Aortic aneurysm repair is associated with a lower inflammatory response compared with surgery for inflammatory bowel disease.

BACKGROUND: Since the plasma cytokine profile reflects the body's inflammatory response to injury, this study was designed to prospectively observe the plasma cytokine levels in response to the degree of different sorts of abdominal surgical trauma. METHODS: Plasma levels of TNF-alpha, type I TNF receptor (p55), type II TNF receptor (p75), IL-6, IL-8, IL-10, phospholipase A(2) (PLA(2)), and haptoglobin were measured peri-operatively in patients undergoing bowel resection for inflammatory bowel disease or diverticulitis (IBD) (n = 9), elective repair of abdominal aortic aneurysm (AAA) (n = 9), or laparoscopic cholecystectomy (lap chole) (n = 9). RESULTS: The IBD patients showed a significant (p < 0.05) post-operative elevation in plasma IL-6, p55, p75, and PLA(2) levels, but no significant change in TNF-alpha, IL-8, IL-10 or haptoglobin levels. The AAA patients had a significant post-operative rise in IL-10 levels and a significant decrease in plasma haptoglobin levels, but no significant change of TNF-alpha, IL-6, IL-8, p55, p75, or PLA(2) concentrations. The lap chole patients demonstrated no significant change in any of these parameters. CONCLUSION: These data show that IL-6, IL-10, p55, and p75 are markers to measure the degree of inflammatory stress associated with abdominal operative procedures and demonstrate the relative lack of a cytokine response to laparoscopic cholecystectomy.

Interleukin-10 appearance following thoraco-abdominal and abdominal aortic aneurysm repair is associated with the duration of visceral ischaemia.

OBJECTIVES: to evaluate the plasma IL-10 levels during elective operative repair of thoraco-abdominal and abdominal aortic aneurysm repair. To study whether IL-10 plasma levels are associated with the duration of cross-clamping (ischaemia) and clinical outcome. MATERIALS: fifteen consecutive patients undergoing surgery for TAAA and 10 consecutive patients undergoing surgical repair of AAA were included. METHODS: plasma concentrations of IL-10 were measured by ELISA technique. Clinical outcome of the TAAA patients was prospectively analysed. RESULTS: during aortic clamping IL-10 was produced in both populations. The plasma IL-10 peak (934+/-172 pg/ml) of the TAAA group was seen at 4 h after declamping and remained detectable after 48 h. The plasma IL-10 peak (212+/-32 pg/ml) of the AAA group was seen 30 min after declamping and fell to undetectable levels by 24 h. These data show that the peak IL-10 plasma levels in TAAA repair are significantly (p<0.05) higher compared to the peak IL-10 plasma levels as seen during AAA repair. A positive correlation was seen between cross-clamping and peak plasma IL-10 and organ dysfunction. CONCLUSIONS: IL-10 plasma concentrations appear higher, later and are longer detectable in patients undergoing TAAA. Correlations were seen with duration of cross-clamping and MSOD.

A matrix metalloproteinase inhibitor prevents processing of tumor necrosis factor alpha (TNF alpha) and abrogates endotoxin-induced lethality.

Excessive tumor necrosis factor alpha (TNF alpha) production in response to Gram-negative bacteremia or endotoxemia can often lead to hypotension, shock, and increased mortality. Current approaches used to block the deleterious effects of exaggerated TNF alpha production rely on monoclonal antibodies or immunoadhesins that bind TNF alpha and thus prevent the interaction with its cellular receptors. This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNF alpha processing and release and attenuate endotoxin-induced mortality. In human peripheral blood mononuclear cells stimulated in vitro with 1 microgram/mL endotoxin, GM-6001 at concentrations > 5 micrograms/mL blocked release of TNF alpha, but did not affect the release of either IL-1 beta or IL-6. GM-6001 also inhibited the release of soluble TNF receptor (p75) from peripheral blood mononuclear cells stimulated with endotoxin and/or TNF alpha. To confirm the role of secreted TNF alpha in endotoxic shock-induced mortality, C57BL/6 mice were challenged with either endotoxin alone (500 micrograms/mouse) or endotoxin (100 ng/mouse) plus D-galactosamine (8 mg/mouse). GM-6001 pretreatment (100 mg/kg) significantly attenuated the 90-minute plasma TNF alpha response in both models and improved survival in mice treated with low-dose endotoxin plus D-galactosamine. However, plasma IL-1 beta and IL-6 concentrations at 90 min after endotoxin treatment were unaffected by GM-6001 following lethal endotoxin challenge, confirming the in vivo specificity of this matrix metalloproteinase inhibitor for TNF alpha processing. These findings demonstrate that a novel inhibitor of matrix metalloproteinases can prevent the release of TNF alpha both in vitro and in vivo, and can abrogate the harmful sequelae of endotoxemic shock.

Involvement of 26-kDa cell-associated TNF-alpha in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor.

TNF-alpha is a pleiotropic cytokine that exists both as a 26-kDa cell-associated and a 17-kDa soluble form. Recently, a class of matrix metalloproteinase inhibitors has been identified that can prevent the processing by TNF convertase of 26-kDa TNF-alpha to its 17-kDa form and can reduce mortality from normally lethal doses of D-galactosamine plus LPS (D-GalN/LPS). Here we report that a matrix metalloproteinase inhibitor, GM-6001, improves survival but does not protect against liver injury from D-GalN/LPS-induced shock in the mouse. In Con A-induced hepatitis, GM-6001 actually exacerbates hepatocellular necrosis and apoptosis despite greater than 90% reduction in plasma TNF-alpha concentrations. Treatment with GM-6001 also has minimal effect on the concentration of membrane-associated TNF-alpha in the livers of animals with Con A induced hepatitis. In contrast, a TNF binding protein (TNF-bp), which neutralizes both membrane-associated and soluble TNF-alpha, prevents D-GalN/LPS- and Con A-induced hepatitis. Our studies suggest that cell-associated TNF-alpha plays a role in the hepatocellular necrosis and apoptosis that accompany D-GalN/LPS- or Con A-induced hepatitis, and that matrix metalloproteinase inhibitors are ineffective in preventing this hepatic injury.

Visceral ischemia-reperfusion injury promotes tumor necrosis factor (TNF) and interleukin-1 (IL-1) dependent organ injury in the mouse.

Acute visceral ischemia and subsequent reperfusion injury, which accompanies the surgical repair of a thoracoabdominal aorta aneurysm, is associated with high rates of morbidity and mortality. The purpose of the present study was to determine whether endogenous tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) production contributes to organ dysfunction in animals subjected to visceral ischemia secondary to 30 min of supraceliac aortic occlusion. C57BL6/j mice were treated with either a TNF binding protein (TNF-bp-10 mg/kg) or an anti-IL-1 receptor type 1 antibody (150 micrograms) 2 h prior to 30 min of supraceliac aortic occlusion. An additional group of mice received 30 min of infrarenal aortic occlusion to determine the contribution of lower torso ischemia-reperfusion injury to the changes seen following supraceliac aortic occlusion. Visceral organ ischemia for 30 min produced by supraceliac aortic occlusion followed by 2 h of reperfusion produced measurable TNF-alpha in 38% of untreated mice, but TNF-alpha was undetectable in both sham-operated mice and following infrarenal aortic occlusion. After 2 h of reperfusion, lung myeloperoxidase levels were significantly elevated in the mice experiencing visceral ischemia-reperfusion compared with either a sham operation or infrarenal ischemia-reperfusion (11.6 +/- 1.3 U/g vs. 3.4 +/- .2 U/g and 3.7 +/- 1.0 U/g, respectively, p < .05). Pretreatment with TNF-bp and anti-IL-1 antibody decreased lung neutrophil recruitment (7.2 +/- 1.2 U/g and 4.6 +/- 1.1 U/g) and capillary membrane permeability changes in mice following visceral ischemia-reperfusion. The present study demonstrates that brief (30 min) clinically relevant visceral ischemia produces TNF-alpha and IL-1 dependent lung injury.

A human tumor necrosis factor p75 receptor agonist stimulates in vitro T cell proliferation but does not produce inflammation or shock in the baboon.

Tumor necrosis factor (TNF) is a potentially useful adjunct to anticancer therapies. However, the clinical utility of TNF has been limited by generalized toxicity and hypotension. Recently, studies have begun to dissect the individual proinflammatory and immunologic responses that result from TNF binding to its two cellular receptors, p55 and p75, in an attempt to develop TNF receptor agonists with reduced systemic toxicity. To evaluate a p75 receptor selective TNF mutant (p75TNF), TNF and p75TNF were administered to healthy anesthetized baboons. Intravenous infusion of the p75TNF produced none of the hemodynamic changes seen after the infusion of TNF. Infusion of p75TNF also failed to induce the plasma appearance of interleukins 6 and 8. However, p75TNF enhanced in vitro baboon thymocyte proliferation to concanavalin A, and infusion of p75TNF resulted in increased soluble p55 and p75 receptor plasma concentrations. Local skin necrosis and tissue neutrophil infiltration were seen after subcutaneous injections of TNF and p55TNF. Subcutaneous injection of p75TNF did not result in skin necrosis but did result in a modest dermal infiltration of lymphocytes and macrophages. The findings suggest that p75TNF may stimulate T cell proliferation without the systemic and local toxicity seen with TNF.

Increased soluble interleukin-1 type II receptor concentrations in postoperative patients and in patients with sepsis syndrome.

Plasma interleukin-1 (IL-1) activity is modulated in part through the simultaneous appearance of several inhibitors of IL-1 action, including interleukin-1 receptor antagonist (IL-1ra) and the soluble IL-1 type II receptor (IL-1RII). However, little is known concerning the plasma appearance of these inhibitors in patients following operative trauma or those with sepsis syndrome. In the present report, plasma IL-1beta, IL-1ra, and soluble IL-1RI and IL-1RII concentrations were evaluated in 118 patients with sepsis syndrome or after elective operative trauma. Plasma concentrations of IL-1ra increased significantly following elective operative repair of thoraco-abdominal and abdominal aortic aneurysms, and after bowel resection for inflammatory bowel disease, but did not increase after laparoscopic cholecystectomy. Plasma IL-1ra levels were also elevated in patients with sepsis syndrome. In contrast, soluble IL-1RII levels were only increased in patients after operative repair of thoraco-abdominal aortic aneurysms and in sepsis syndrome, whereas concentrations were unaffected by the other more modest surgical procedures. Plasma IL-1RI concentrations decreased in all postoperative patients in the first 24 hours after surgery. We conclude that both plasma IL-1ra and soluble IL-1RII concentrations often increase in sepsis and following some operative trauma. Less severe operative trauma increases the plasma concentration of only IL-1ra, whereas both IL-1ra and soluble IL-1RII are increased in patients with sepsis syndrome or following thoraco-abdominal aneurysm repair.

Interleukin 1 binding to its type I, but not type II receptor, modulates the in vivo acute phase response.

Neutralizing monoclonal antibodies against the murine interleukin 1 (IL-1) type I (mAb 35F5) and type II receptor (mAb 4E2) were used to passively immunize mice prior to exogenous murine IL-1 alpha administration or a sterile-turpentine induced abscess. When mice were passively immunized with 35F5, the anorexia, weight loss and increased plasma acute phase protein levels in response to exogenous IL-1 alpha administration or a turpentine abscess were significantly attenuated. In contrast, passive immunization with 4E2 had only variable effects on food intake, body weight and the hepatic acute phase response in mice administered IL-1 alpha. In mice following a turpentine abscess, type II receptor blockade (4E2) either had no effect, or in some cases, actually increased the plasma IL-6 and acute phase protein responses. We conclude that in response to a turpentine abscess, the anorexia, weight loss and the induction of several hepatic acute phase reactants result in part from IL-1 binding to its type I receptor. Binding of IL-1 to the type II IL-1 receptor does not appear to be involved in the induction of these host nonspecific responses to inflammation.

Interleukin-1 and interleukin-1 antagonism in sepsis, systemic inflammatory response syndrome, and septic shock.

Interleukin-1 (IL-1) is one of several proinflammatory cytokines produced during infection, sepsis, and the systemic inflammatory response syndrome (SIRS) that serves to initiate the host inflammatory response and to integrate nonspecific immunity. Many of IL-1's biologic effects are beneficial to the host in times of stress, but when produced for extended periods of time or in excessive quantities, IL-1 contributes to morbidity and mortality. In fact, excessive IL-1 production has been directly linked to the development of hypotension, shock, multi-organ system failure, hematologic dyscrasia, and death in patients and animals with sepsis, SIRS, and septic shock. Recent research interest has focused on IL-1 inhibition to improve outcome in sepsis and septic shock. This article will review the role for IL-1 in sepsis and septic shock, and the function and status of the IL-1 receptors and IL-1 receptor antagonist in modulating IL-1 actions. The results of investigations of IL-1 inhibition in animal models and in human subjects with sepsis and septic shock will also be reviewed.

A mouse model for neural tube defects: the curtailed (Tc) mutation produces spina bifida occulta in Tc/+ animals and spina bifida with meningomyelocele in Tc/t.

Curtailed (Tc), a dominant mutation on mouse chromosome 17, causes a tailless phenotype and occasional hindlimb paralysis in heterozygotes. Histologically, Tc/+ embryos show a variety of abnormalities including budding and ventral duplication of the developing spinal cord, duplication and intermittent absence of the notochord, and partial or complete absence of bony vertebrae, all posterior to midliver level. When Tc is heterozygous with t-haplotypes that contain the "tail interaction factor," tct, the phenotype is more severe, and a dorsal blood blister exists in the lumbosacral area. Our microscopic observations reveal that Tc/tw5 mice have a lumbosacral spina bifida with meningomyelocele. This results from the absence of bony vertebrae, extensive thinning of the dermis dorsally, and the rupturing of the previously closed neural tube, probably by increased cerebrospinal fluid (CSF) pressure on the necrotic, attenuated roof plate. Thinning of the roof plate, which facilitates the rupturing of the spinal cord, is not observed in Tc/+, which suggests that this phenomenon is associated with the interaction of Tc with the t-allele. Later in the development of Tc/tw5 embryos, adjacent blood vessels are ruptured, resulting in hemorrhage into the CSF space to give the external appearance of a blood blister. Tc/+ mice also show an absence of bony vertebrae dorsally in the lumbosacral region, but they lack the dorsal blood blister, and the dermal layer overlying the bony defect retains its normal thickness; these observations describe a spina bifida occulta.