Journal Article The Relationship between Plasma IL-18 Concentrations and the Outcomes of Burned Patients Get access D. Saitoh, MD, D. Saitoh, MD 1National Defense Medical College, Tokorozawa, Japan Search for other works by this author on: Oxford Academic Google Scholar S. Seki, MD, S. Seki, MD 1National Defense Medical College, Tokorozawa, Japan Search for other works by this author on: Oxford Academic Google Scholar S. Sato, PhD, S. Sato, PhD 1National Defense Medical College, Tokorozawa, Japan Search for other works by this author on: Oxford Academic Google Scholar T. Kiyozumi, MD, T. Kiyozumi, MD 1National Defense Medical College, Tokorozawa, Japan Search for other works by this author on: Oxford Academic Google Scholar K. Fukuzuka, MD, K. Fukuzuka, MD 1National Defense Medical College, Tokorozawa, Japan Search for other works by this author on: Oxford Academic Google Scholar A. Takasu, MD, A. Takasu, MD 1National Defense Medical College, Tokorozawa, Japan Search for other works by this author on: Oxford Academic Google Scholar T. Sakamoto, MD, T. Sakamoto, MD 1National Defense Medical College, Tokorozawa, Japan Search for other works by this author on: Oxford Academic Google Scholar Y. Okada, MD Y. Okada, MD 1National Defense Medical College, Tokorozawa, Japan Search for other works by this author on: Oxford Academic Google Scholar The Journal of Burn Care & Rehabilitation, Volume 23, Issue suppl_2, March-April 2002, Page S98, https://doi.org/10.1097/00004630-200203002-00114 Published: 01 March 2002

Pharmacokinetics and immunogenicity of six different recombinant human soluble p55 tumor necrosis factor (TNF) receptor I (sTNFR-I) constructs were evaluated in juvenile baboons. The constructs included either an sTNFR-I IgG1 immunoadhesin (p55 sTNFR-I Fc) or five different sTNFR-I constructs covalently linked to polyethylene glycol. The constructs were administered intravenously three times, and pharmacokinetics and immunogenicity were examined over 63 days. All of the constructs were immunogenic, with the exception of a 2.6-domain monomeric sTNFR-I. To evaluate whether the nonimmunogenic 2.6-domain monomeric construct could protect baboons against TNF-alpha-induced mortality, baboons were pretreated with 1, 5, or 10 mg/kg body wt and were compared with baboons receiving either placebo or 1 mg/kg body wt of the dimeric 4.0-domain sTNFR-I construct (n = 3 each) before lethal Escherichia coli bacteremia. The monomeric construct protected baboons and neutralized TNF bioactivity, although greater quantities were required compared with the dimeric 4.0-domain sTNFR-I construct. We conclude that E. coli-recombinant-derived human sTNFR-I constructs can be generated with minimal immunogenicity on repeated administration and still protect against the consequences of exaggerated TNF-alpha production.

The aim of this study was to examine three types of superoxide dismutase (SOD) in plasma after burns, and especially to clarify the characteristics of plasma extracellular SOD (EC-SOD) in burned patients. A total of 71 blood samples were collected from 18 patients on arrival, day 1, day 3 and day 5 after burns. We measured three types of SOD (Mn, Cu/Zn, EC) in plasma using ELISA, and the relationships among the three types of SOD concentrations were examined. We next analyzed the characteristics of plasma EC-SOD using stepwise multivariate regression analysis. Any plasma SOD isoenzyme concentration measured after burns was beyond the normal range and EC-SOD accounted for the major part of plasma SODs. EC-SOD and Cu/Zn-SOD were positively correlated, whereas Mn-SOD was not related to the other SODs. Also, plasma EC-SOD was significantly related to existence of inhalation injury, %TBSA and age, respectively. The plasma EC-SOD might therefore play some roles in the pathophysiology of burned patients.

The aim of this study is to examine the characteristics of nitrite/nitrate (NOx), the final metabolite of nitric oxides, in plasma after burn injury. A total of 83 blood samples were collected from 19 patients on arrival, day 1, day 3, and day 5 after suffering burn injuries and from 7 non-burned volunteers. We measured the NOx levels in plasma using, the Griess method, and analyzed the relationships among plasma the NOx levels, the burn-magnitude, and the blood examination data using a stepwise multivariate regression analysis. The plasma NOx levels at hospital-arrival after burns significantly exceeded those of non-burned volunteers, and the NOx levels in the plasma returned to normal range after day 1. Based on the findings of a multivariate analysis, the plasma NOx levels at admission to the hospital were not found to be related to the total burn surface area, the burn index or inhalation injury, but they were significantly related to age. Furthermore, these plasma NOx levels were also related to the platelet count, neutrophil count and blood urea nitrogen. The increase in the plasma NOx level may therefore play an important role in the pathophysiology of elderly burned patients, while the nitric oxide levels in the plasma might also play a role in inhibiting the constriction of microvascular smooth muscle in extensively burned patients.

The objectives of this study were to analyze changes in serum interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) levels in patients that restored spontaneous circulation after cardiopulmonary arrest (CPA), and to clarify the cause and significance of elevated serum cytokines after resuscitation. Twenty-eight patients who were admitted to our hospital after out of hospital CPA were studied. Patients' IL-8 levels and TNF-alpha levels in serum increased to a peak within 12 h and within 6 h after the return of spontaneous circulation (ROSC), respectively. Serum IL-8 levels in patients who died or became brain dead within 1 week after ROSC were significantly higher than those in other patients. In stepwise multiple regression analysis, maximum IL-8 values were significantly correlated with maximum TNF-alpha values within post-ROSC 24 h, with the total dose of administered epinephrine and with peripheral neutrophil counts. It is especially noteworthy that the total dose of epinephrine administered during and after resuscitation markedly influenced the elevation of serum IL-8 after ROSC. The increases in serum IL-8 induced by excessive administration of epinephrine might be harmful in the ROSC-patients resuscitated after CPA.

Background: The purpose of this study was to examine the effects of a steam burn injury on apoptosis in gut-associated lymphoid tissue and to determine whether endogenous glucocorticoid and Fas ligand signaling were involved in this process.Methods: Histologic analysis, in situ deoxynucleotidyl transferase dUTP nick-end labeling staining and annexin V and 7-amino-actinomycin-D flow cytometry of lymphocyte populations were evaluated in intraepithelial lymphocytes and Peyer's patch. Additional mice were pretreated with a glucocorticoid receptor antagonist (mifepristone) before the steam burn. Similarly, C3H/HeJ-FasL(gld) mice lacking functional Fas ligand were also studied.Results:Apoptosis was significantly increased in intraepithelial lymphocytes and Peyer's patch after the burn injury. Mifepristone pretreatment significantly reduced apoptosis in both T- and B-cell populations in intraepithelial lymphocytes after the burn injury. In contrast, the increased apoptosis seen in B-cells from Peyer's patch was not seen in C3H/HeJ-FasL(gld) mice, whereas the increased apoptosis in CD8(+) T-cells was unaffected.Conclusion: Both corticosteroids and FasL contribute to the apoptosis in gut-associated lymphoid tissues early after burn injury.

Tumor necrosis factor (TNF)-alpha and Fas ligand (FasL) are trimeric proteins that induce apoptosis through similar caspase-dependent pathways. Hepatocytes are particularly sensitive to inflammation-induced programmed cell death, although the contribution of TNF-alpha and/or FasL to this injury response is still unclear. Here, we report that D-galactosamine and lipopolysaccharide-induced liver injury in C57BL/6 mice is associated with increased hepatic expression of both TNF-alpha and FasL mRNA. Pretreatment of mice with a TNF-binding protein improved survival, reduced plasma aspartate aminotransferase concentrations, and attenuated the apoptotic liver injury, as determined histologically and by in situ 3' OH end labeling of fragmented nuclear DNA. In contrast, pretreatment of mice with a murine-soluble Fas fusion protein (Fasfp) had only minimal effect on survival, and apoptotic liver injury was either unaffected or exacerbated depending on the dose of Fasfp employed. Similarly, mice with a spontaneous mutation in FasL (B6Smn.C3H-Fasl(gld) derived from C57BL/6) were equally sensitive to D-galactosamine/lipopolysaccharide-induced shock. We conclude that the shock and apoptotic liver injury after D-galactosamine/lipopolysaccharide treatment are due primarily to TNF-alpha release, whereas increased FasL expression appears to contribute little to the mortality and hepatic injury.

Nonobese diabetic (NOD/LtJ or NOD) mice are resistant to doses of LPS and d-galactosamine that uniformly produce lethality in C57BL/6J (B6) mice (p < 0.01). Liver caspase-3-like activity, serum transaminase levels (both p < 0.05), and the numbers of apoptotic liver nuclei were also reduced in NOD compared with B6 mice treated with LPS (100 ng) and d-galactosamine (8 mg). NOD mice were also at least 100-fold more resistant to recombinant human TNF-α and d-galactosamine treatment than B6 mice (p < 0.001). Binding of recombinant human TNF-α to splenocytes from NOD mice was similar to that seen in B6 mice, suggesting that the defect in responsiveness was not due to an inability of recombinant human TNF-α to bind the NOD TNF type 1 (p55) receptor. Because the TNF type 1 (p55) receptor shares a common signaling pathway with Fas (CD95), NOD and B6 mice were treated with the Fas agonist antibody, Jo-2. Surprisingly, NOD mice were as sensitive as B6 mice to Fas-induced lethality and hepatic injury. In addition, primary hepatocytes isolated from NOD mice and cultured in vitro in the presence of d-galactosamine with or without TNF-α were found to be resistant to apoptosis and cytotoxicity when compared with B6 mice. In contrast, Jo-2 treatment produced similar increases in caspase-3 activity and cytotoxicity in primary hepatocytes from NOD and B6 mice. The resistance to LPS- and TNF-α-mediated lethality and hepatic injury in d-galactosamine-sensitized NOD mice is apparently due to a post-TNFR binding defect, and independent of signaling pathways shared with Fas.

Immune suppression and increased apoptotic loss of circulating lymphocytes have been reported after burn injury. However, little is known about the underlying mechanisms responsible for the increased apoptosis of lymphoid and parenchymal cells in solid organs and the role played by inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL), as well as by glucocorticoids. To evaluate the role of endogenously produced glucocorticoids and FasL, mice subjected to a 20% steam burn were pretreated with a glucocorticoid receptor antagonist (mifepristone) or a neutralizing murine Fas fusion protein. Three and twenty-four hours after burn injury, histological analysis, caspase-3 activity, and in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and phenotyping of lymphocyte populations for apoptosis were evaluated. Burn injury increased the number of apoptotic cells and caspase-3 activity in thymus and spleen, but not in other solid organs. Increased apoptosis was seen in several T and B cell populations from both thymus and spleen. Mifepristone pretreatment significantly reduced the apoptosis and caspase-3 activity after burn injury, whereas blocking FasL activity had only minimal effects. We conclude that corticosteroids, and not FasL, are primarily responsible for the increased caspase-3 activity and apoptosis in thymus and spleen cell populations early after burn injury.

Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose-dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-alpha and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. beta-Galactosidase expression in mice receiving intratracheal instillation of Adv/beta-gal (adenovirus construct expressing beta-galactosidase) was transient (less than 14 days), but a significant early increase of beta-galactosidase expression was seen in mice lacking either or both TNF-alpha receptors, Absence of TNF-alpha or the p55 receptor significantly attenuated the iib response to both adenovirus and beta-galactosidase, Human IL-10 expression in the lung suppressed local TNF-alpha production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with beta-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10, We conclude that TNF-alpha signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with beta-galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is wed tolerated, has extended expression compared with beta-galactosidase, and is nonimmunogenic in the lung.

Fukuzuka, K.*; Minter, R.*; Rectenwald, J.*; Edwards, C. K. III*; Moldawer, L.; Mozingo, D. Author Information

Background: Tumor necrosis factor-α (TNF-α) is a member of a large family of predominantly homotrimeric type II membrane-associated proteins with both proinflammatory and apoptosis-inducing properties. Although TNF-α expression has been studied extensively, little is known about the expression of other members of the TNF-α superfamily during acute inflammatory processes. Methods: TNF-α, Fas ligand (FasL), and TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) messenger RNA (mRNA) expression were examined in liver, lung, spleen, and kidney after either a cecal ligation and puncture or endotoxemic shock with use of semiquantitative reverse transcriptase–polymerase chain reaction. Results: Cecal ligation and puncture increased TNF-α mRNA in lung and liver (both P < .05) within 3 hours, which was paralleled by increased FasL mRNA. In the spleen TNF-α and FasL mRNA significantly declined (both P < .05). In contrast to TNF-α and FasL, TRAIL mRNA levels were unchanged in all organs except lung, where it was reduced at 24 hours (P < .05). Endotoxemic shock also increased lung TNF-α and FasL mRNA levels (both P < .05). Conclusions: In acute inflammatory processes TNF-α and FasL mRNA increase concordantly in several solid organs. In contrast, TRAIL mRNA levels do not consistently change during these acute inflammatory processes, suggesting that its expression is under independent and discordant regulatory control. (Surgery 1999;126:349-57.)

Fukuzuka, K.; Rosenberg, J.; Gaines, G.; Abouhamze, A,; Auffenberg, T.; Tannahill, C.; MacKay, S.; Moldawer, L. L.; Mozingo, D. Author Information

closest reasonable medical facility or to the patient's home country. Problems related to long-distance air-medical transport include: 1) The pilot's duty-time restrictions com-bined with the demand for the quickest possible transfer of the patient to a receiving hospital; and 2) Long-range, wide-body aircraft are too expensive to use for air-med-ical transport. Solution: A functional world-wide service network cre-ated by service providers in different geographical areas should be established by which a coordinated, unbroken logistic chain of air-medical transport service providers would use several air-ambulance aircraft in combination with commercial intercontinental airline services. Benefits: Expanded world-wide service program would be available for patients wherever the need arises. This would provide cost-effective, reliable, and coordinated repatriation of the patients under supervision of air-medical professionals. 3) Brain blood flow disorders registered by transcranial doppler monitoring as a total vasospasm were observed in 78% of the cases. Nimodipine administration for 7—10 days reduced these phenomena. Thereby, chronic intoxication by neurotropic poisons such as an ethanol, changes in brain pathomorphology and clinical pictures must be consid-ered when rendering a care to this category of damaged beings during evacuation stages. Objective: The aim of this study was to evaluate the effectiveness of the Japanese emergency system for out-of-hospital cardiopulmonary arrest (oh-CPA). Background: Sudden CPA patients in Tokorozawa City and the surrounding cities (population of approximately one million) are transported to the hospital by the Japanese Emergency Medical Service (EMS). In the past, Japanese EMS personnel were permitted to perform only bag-valve-mask ventilation and external cardiac compressions for CPA patients. However, since 1991, specially trained emergency medical technicians (EMT) have used defibrillators and intubation devices (except for endotracheal tubes). Patients and Methods: 1,039 CPA cases were studied. Prognostic factors influencing outcomes from CPA were evaluated using multivariate analysis (quantification the-ory type); these variables included etiology, age, gender, witnessed arrest, bystander CPR, crew of EMS (EMT or not), time interval from collapse to arrival, and arrival status (CPA or not). Results: Spontaneous circulation returned in 393/1039 patients (37.8%), and 263 (25.3%) were admitted to the hospital wards. Forty-eight (4.6%) survived, and 13 (1.3%) recovered fully. Five full recovery cases were resuscitated by an EMT, and four of them returned to spontaneous circulation following defibrillation during ambulance transport. Influential factors for survival were arrival status, time, and etiology. Conclusion: Further improvement of the Japanese EMS system is needed. Continued EMT education will be necessary to accomplish the goal. Introduction: Remarkable improvement in the results of the management of acute peroral poisonings with organophosphate insecticides (OPI) have been attained. Despite these gains, the problem has not resolved com-pletely. A mortality rate of 25-30% still exists. Subjects: The causes of death in the group of patients admitted with acute peroral poisoning of OPI were studied. The data were abstracted from clinical observa-tions and results of medical forensic examinations. Results: The causes of death in the group of 87 patients who died of acute OPI poisoning were investigated. Of the total number of deaths, 39.1% occurred during the toxicogenic phase and 60.9%. during the somatogenic phase. It should be emphasized that within the first 12 h, the main causes of death were due to coma with brain oedema and respiratory center paralysis and exotoxic shock (90% of all deaths). In the late toxicogenic phase (12-48 h), the main cause of death was exotoxic shock (65%). In the early somatogenic phase (3-6 days) the main cause of death was related to complications due to infection, mostly pulmonary (48.8%), and hemodynamic failure. The forms of hemodynamic failure were acute left ventricular failure, secondary somatogenic collapse, and dysrythmias despite treatment with potassium. There were no significant differences between the clini-cian's and pathologist's decisions regarding the cause of death. Conclusion: These data provide directions to improve the methods of intensive care for acute OPI poisoning.