Suppression of interleukin 2 production in an animal model of thermal injury is related to prostaglandin synthesis

We performed studies using an animal model of thermal injury to confirm the observed decrease in interleukin 2 (IL-2) production in burned patients and to explore the underlying mechanisms. Ten mice subjected to a 25% scald were compared with ten anesthetized littermates (controls) and six untreated mice (normal mice) 1, 3, 5, 7, 10, 14, and 21 days after burn. Production of IL-2 by splenocytes was stimulated by concanavalin A alone, or in the presence of the cyclooxygenase inhibitor indomethacin or flurbiprofen. The IL-2 content of the resulting supernatant was determined by the response of the IL-2-dependent cell line CTLL-2. The IL-2 production was significantly suppressed in the burned mice at three days (mean +/- SEM, 30.9% +/- 5.2%), five days (19% +/- 5.5%), seven days (41.6% +/- 6.4%), and 21 days (20% +/- 4.5%). Significant enhancement of IL-2 production by indomethacin was seen in the burned group (mean, 95%), but not in controls (mean, 23.8%) or normal mice (mean, 17.2%), and similar effects were seen with flurbiprofen. In separate experiments the effects of exogenous prostaglandin E2 on lymphocyte blastogenesis and IL-2 production were studied, and an increased susceptibility to the inhibitory effects of prostaglandin E2 was observed following thermal injury.     

Temporal correlation of impaired immune response after thermal injury with susceptibility to infection in a murine model

Suppression of cellular immunity and increased susceptibility to sepsis frequently accompany thermal injury. However, a convincing association between the two has been difficult to establish in human beings. Therefore we chose to investigate the relationship of impaired cell-mediated immunity with susceptibility to sepsis in an animal model. We studied the response to phytohemagglutinin (PHA) and interleukin-2 (IL-2) production by splenocytes from mice subjected to a standard 25% scald burn and killed at intervals of 3, 5, 7, 10, 14, and 25 days after thermal injury. Burned mice were compared in all instances to sham-burn animals (i.e., animals that had been anesthetized and shaved but not burned). We also studied mortality after cecal ligation and puncture (CLP), as a septic challenge, in burned and control animals at the same postburn intervals. We found maximal suppression (50% to 55%) of the PHA response at 10 to 14 days after injury and maximum suppression (68%) of IL-2 production at 7 days. Both of these parameters returned to normal by postinjury day 28. Mortality after CLP increased gradually from control levels after thermal injury up to a maximum of 88% on postburn day 10 and also returned to control levels after 28 days after burn. Significant correlations were found between mortality after CLP in the postburn period and suppression of the PHA response, on the one hand, and the suppression of IL-2 production, on the other (r = 0.89 and 0.91, respectively; p less than 0.05). This result implies a causal relationship between impaired cell-mediated immunity and susceptibility to sepsis after burn injury.     

Effect of low dose recombinant interleukin 2 plus indomethacin on mortality after sepsis in a murine burn model

Under anaesthesia, 129 8-week-old male A/J mice were subjected to a 25 per cent scald or sham burn and then resuscitated. They were divided at random into two groups. Mice from the first group were allocated into two groups. Mice from the first group were allocated into four subgroups to receive 6 days intraperitoneal (I.P.) injections as follows: (i) recombinant human interleukin 2 (rhIL-2) (250 units day-1); (ii) saline; (iii) indomethacin (5 micrograms-1 day-1); or (iv) rhIL-2 (250 units) + indomethacin (5 micrograms). Sham burned mice served as no treatment controls. All animals were subjected to peritonitis induced by caecal ligation and puncture 10 days after the burn and mortality was assessed. Mice from the second group were allocated to two subgroups to receive 6 days intraperitoneal injections of: (i) rhIL-2 + indomethacin; or (ii) saline. Animals in this group did not undergo septic challenge. They were randomly killed on days 7, 9 or 10 after the burn. Their splenocytes were harvested and assayed for response to the mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A), and for production of interleukin 2. Mortality rate in animals subjected to burn and septic challenge without treatment was 75 per cent; in mice receiving rhIL-2 alone it was 68 per cent, in mice receiving indomethacin alone it was 62 per cent (no significance) and in mice receiving rhIL-2 + indomethacin it was reduced to 38 per cent (P less than 0.02). Splenocytes from animals receiving combination therapy had markedly improved responses to PHA on days 7 (P = 0.01), 9 (P = 0.02), and 10 (P = 0.008), and to Con A on days 7 (P = 0.001), 9 (P = 0.002) and 10 (P = 0.001), after burn injury. Interleukin 2 production was also significantly (P = 0.004) improved by therapy with rhIL-2 + indomethacin. These data suggest that low dose rhIL-2 in combination with indomethacin may have potential use in the therapy of burn victims.     

In vivo monitoring of postburn immune response

Following a severe thermal injury (30% TBSA), 50% of the burned mice died within 48 hours. The immune response of the survivors was evaluated in vivo using the popliteal lymph node assay (PLNA) for host versus graft (HVG) or graft versus host (GVH) response. Suppression of GVH reactivity was observed using isolated splenocytes from burned mice harvested on postburn days 3, 8, and 11. Lymphocyte response evaluated in the burn environment using the HVG assay was profoundly deficient on postburn days 3 and 11. Recovery of immune function as determined by measurements of both responses occurred by postburn days 14-21, and coincided with wound healing. The PLNA proved to be a sensitive measure of immune function, and allowed for the evaluation of isolated cell populations, as well as measurement of lymphocyte function in the burn environment in the presence of circulating suppressor factors.     

Temporal analysis of murine lymphocyte subpopulations by monoclonal antibodies and dual-color flow cytometry after burn and nonburn injury

The immune suppression that frequently accompanies severe injury undoubtedly contributes to subsequent infectious complications. Various lymphocyte subpopulations may be identified by surface antigen expression, and alterations in antigen expression by lymphocytes may reflect host immune competence. Using monoclonal antibodies (Moabs) and dual-color flow cytometry, we studied lymphocyte phenotypic expression in mice after either controlled burn injury or hind-limb amputation, with use of peripheral blood, lymph node, and spleen for cell preparation. Moabs were utilized specific for T cells (Lyt-1), helper/inducer cells (L3T4), suppressor/cytotoxic cells (Lyt-2), B cells (IgG), and activated T cells (Ia or IL-2 receptor). The assay techniques called for small amounts of tissue and avoided gradient procedures that might result in selective loss of some lymphocyte populations. The most consistent changes observed were depressions in percentages of L3T4+ and Lyt-2+ cells in spleens of burned mice, accompanied by depression in Ia+ (possibly activated or proliferating) subsets of L3T4+ and Lyt-2+ cells, and the appearance of increased percentages of non-B, non-T lymphocytes. Changes in lymph node cells were minimal. The major alteration seen in peripheral blood was substantial depression of Ia+ subsets, although burned mice had increased circulating Lyt-2+ cells on several late postburn days. Burned mice, unlike limb-trauma mice, had marked splenic hypertrophy with more than a 300% increase in spleen weight after the 30-day postburn period. Eschar excision/implantation experiments indicated that splenic hypertrophy and splenocyte phenotypic changes are related to the presence of burned tissue, which suggests that burned tissue may partially mediate immune changes that accompany severe burn injury.     

Simvastatin treatment improves survival in a murine model of burn sepsis: Role of interleukin 6

Infection is the most common and most serious complication of a major burn related to burn size. Recent studies have demonstrated that statin treatment can decrease mortality in murine or human sepsis. In the current study mice were anesthetized and subjected to a dorsal 30% TBSA scald burn. Simvastatin or placebo were administered by intraperitoneal injection once daily or every 12 h. On post burn day 7 cecal ligation and puncture with a 21-gauge needle (CLP) was performed under ketamine/xylazine anesthesia, the two different dosing schedules were continued and survival was monitored. In other groups of mice, interleukin-6 (IL-6) levels in blood were measured in mice at 7 days after injury. A simvastatin dependent improvement in survival was observed in the burn sepsis model. This protection was found to be dose and time dependent. In addition, statin treatment reduced the elevation in IL-6 levels of mice burned 7 days previously. However, IL-6 levels in burned mice with or without statin treatment were elevated by CLP to the same degree. The results of these studies suggest that statin treatment reduces mortality in mice with burns and CLP and that this effect may not be mediated via IL-6 levels.     

Changes in circulating levels of an anti-inflammatory cytokine interleukin 10 in burned patients

In order to understand the role of an anti-inflammatory cytokine interleukin 10 (IL-10) in the pathophysiology of burn injury, IL-10 levels in serial serum samples of 22 burned patients were analyzed. The total body surface areas (TBSA) of the burn injury ranged from 30 to 90%. Among these 22 patients, 14 recovered and the other eight, who were septic, expired. A significant difference in serum IL-10 values on admission (5-20 h postburn) was found (P<0.05) between patients who survived or died from burn injury as analyzed by the Student's t test. In addition, a significant difference in serum IL-10 on admission was also found (P<0.05) between patients with TBSA of greater or less than 50%. An initial peak serum IL-10 response was detected within 2.5 days postburn. Significant differences in the peak serum IL-10 levels were not found between patients with TBSA of greater or less than 50% and patients who survived or expired from burn injury. Afterwards, serum IL-10 remained low in the survivors, while an increase in serum IL-10 could be detected in the non-survivors with proven sepsis. Levels of circulating IL-6 in these non-surviving patients showed a tendency to increase starting from about 1-2 weeks postburn which coincided temporally with the detection of infections. However, marked increases in circulating IL-10 levels were observed just before death in four of the eight non-survivors. The serum samples of these four patients were collected at 31 h (404.8 pg/ml), 2 h (773.9 pg/ml), 5 days (150.7 pg/ml) and 12 h (177.1 pg/ml) before the expiration of these patients, respectively. IL-10 levels of 28.6, 27. 5 and 13.5 pg/ml were detected in sera of three of the remaining four non-survivors that were collected at 2.5 h, 36 h and 30 h before the expiration of these patients, respectively. There was one non-surviving patient who suffered an 80% burn (patient D4 in Table 1 and Fig. 4) and his IL-10 level at 20 days postburn was 13.4 pg/ml. The serum sample of this patient was collected 22 days before death and he was not suffering from sepsis at this stage. In conclusion, an initial increase in serum levels of IL-10 was detected postburn. A marked increase in serum levels of IL-10 was detected in four of the eight septic patients just before their death. It was considered that a lack and/or a delay in the increase of circulating IL-10 may play a significant role in the pathophysiology of sepsis in burned patients.     

Chronic ethanol exposure before injury produces greater immune dysfunction after thermal injury in rats

Chronic alcoholics constitute a small but significant subgroup of burned patients. The effects of chronic alcohol exposure on immune function in burned patients has not to our knowledge been studied. This study was designed to determine the effect of chronic alcohol exposure before burn injury on immune function after injury in rats. Immune function assessed by in vivo chemotaxis and responsiveness of non-adherent splenocytes to both a T-cell mitogen, concanavalin A, and a B-cell mitogen, lipopolysaccharide, was measured at 4 days after a 20% BSA full-thickness burn injury and/or gavage of 2.4 gm/kg/day of ethanol for 14 days. Chronic ethanol ingestion before burn injury produced significant suppression in chemotaxis and response to lipopolysaccharide but not in response to concanavalin A. These results suggest that chronic alcohol exposure before injury can contribute to further impaired immune function after injury, and may lead to increased susceptibility to infection and increased mortality.     

Postburn immune suppression: an inflammatory response to the burn wound?

In an effort to elucidate the causes of immune suppression which follows severe burn injury, we studied the immunologic effects of subcutaneous implantation of burned skin, as well as implantation of other materials, in mice. Ten days following the implantation, splenic lymphocyte proliferation and lymphocyte surface expression of activation antigens (IL-2R and Ia) were analyzed following a 3-day culture period. In addition, peritoneal neutrophils were analyzed for oxidative burst activity using flow cytometry and a dye which reacts with intracellular hydrogen peroxide. Implantation of a 2 x 2 cm section of burned/unburned skin as well as implantation of a similar-sized piece of cotton gauze or collagen sheet resulted in subsequent suppression of both lymphocyte activation proliferation and neutrophil oxidative burst activity. An intense local inflammatory response to the burn wound may play a role leading to the profound systemic immune suppression which follows severe burn injury.     

Major injury induces increased production of interleukin-10 by cells of the immune system with a negative impact on resistance to infection.

OBJECTIVE: The purpose of this study was to compare the production of interleukin-10 (IL-10) by peripheral blood mononuclear cells (PBMC) from injured patients and control subjects to determine the responsible cell types and to relate IL-10 production to the occurrence of sepsis. A mouse model of burn injury was used to confirm the human findings and to assess the importance of IL-10 in the lowered resistance to infection after injury. SUMMARY BACKGROUND DATA: Severe injury is associated with depressed immune responses. Although IL-10 is known to inhibit several aspects of immune reactivity, the role of IL-10 in postinjury immune suppression remains controversial. METHODS: Peripheral blood mononuclear cells from 14 burn and 12 trauma patients and 16 healthy individuals were studied at serial intervals for IL-10 production stimulated by a T-cell mitogen, phytohemagglutinin, and by bacterial lipopolysaccharide. To determine the source of IL-10, CD4+ and CD8+ lymphocyte subsets were obtained by selective depletion of PBMC with antibody-coated magnetic beads and were stimulated by anti-CD3 antibody to induce IL-10 secretion. In addition, IL-10 production by patients' PBMC in the first 10 days after injury was assessed for correlation with subsequent septic events. Anti-CD3-stimulated IL-10 production also was determined for CD4- and CD8-enriched lymphocyte subsets obtained by antibody and complement depletion of splenocytes harvested from groups of burn and sham burn mice at day 10 after injury, the time of maximal susceptibility to a septic challenge, cecal ligation and puncture (CLP). Finally, to test the importance of IL-10 in immune suppression in vivo, groups of burn and sham burn mice were treated with anti-IL-10 monoclonal antibody or control immunoglobulin G (IgG) on days 1 and 3 postinjury and were observed for survival after CLP on day 10. RESULTS: Patients' PBMC produced significantly more IL-10 than did controls' PBMC 7 to 14 days after injury. Patients' CD4+ (T-helper) but not CD8+ (T-cytotoxic) lymphocytes also showed increased IL-10 production versus those of control subjects early after injury. Increased PBMC IL-10 production in the first 10 days postinjury correlated significantly (p < 0.05) with subsequent septic events. Burn mouse CD4-enriched but not CD8-enriched splenocytes produced more IL-10 than did sham burn splenocyte subsets on day 10 after injury. Burn mice treated with anti-IL-10 antibody but not with control IgG had significantly increased survival after CLP. CONCLUSION: Serious injury in humans and in a mouse burn model is followed by increased stimulated production of IL-10 by cells of the immune system. The CD4+ T-helper cells appear to be a major source of IL-10 after injury. In injured patients, increased IL-10 production is correlated with subsequent septic events, and in the burn mouse, IL-10 appears to induce decreased resistance to infection.     

Adoptive immunotherapy using lymphokine-activated killer cells and recombinant interleukin-2 in preventing and treating spontaneous pulmonary metastases of syngeneic Dunning rat prostate tumor

Lymphokine-activated killer (LAK) cells were generated from splenocytes of rats bearing a weakly immunogenic Dunning prostate tumor (R-3227 AT-3) and activated with recombinant interleukin-2 (rIL-2). The maximal LAK activity was obtained from splenocytes of rats bearing tumors for 10 to 14 days after incubation with 1000 U/ml./day of rIL-2 for five to eight days. The majority of these LAK cells expressed high levels of asialo GM1 (89%), laminin (83%), OX-19 (80%) and OX-8 (88%) surface markers. LAK cells exhibited higher cytotoxicity to rat prostate tumor cells and mouse lymphoma in vitro than to other non-prostate tumor cells or normal rat splenocytes and thymocytes. Splenocytes of rats bearing prostate tumors have higher LAK activity than normal splenocytes. The Winn type assay showed that Dunning prostate tumor growth was inhibited effectively by LAK cells at a tumor cell:LAK cell ratio of 1:50. The therapeutic efficacy of LAK cells in the treatment of primary solid prostate tumors and pulmonary metastases of Dunning rats was evaluated. LAK cells in combination with rIL-2 showed a greater therapeutic benefit in 1) prevention of prostate tumor metastases to lung, 2) retardation of the primary tumor growth, 3) regression of spontaneously established pulmonary metastases, and 4) prolongation of survival as compared to untreated controls or those groups treated with LAK cells or rIL-2 alone. The results of this study indicate that the conjunctive therapeutic approach of using surgical therapy to remove primary solid tumors followed by adoptive immunotherapy with LAK cells plus in vivo administration of IL-2 may be potentially valuable in the treatment of prostate tumors, particularly for the spontaneous pulmonary metastases.     

One-hit wonder: Late after burn injury,granulocytes can clear one bacterial infection but cannot control a subsequent infection

ObjectiveBurn injury induces an acute hyperactive immune response followed by a chronic immune dysregulation that leaves those afflicted susceptible to multiple secondary infections. Many murine models are able to recapitulate the acute immune response to burn injury, yet few models are able to recapitulate long-term immune suppression and thus chronic susceptibility to bacterial infections seen in burn patients. This has hindered the field, making evaluation of the mechanisms responsible for these susceptibilities difficult to study. Herein we describe a novel mouse model of burn injury that promotes chronic immune suppression allowing for susceptibility to primary and secondary infections and thus allows for the evaluation of associated mechanisms.MethodsC57Bl/6 mice receiving a full-thickness contact burn were infected with Pseudomonas aeruginosa 14 days (primary infection) and/or 17 days (secondary infection) after burn or sham injury. The survival, pulmonary and systemic bacterial load as well as frequency and function of innate immune cells (neutrophils and macrophages) were evaluated.ResultsFollowing secondary infection, burn mice were less effective in clearance of bacteria compared to sham injured or burn mice following a primary infection. Following secondary infection both neutrophils and macrophages recruited to the airways exhibited reduced production of anti-bacterial reactive oxygen and nitrogen species and the pro-inflammatory cytokineIL-12 while macrophages demonstrated increased expression of the anti-inflammatory cytokine interleukin-10 compared to those from sham burned mice and/or burn mice receiving a primary infection. In addition the BALF from these mice contained significantly higher level so of the anti-inflammatory cytokine IL-4 compared to those from sham burned mice and/or burn mice receiving a primary infection.ConclusionsBurn-mediated protection from infection is transient, with a secondary infection inducing immune protection to collapse. Repeated infection leads to increased neutrophil and macrophage numbers in the lungs late after burn injury, with diminished innate immune cell function and an increased anti-inflammatory cytokine environment.     

Prevention of suppressed cell-mediated immunity in burned mice with histamine-2 receptor antagonist drugs

Thermal injury has been shown to suppress many aspects of both specific and nonspecific immune responses. We investigated the effect of two histamine H-2 antagonist drugs on cell-mediated immunity in burned mice, utilizing a method of quantitating the degree of contact sensitivity elicited to the antigen. 2,4-dinitrofluorobenzene (DNFB). Following sensitization by painting the abdomen with DNFB, animals were challenged 5 days later by painting the ears; subsequent ear swelling is a sensitive and reproducible measure of cell-mediated immunity. We have previously demonstrated that burned mice are maximally immunosuppressed 10 to 14 days following burn injury. In the present study we found that daily intraperitoneal administration of appropriate doses of the H-2 antagonists cimetidine (2 and 10 mg/kg/day) and ranitidine (2 and 10 mg/kg/day) resulted in maintenance of normal cell-mediated immunity in burned animals. Neither a lower dose of ranitidine (0.2 mg/kg/day) nor higher doses of cimetidine (20 and 50 mg/kg/day) restored immunity, and diphenhydramine, an H-1 antagonist, had no effect. There was no augmentation of contact sensitivity in unburned mice treated with cimetidine. The immunorestorative effect is probably secondary to antagonism of histamine H-2 receptors on suppressor T lymphocytes, and may reflect increased suppressor cell activity in burned mice; however, other mechanisms may be involved.     

白细胞介素-6在全身炎症反应中对冠脉内皮细胞的作用

目的 应用基因敲除小鼠模型研究白细胞介素(IL)-6在这一损伤过程中对内皮细胞的损伤作用及其机制.方法 IL-6 knockout(IL-6 KO,C57BL/6J-116tmlKopf,实验组)小鼠与其野生型小鼠C57BL/6J(对照组)分别给予40%烧伤,用Langendorff离体工作心模型观察烧伤后鼠心心功能及冠脉流量的变化,并观察内皮细胞对乙酰胆碱的反应性,用HE和Tunel染色观察心肌血管及其内皮细胞的变化.结果 在非烧伤应急情况下,对照组与实验组的冠脉流量、心排出量及对乙酰胆碱刺激的反应均无明显差异,病理学差异无统计学意义.但在烧伤后,对照组冠脉流量(1.94±0.17比2.32±0.21 mL/min,P＜0.05)与心排量(3.7±0.3)比(7.5±0.4)ml/min,P＜0.05)均显著减少,对乙酰胆碱刺激的反应显著低于实验组(2.34±0.23)比(2.88±0.26);(5.0±0.4)比(8.4±0.4),P＜0.05);病理学上对照组血管内皮肿胀、排列紊乱及内皮细胞凋亡现象.结论 循环血液中IL-6对内皮细胞的损伤作用可能是其心功能抑制的始动环节.     

Postburn immunosuppression in an animal model. III. Maintenance of normal splenic helper and suppressor lymphocyte subpopulations by immunomodulating drugs

Delineation of lymphocyte subpopulations by labeling cells with specific monoclonal antibody now appears to be a reliable means of measuring cellular immunity in various disease states. We determined splenic helper/inducer and suppressor/cytotoxic lymphocyte populations in mice given a 20% to 25% body surface area steam burn injury. The lymphocyte helper: suppressor ratio fell from 3.13 +/- 0.06 in control mice to 1.77 +/- 0.04 in burned animals (p less than 0.0005) 14 days after burn. Immediate postburn eschar removal resulted in improvement in the ratio 14 days later (2.66 +/- 0.14) although not in restoration to normal levels. Postburn treatment of burned mice with intraperitoneal cimetidine, ibuprofen, indomethacin, cyclophosphamide, and topically applied cerium nitrate resulted in substantial restoration of the lymphocyte ratio toward normal values; in animals treated with cimetidine and ibuprofen the resultant lymphocyte ratio was not statistically different from that in control (unburned) mice. These drugs probably inhibit suppressor cell populations or suppress the immunosuppressive effect of toxic materials in the burn wound. Specific pharmacologic therapy improves immune function in burned mice and may result in increased resistance to infection.     

Opiate analgesics contribute to the development of post-injury immunosuppression

BACKGROUND: Immune dysfunction and post-injury infections are complications associated with thermal injury. Opiates, the analgesic of choice for the treatment of post-burn pain, can also induce similar immune complications. However, the impact of therapeutic opiates on post-burn immune dysfunction is unknown. MATERIALS AND METHODS: C57BL/6 mice were subjected to a small 6.25% total body surface area (TBSA) burn or sham procedure. The mice were left untreated or treated with morphine sulfate by subcutaneous implantation of an Alzet pump that administered morphine sulfate at a rate of 2 mg/kg body weight/day. Plasma, splenocytes and splenic macrophages were isolated for in vitro analysis 1, 4, or 7 days later. RESULTS: Neither burn injury nor morphine treatment alone significantly altered splenic T-cell proliferation at 1, 4, or 7 days post-injury/treatment. In contrast, morphine treatment of injured mice suppressed splenic T-cell proliferation at 4 and 7 days post-injury/treatment. The suppressed proliferation of T-cells correlated with increased levels of the nitric oxide and an immunosuppressive Th-2 type phenotype. In contrast morphine treatment did not accentuate the suppressed T-cell proliferative responses associated with larger injuries covering 12.5% and 25% TBSA. Splenic macrophage function was unaffected with the exception that LPS-induced nitric oxide production was elevated in the injured mice treated with morphine. CONCLUSIONS: These findings demonstrate that those mice treated with a clinically relevant dose of morphine sulfate after an "immunologically insignificant" burn displayed immunosuppression and a Th-2 cytokine profile. Thus, the therapeutic administration of exogenous opiates appears to contribute to the development of post-burn immune dysfunction.     

The suppressive activity of T-lymphocytes and serum factors in burned patients

This study was performed to investigate the cell-mediated immune response in burned patients with no septic episodes.The results show that burned patients with percentage body burn higher than 20 had an impaired lymphocyte reactivity to phytohaemagglutinin and conconavalin A. This hyporesponsiveness appeared on day 3–4 and in all cases reached its maximum on day 7–8 post burn, while recovery occurred between day 11 and 29 depending on the severity of the injury.The serum from immunodepressed patients was able to inhibit the response to phytohaemagglutinin and conconavalin A of normal lymphocytes. This immunosuppressive activity was present very early after injury (on day 1–2) and before the onset of lymphocyte hyporesponsiveness to mitogens and was no longer detectable on day 7–8 post burn, when patient lymphocytes showed the greatest hyporesponsiveness to mitogens. This late depression was due to T suppressor cells.     

Lack of aromatase improves cell-mediated immune response after burn

Background

Persistent elevation of estrogens after injury or sepsis correlates with increased mortality and a pro-inflammatory state. Given that aromatase is elevated after injury, the enzyme's subsequent conversion of androstenedione and testosterone to estrone and estradiol may be a causative factor for this correlation.

Methods

Aromatase knockout (ArKO) and wild type female mice were subjected to a 15% total body surface area burn. The delayed type hypersensitivity (DTH) response and splenocyte production of IL-6 and TNFα were examined 8 days later.

Results

Injury in wild type mice is associated with an impairment in the DTH response, as well as with an increase in IL-6 and TNFα production by stimulated splenocytes. However, for ArKO mice, the impairment in DTH was blunted and there was no difference in IL-6 production between sham- and burn-injured mice. Sham-injured ArKO mice produced nearly 50% more TNFα than wild type mice, while injury did not result in a significant increase in TNFα production for ArKO mice.

Conclusion

The complete deficiency in aromatase correlated with a decrease in the production of the inflammatory cytokine IL-6 and partial restoration of the DTH response after severe burn. However, a deficiency of aromatase did not effect TNFα production after injury.