significantly by 48.3%, 36.6%, and 36.8%, respectively, on postoperative day 1 after CCE, but not after LCE. These results indicate severe suppression of Th1-type and proinflammatory cytokines after the open operation. In contrast, IL-4 and IL-10 did not show significant changes in either group suggesting that Th2 cell response and anti-inflammatory activity remained normal. CONCLUSIONS: The present study shows that open, but not laparoscopic cholecystectomy is associated with a marked suppression of T lymphocytes functions as indicated by deregulation of both the Th1/Th2 and the pro-/anti-inflammatory cytokine balance. The results therefore suggest that downregulation of Th1 cell-mediated immune response and pro-inflammatory activity of T cells is a hallmark of open, but not laparoscopic surgery.     

Endotoxin desensitization of human mononuclear cells after cardiopulmonary bypass: role of humoral factors

BACKGROUND: The ability of leukocytes to release proinflammatory cytokines on lipopolysaccharide stimulation in vitro is impaired after cardiopulmonary bypass (CPB). This study tested contribution and interaction of humoral factors in altered leukocyte responsiveness to lipopolysaccharide. METHODS: Whole blood and isolated peripheral-blood mononuclear cells (PBMCs) from 10 patients obtained after induction of anesthesia (T1) and 20 min (T2) and 24 h (T3) after CPB were cultured in the absence or presence of lipopolysaccharide and assessed for release of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta and their functional antagonists, IL-1 receptor antagonist (IL-1ra) and IL-10. In addition, dose-response characteristics and interaction of IL-10 and norepinephrine as modulators of TNF-alpha release were studied. RESULTS: Cardiopulmonary bypass induced release of antiinflammatory (T2: IL-10: median 25 pg/ml, 25th-75th percentile 9-42; IL-1ra: median 1,528 pg/ml, 25th-75th percentile 1,075-17,047; P < 0.05 compared with T1) but failed to induce proinflammatory cytokines (T2: TNF-alpha: median 0 pg/ml, 25th-75th percentile 0-6; IL-1beta: median 1 pg/ml, 25th-75th percentile 0-81; nonsignificant). Removal of plasma at T2 increased TNF-alpha response to lipopolysaccharide (+83.8%; P < 0.05), whereas it suppressed IL-10 (-36.8%; P < 0.05). Similarly, incubation of PBMCs (T1) with plasma obtained after CPB (T2) as well as addition of IL-10 or norepinephrine in concentrations present in plasma after CPB led to a reduced lipopolysaccharide-stimulated TNF-alpha and an increased IL-10 response. Coadministration of norepinephrine and IL-10 had synergistic effects. Although pretreatment with an anti-IL-10 antibody and labetalol before addition of plasma obtained at T2 largely restored the TNF-alpha response in vitro, their addition post-treatment failed to restore the monocytic TNF-alpha response. CONCLUSIONS: Plasma contains interacting factors that inhibit the release of TNF-alpha and increase the release of IL-10, presumably attenuating the inflammatory response to CPB. Although norepinephrine fails to induce a cytokine response in the absence of other stimuli, its administration seems to augment the antiinflammatory IL-10 response while attenuating the TNF-alpha response.     

Plasma and urinary cytokine homeostasis and renal dysfunction during cardiac surgery

BACKGROUND: Cardiac surgery induces changes in plasma cytokines. Proinflammatory cytokines have been associated with a number of renal diseases. The proinflammatory cytokines interleukin 8 (IL-8), tumor necrosis factor alpha (TNFalpha), and interleukin 1beta (IL-1beta) are smaller than the antiinflammatory cytokines interleukin 10 (IL-10), interleukin 1 receptor antagonist (IL-1ra), and TNF soluble receptor 2 (TNFsr2), and thus undergo glomerular filtration more readily. Accordingly, this study investigated the relation between plasma and urinary cytokines and proximal renal dysfunction during cardiac surgery. METHODS: Twenty patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB) were studied. Blood and urine samples were analyzed for proinflammatory and antiinflammatory cytokines. Proximal tubular dysfunction was measured using urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine and alpha1-microglobulin/creatinine ratios. RESULTS: Plasma IL-8, IL-10, IL-1ra, and TNFsr2 values were significantly elevated compared with baseline. Urinary IL-1ra and TNFsr2 were significantly elevated. Urinary NAG/creatinine and alpha1-microglobulin/creatinine ratios were also elevated. Plasma TNFalpha at 2 h correlated with urinary NAG/creatinine ratio at 2 and 6 h (P < 0.05) and with urinary IL-1ra at 2 h (P < 0.05). Plasma IL-8 at 2 h correlated with NAG/creatinine at 6 h (P < 0.05). Urinary IL-1ra correlated with urinary NAG/creatinine ratio after cross-clamp release and 2 and 6 h after CPB (P < 0.05). CONCLUSIONS: Cardiac surgery using CPB leads to changes in plasma and urinary cytokine homeostasis that correlate with renal proximal tubular dysfunction. This dysfunction may be related to the renal filtration of proinflammatory mediators. Renal autoprotective mechanisms may involve the intrarenal generation of antiinflammatory cytokines.     

Proinflammatory and antiinflammatory cytokines after cardiac operation: different cellular sources at different times

BACKGROUND: Cardiac operation produces substantial alterations within the immune system, which possibly predispose postoperative complications. However, the interplay between proinflammatory and antiinflammatory reactions and the cells involved in this process are not completely clear. Therefore, we investigated serum levels, as well as synthesis patterns, of proinflammatory and antiinflammatory cytokines. METHODS: Serum levels and production of interleukin (IL) IL-5, IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma, using a mixed cell culture, (ie, monocytes, macrophages, and lymphocytes), as well as a purified lymphocyte culture were measured preoperatively (day 0), on postoperative day 1, on postoperative day 3, and on postoperative day 5 in 25 patients undergoing cardiac operations and were compared with 10 healthy volunteers. RESULTS: Serum level and mixed cell culture, production of IL-6, tumor necrosis factor-alpha, and IL-10 increased on postoperative day 1, but decreased in lymphocyte culture. Base line values were reached on postoperative day 5. Interferon-gamma serum levels remained unchanged, whereas IL-5 serum levels increased on postoperative days 3 and 5. Cell culture synthesis showed a significant suppression for both mediators in both cell cultures, which returned to baseline on postoperative day 3 in mixed cell culture. Interferon-gamma production by lymphocytes was suppressed until postoperative day 5, whereas IL-5 returned to preoperative values on postoperative day 5. CONCLUSIONS: Cardiac operation induces a biphasic immune response. The first phase (postoperative day 1) appears to represent the proinflammatory and antiinflammatory reaction of the innate immune system returning to base line on postoperative day 3. The second phase (postoperative day 5) may represent the response of the adaptive immune system and is characterized by an antiinflammatory type of reaction. This may explain why the systemic inflammatory response occurs immediately after cardiac operation, whereas infections occur later.     

The influence of gender on human innate immunity

BACKGROUND: Several experimental, clinical, and epidemiologic studies indicate a better prognosis in women after an infectious challenge. The monocyte/macrophage, as coordinators of the innate immune response to sepsis, secrete plasma inflammatory cytokines. Elevated plasma cytokine levels are inversely correlated with outcome. In addition, single-nucleotide polymorphisms related to these cytokine genes and in genes important for lipopolysaccharide (LPS) detection, particularly toll-like receptor-4, have been associated with variations in clinical outcome. We hypothesize that the gender differences in clinical outcome are due to measurable differences in cytokine responses and intracellular signaling, and these differences are independent of polymorphism carrier status. METHODS: Venous blood samples from healthy subjects (56 men, 23 women) were incubated with LPS, and supernatant cytokine levels were determined by enzyme-linked immunosorbent assay. In a randomly chosen subgroup, (8 men, 4 women), peripheral blood mononuclear cells were isolated, and LPS-mediated intracellular mitogen-activated protein kinase (MAPK) phosphorylation was assayed via Western blot analysis. Each subject was screened for the following SNPs: tumor necrosis factor alpha (TNF-alpha) -308G/A, interleukin (IL)-6 -174G/C, IL-1beta -31C/T, and toll-like receptor-4 (TLR4) +896A/G. RESULTS: Women produced significantly less LPS-induced TNF-alpha and IL-1beta but not IL-6. When the analysis was adjusted for the presence of each polymorphism, the differences in TNF-alpha and IL-1beta accumulation persisted. Female gender was associated with lower MAPK phosphorylation at each LPS concentration but was not statistically significant. CONCLUSIONS: Gender-specific differences in LPS-induced TNF-alpha and IL-1beta were observed, possibly attributed to alterations in MAPK phosphorylation. Furthermore, studies investigating the influence of genomic variation on the innate immune response should address potential gender-related differences.     

Assessment of immunological status in the critically ill

The systemic inflammatory response (SIRS) results from various types of injuries such as severe infection, trauma, ischemia-reperfusion and major surgery including cardiac surgery with cardio-pulmonary bypass. This response involves immune cell activation and a complex network of proinflammatory cytokines, which may induce multiple organ failure when uncontrolled. The monocyte plsys a central role in the response to infection with the release of TNF-alpha, IL-1 beta, and IL-12. In addition, monocytes present antigens to T lymphocytes. An optimal antigen presentation requires the expression of MHC class II HLA-DR on monocytes surface and of costimulatory molecules such as CD54 on monocytes and LFA-1 on lymphocytes. It has become increasingly apparent that the proinflammatory response is balanced by concomitant anti-inflammatory mechanisms that results in monocyte deactivation, characterized by a decrease in HLA-DR expression and the release of anti-inflammatory cytokines such as IL-10. This counterregulatory response, if prolonged or predominant, may predispose the patient to a higher risk of infection. Further studies need to be conducted to precise: i) the intensity of depression of the surface molocule expression assessing monocyte function, such as HLA DR and CD54; ii) the level of IL-10 and IL-12 release in patients with severe sepsis; iii) the immuno-modulating effects of frequently used treatments in these patients with severe sepsis and in surgical patients; iv) the time course of recovery; v) if the monitoring of HLA-DR, CD54, IL-10 and IL-12 will better predict the clinical outcome than clinical parameters.     

Electrolytic liver ablation is not associated with evidence of a systemic inflammatory response syndrome

BACKGROUND: Local ablation has been proposed for treatment of liver tumours. Cryoshock, a variant of the systemic inflammatory response syndrome (SIRS), is a potentially fatal complication of cryoablation caused by systemic release of necrotic breakdown products from ablated liver. The proinflammatory cytokines tissue necrosis factor (TNF) alpha and interleukin (IL) 1 are important mediators of this response. This study assessed the risk of SIRS complicating electrolytic liver ablation by measuring circulating levels of inflammatory cytokines, other inflammatory markers and clinical markers of organ function. METHODS: Electrolytic liver ablation was performed in 16 pigs and four pigs served as controls. Platelet count, and serum levels of urea, creatinine, liver enzymes, C-reactive protein (CRP), TNF-alpha and IL-1beta were measured before treatment and for 72 h after the procedure. RESULTS: There were significant dose-related increases in CRP and alanine aminotransferase levels with liver electrolysis. There was no significant derangement in renal function or platelet count following ablation. A rise in serum TNF-alpha and IL-1beta levels was not associated with liver electrolysis. CONCLUSION: There was no evidence of organ failure or significantly raised levels of proinflammatory cytokines as a result of liver electrolysis, suggesting that this is a safe procedure for liver ablation.     

Bupivacaine's action on the carrageenan-induced inflammatory response in mice: cytokine production by leukocytes after ex-vivo stimulation

We aimed to study the effect of bupivacaine on the systemic response elicited by intraplantar injection of carrageenan. To that purpose, we studied the effects of carrageenan, bupivacaine, or both on the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 by whole blood cultured in the presence of lipopolysaccharide (LPS) and of heat-killed Staphylococcus Aureus Cowan (SAC). Mice received a hindpaw injection of carrageenan with or without encapsulated IM bupivacaine given contralaterally. Whole blood was sampled 15 h later and cultured for 24 h with LPS or SAC. The amounts of TNF-alpha, IL-1beta, and IL-10 in the supernatants were measured. In the presence of LPS or SAC, proinflammatory cytokine (TNF-alpha and IL-1beta) production was increased after carrageenan. Bupivacaine prevented this inflammatory response: 992 +/- 102 versus 2146 +/- 338 versus 919 +/- 116 pg/mL for TNF-alpha (bupivacaine + carrageenan versus carrageenan versus control after LPS stimulation). This effect of bupivacaine was less after SAC stimulation. Moreover, IL-10 was not involved in the inhibition of proinflammatory cytokine production observed after treatment by bupivacaine alone. These experiments show that carrageenan-induced hindpaw inflammation modifies the blood cell reactivity to LPS and SAC and that bupivacaine regulates the systemic response elicited by carrageenan. Furthermore, IL-10 does not seem to be a factor of the antiinflammatory response induced by bupivacaine. The precise mechanism underlying this effect of bupivacaine remains to be clarified.     

The inflammatory response and its consequence for the clinical outcome following aortic aneurysm repair.

OBJECTIVE: to review published studies on the outcome of the inflammatory response after abdominal aortic aneurysm (AAA) repair. METHODS: a literature search on PubMed was performed. All studies that determined the inflammatory response (cytokine release) after AAA repair were included. The results of the studies and differences between open and endoluminal repair were compared and evaluated. RESULTS: seventeen studies were identified. In most studies the investigated cytokines were TNF-alpha and IL-6. Determination of IL-1 beta, IL-8, TNFsr1 and TNFsr2 were less often performed. TNF-alpha may reflect, but not strictly predict, the clinical outcome in patients with ruptured AAA. IL-6 levels correlate well with the surgical trauma per se. Variations in recorded cytokine release during endovascular AAA repair may depend on the times of blood sampling. CONCLUSION: both open and endovascular AAA repair provoke a cytokine response. This response is greater during open repair than during endovascular aortic aneurysm exclusion.     

Cytokine pattern in aneurysmal and occlusive disease of the aorta.

BACKGROUND: Prominent inflammatory infiltrates of macrophages and T-lymphocytes are found in both aortic occlusive disease (AOD) and abdominal aortic aneurysms (AAA). These cells secrete different cytokines that might affect matrix turnover through modulation of matrix metalloproteinase expression. A different cytokine pattern might account for the evolution of AOD vs AAA. MATERIALS AND METHODS: Six different cytokines were examined to determine whether AOD and AAA could be characterized by unique cytokine patterns. AOD (n = 8) and AAA (n = 8) tissues were collected and serially treated with salt, dimethyl sulfoxide, and urea buffers to extract the soluble matrix or cell-bound cytokines. Levels of IL-1 beta, TNF-alpha, IL-10, IL-12, and IFN-gamma were measured by immunoenzymatic methods. Additionally, RNA levels of IL-12 and IFN-gamma were measured. RESULTS: AAA tissue contained higher levels of IL-10 compared to AOD tissue (P < 0.05). Higher levels of the proinflammatory cytokines IL-1 beta, TNF-alpha, and IL-6 were found in AOD (P < 0.05). mRNA levels of IL-12 and IFN-gamma did not differ between the diseases. Aortic tissues contained large amounts of matrix or cell-bound cytokines. CONCLUSIONS: AAA is characterized by greater levels of IL-10 while IL-1 beta, TNF-alpha, and IL-6 are higher in AOD. Targeted deletion of these cytokines in animal models might help in identifying their role in the progression of AAA.