Muscle glutamine depletion in the intensive care unit

Glutamine is primarily synthesized in skeletal muscle and enables transfer of nitrogen to splanchnic tissues, kidneys and immune system. Discrepancy between increasing rates of glutamine utilization at whole body level and relative impairment of de novo synthesis in skeletal muscle leads to systemic glutamine deficiency and characterizes critical illness. Glutamine depletion at whole body level may contribute to gut, liver and immune system disfunctions, whereas its intramuscular deficiency may directly contribute to lean body mass loss. Severe intramuscular glutamine depletion also develops because of outward transport system upregulation, which is not counteracted by increased de novo synthesis. The negative impact of systemic glutamine depletion on critically ill patients is suggested both by the association between a lower plasma glutamine concentration and poor outcome and by a clear clinical benefit after glutamine supplementation. Enteral glutamine administration preferentially increases glutamine disposal in splanchnic tissues, whereas parenteral supplementation provides glutamine to the whole organism. Nonetheless, systemic administration was ineffective in preventing muscle depletion, due to a relative inability of skeletal muscle to seize glutamine from the bloodstream. Intramuscular glutamine depletion could be potentially counteracted by promoting de novo glutamine synthesis with pharmacological or nutritional interventions.     

The role of glutamine in the immune system and in intestinal function in catabolic states

Summary Glutamine is designated a non-essential amino acid: however, evidence is accumulating that glutamine becomes essential when catabolic conditions prevail.It has been established that glutamine is an important fuel for lymphocytes and macrophages, even when resting. Plasma and muscle glutamine concentrations are decreased after trauma such as burns, major surgery, and in sepsis. The effectiveness of the immune system is decreased after trauma: this may be due, in part, to the decrease in plasma glutamine concentrations.Most studies on sepsis in humans have shown plasma glutamine concentrations to bedecreased: this may be due to an increased rate of utilization of glutamine by lymphocytes and macrophages during proliferation or phagocytosis. In contrast, several studies on rats showincreased plasma glutamine levels in sepsis. A species difference in the way in which glutamine is metabolised could be the main reason for the conflicting results. Other contributory factors could be diurnal variation and timing of sample collection.A substantial amount of dietary glutamine is taken up by intestinal cells. When the supply of glutamine via the diet is decreased, glutamine is taken up from the circulation by the intestine. In total parenteral nutrition (TPN) sepsis can sometimes occur because the gut is rested, leading to villous atrophy and increased gut mucosal barrier permeability. There is now a move towards the use of enteral nutrition in preference to TPN. Provision of exogenous glutamine has had beneficial effects in humans and animals, particularly in improving intestinal function. The safety and efficacy of glutamine administration to humans is discussed in detail.     

Plasma glutamine concentration in spinal cord injured patients

Glutamine, a non-essential amino acid, is the most important source of energy for macrophages and lymphocytes. Reduction in its plasma concentration is related with loss of immune function, as leukocyte proliferation and cytokine production. It is well known that glutamine is largely produced by the skeletal muscle which is severely compromised as a consequence of the paralysis due to the damage of the spinal cord. In spinal cord injury (SCI) patients, infections, such as pneumonia and sepsis in general, are a major cause of morbidity and mortality. In comparison with the control group, a 54% decrease in plasma glutamine concentration was observed as well as a decrease in the production of TNF and IL-1 by peripheral blood mononuclear cells cultivated for 48 h in SCI patients. Therefore, we propose that a decrease in plasma glutamine concentration is an important contributor to the immunosuppression seen in SCI patients.     

Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response

Hepatic expression of iron homeostasis genes and serum iron parameters predict the success of immunosuppression withdrawal following clinical liver transplantation, a phenomenon known as spontaneous operational tolerance. In experimental animal models, spontaneous liver allograft tolerance is established through a process that requires intra-hepatic lymphocyte activation and deletion. Our aim was to determine if changes in systemic iron status regulate intra-hepatic lymphocyte responses. We used a murine model of lymphocyte-mediated acute liver inflammation induced by Concanavalin A (ConA) injection employing mice fed with an iron-deficient (IrDef) or an iron-balanced diet (IrRepl). While the mild iron deficiency induced by the IrDef diet did not significantly modify the steady state immune cell repertoire and systemic cytokine levels, it significantly dampened inflammatory liver damage after ConA challenge. These findings were associated with a marked decrease in T cell and NKT cell activation following ConA injection in IrDef mice. The decreased liver injury observed in IrDef mice was independent from changes in the gut microflora, and was replicated employing an iron specific chelator that did not modify intra-hepatic hepcidin secretion. Furthermore, low-dose iron chelation markedly impaired the activation of isolated T cells in vitro. All together, these results suggest that small changes in iron homeostasis can have a major effect in the regulation of intra-hepatic lymphocyte mediated responses.     

Development of immunity in human severe primary T cell deficiency following haploidentical bone marrow stem cell transplantation

Recent advances in the prevention of graft-vs-host disease (GVHD) have allowed the use of haploidentical bone marrow cells for correction of lethal genetic defects of the immune system. Sequential analyses of blood lymphocyte phenotypes and functions were done before and after transplantation of haploidentical marrow stem cells into 17 infants with severe primary T cell deficiencies. The marrow was depleted of post-thymic T cells and most other mature marrow cells by soy lectin agglutination and sheep erythrocyte rosetting. The studies were performed to define the time course and extent of appearance of immune function, and to identify factors leading to resistance to engraftment. No pretransplant immunosuppression was used. T cell function was detected between 34 and 287 days after transplantation, but a sharp rise usually occurred between 84 and 115 days, and normal function was reached between 113 and 210 days. Fifteen of the patients are alive from 6 to 41 mo post-transplantation, 12 have improved or have normal T lymphocyte function, and nine have proven T cell chimerism. Increased immunoglobulins of several isotypes have been noted in 11 patients and specific antibodies in seven patients, although B cell chimerism has been detected in only one patient. B cell function required 2 to 2.5 yr for normalization. No GVHD occurred in 14 patients, and the other three had only transient mild skin rashes. Two patients died of viral infections. Failure to engraft was correlated with some pre-transplant lymphocyte responses to mitogens and allogeneic cells (three cases), but not with the presence of pre-transplant natural killer cell function (five cases) nor with the presence of purine salvage pathway enzyme deficiencies (four cases). The latter, however, was associated with poor lymphoid function in two patients. These studies indicate that the thymic microenvironment of most infants with severe combined immunodeficiency disease is capable of differentiating donor stem cells to mature and functioning T lymphocytes which can cooperate with apparently normal host B cells for antibody production.     

Decreased Essential Antioxidants and Increased Lipid Hydroperoxides Following High-Dose Radiochemotherapy

The blood from 19 patients having bone marrow transplantation was examined for the essential antiox-idants alpha-tocopherol and beta-carotene as well as lipid hydroperoxides before, at and after bone marrow transplantation (BMT). Conditioning therapy, preceding BMT in order to achieve marrow ablation and immunosuppression, consists of high-dose chemotherapy which is mostly combined with total body irradiation (TBI). In order to see a possible difference between patients with and without additional TBI, we divided the patients up into two groups; patients receiving TBI (RT⁺) and patients without TBI (RT-). All patients required total parenteral nutrition beginning one week prior to BMT.

After conditioning therapy plasma levels of absolute and lipid-standardized alpha-tocopherol and beta-carotene decreased in both groups, presumably as a result of an enhanced breakdown of these antioxidants. The loss of these lipid-soluble antioxidants has to be considered as a possible cause for early post-transplant toxicity. Lipid hydroperoxides increase significantly in the group of patients with additional TBI, whereas the other group, receiving no additional TBI, showed no significant change.

We suggest high-dose supplementation of essential antioxidants for patients undergoing BMT.     

Neonatal induction of tolerance to skeletal tissue allografts without immunosuppression

Vascularized allogeneic skeletal tissue transplantation without the need for host immunosuppression would increase reconstructive options for treating congenital and acquired defects. Because the immune system of a fetus or neonate is immature, it may be possible to induce tolerance to allogeneic skeletal tissues by alloantigen injection during this permissive period. Within 12 hours after birth, 17 neonatal Lewis rats were injected through the superficial temporal vein with 3.5 to 5 million Brown Norway bone marrow cells in 0.1 ml normal saline. Ten weeks after the injection, peripheral blood from the Lewis rats was analyzed for the presence of Brown Norway cells to determine hemopoietic chimerism. The Lewis rats then received a heterotopic, vascularized limb tissue transplant (consisting of the knee, the distal femur, the proximal tibia, and the surrounding muscle on a femoral vascular pedicle) from Brown Norway rat donors to determine their tolerance to the allogeneic tissue. A positive control group (n = 6) consisted of syngeneic transplants from Lewis rats into naive Lewis rats to demonstrate survival of transplants. A negative control group (n = 6) consisted of Brown Norway transplants into naive Lewis rats not receiving bone marrow or other immunosuppressive treatment. The animals were assessed for transplant viability 30 days after transplantation using histologic and bone fluorochrome analysis. All the syngeneic controls (Lewis to Lewis) remained viable throughout the experiment, whereas all the Brown Norway to Lewis controls had rejected. Ten of the 17 allografts transplanted into bone marrow recipients were viable at 30 days, with profuse bleeding from the ends of the bone graft and the surrounding graft muscle. The percent of chimerism correlated with survival, with 3.31 percent (SD = 1.9) of peripheral blood, Brown Norway chimerism present in the prolonged survival groups and 0.75 percent (SD = 0.5) of Brown Norway chimerism in the rejected graft group. This study demonstrated prolonged survival of allogeneic skeletal tissue without immunosuppression after early neonatal injection of allogeneic bone marrow in a rat model.     

Relative antigenicity of components of a vascularized limb allograft

At present, the transplantation of vascularized limb-tissue allografts can be achieved only with generalized host immunosuppression, which results in significant systemic toxicity, thereby precluding their clinical use. A better understanding of the immunogenic mechanisms of these allografts may permit less toxic and thus clinically applicable means of host immunosuppression. In this study, individual vascularized limb tissues (skin, subcutaneous tissue, muscle, bone, and blood vessels) and a whole limb were transplanted microsurgically across a strong histocompatibility barrier in rats. The respective cell-mediated and humoral immune responses generated in the hosts were determined by means of mixed lymphocyte cultures by radioactive 51Cr release assays and compared. No single tissue predominated in the elicited immune response. Rather, the various tissue components interacted with the host immune system in a complex but predictable pattern with differing timing and intensity. Surprisingly, the whole-limb allograft elicited less immune response than did allografts of its individual components. The data presented here also serve as a foundation for further elucidation of the immunogenic mechanisms of vascularized limb-tissue allografts.     

肾移植术后人微小病毒B19 感染导致纯红细胞增生障碍性贫血

目的:探讨肾移植术后人微小病毒B19感染所致纯红细胞再生障碍性贫血的诊断及其治疗。方法:回顾性分析4例肾移植术后纯红细胞再生障碍性贫血患者的临床特点,诊断方法,治疗过程及预后。结果:两周内在本中心接受肾移植手术的6例患者中,有4例在术后60天内均出现发热、血红蛋白进行性下降等相似症状;综合骨髓穿刺、ELISA方法检测血清特异性IgG、IgM等方法诊断为人微小病毒B19感染;经静脉注射免疫球蛋白、调整免疫抑制方案等综合治疗后,4例患者病情均明显缓解。结论:(1)贫血是肾移植术后患者感染人微小病毒B19的典型临床症状;(2)PCR检测和/或ELISA方法,结合骨髓穿刺及其他实验室指标可诊断人微小病毒感染;(3)静脉注射免疫球蛋白是肾移植术后人微小病毒B19感染导致PRCA的首选治疗方法,病情反复时,再次应用仍然有效。同时予以调整免疫抑制剂方案等综合治疗,可获得理想疗效。     

Correction or transfer of immunodeficiency due to TNF-LT alpha deletion by bone marrow transplantation.

BACKGROUND: Mice with inactivated tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) genes have profound abnormalities of the immune system including lymphocytosis, lack of lymph nodes, undifferentiated spleen, hypoimmunoglobulinaemia, and defective Ig class switch. Here, we asked whether this phenotype is due to incompetent lymphohemopoietic progenitors or to a defective environment. MATERIALS AND METHODS: Lethally irradiated TNF-LT alpha-deficient and wild-type mice received bone marrow cells from either TNF-LT alpha-deficient or wild-type mice. The reconstitution and transfer of the phenotype was followed by morphological and functional analyses. RESULTS: Bone marrow cells from wild-type mice restored the synthesis of TNF and LT alpha, corrected the splenic microarchitecture, normalized the lymphocyte counts in the circulation, and repopulated the lamina propria with IgA-producing plasma cells of TNF-LT alpha-deficient mice. Furthermore, the formation of germinal centers in the spleen and the defective Ig class switch in response to a T-cell dependent antigen was corrected, while no lymph nodes were formed. Conversely, the TNF-LT alpha phenotype could be transferred to wild-type mice by bone marrow transplantation after lethal irradiation. CONCLUSIONS: These data demonstrate that most TNF- and LT alpha-producing cells are bone marrow derived and radiosensitive, and that the immunodeficiency due to TNF-LT alpha deletion can be corrected to a large extent by normal bone marrow cell transplantation. The genotype of the donor bone marrow cells determines the functional and structural phenotype of the TNF-LT alpha-deficient adult murine host, with the exception of lymph node formation. These findings may have therapeutic implications for the restoration of genetically defined immunodeficiencies in humans.     

Canine models of bone marrow transplantation

Progress in experimental bone marrow transplantation in dogs has provided for the direct transfer of research data to the clinical setting and the therapeutic application of marrow grafting to a variety of human diseases. Animal models of total body irradiation, engraftment and graft-versus-host disease are still needed to solve the existing clinical problems of marrow transplantation. Therefore, work in various canine model systems continues to be of interest. Pet dogs with spontaneously occurring lymphomas are used to study the clinical parameters necessary for applying the technique of transplanting their own marrow (autologous), in conjunction with high dose radiation and/or chemotherapy, to human patients with cancer. A major consideration in the successful transplantation of donor bone marrow (allogeneic) is overcoming histocompatibility barriers to assure engraftment and the prevention of graft-versus-host disease, a major limiting aspect of clinical marrow transplantation. Chemicals, radiation, radiotherapeutic techniques, antisera and monoclonal antibodies have been and continue to be developed in laboratory bred dogs. These approaches suppress the immune system either nonspecifically by ablation of immune reactive tissue, or specifically by affecting certain types of immune reactive cells. Parameters such as clinical effectiveness (engraftment or prevention of graft-versus-host disease), immune reconstitution and undesirable side affects in long-term survivors are all used to determine whether new technology can be transferred from preclinical canine studies to human bone marrow transplantation protocols.     

Feeding a Protective Hydrolysed Casein Diet to Young Diabetes-prone BB Rats Affects Oxidation of L[U?C14] glutamine in Islets and Peyer's Patches,Reduces Abnormally High Mitotic Activity in Mesenteric Lymph Nodes,Enhances Islet Insulin and Tends to Normalize NO Production

The present studies were undertaken to examine concomitant diet-induced changes in pancreatic islets and cells of the gut immune system of diabetes-prone BB rats in the period before classic insulitis. Diabetes-prone (BBdp) and control non-diabetes prone (BBc) BB rats were fed for ~ 17 days either a mainly plant-based standard laboratory rodent diet associated with high diabetes frequency, NIH-07 (NIH) or a protective semipurified diet with hydrolyzed casein (HC) as the amino acid source. By about 7 weeks of age, NIH-fed BBdp rats had lower plasma insulin and insulin/glucose ratio, lower insulin content of isolated islets, lower basal levels of NO but higher responsiveness of NO production to IL-1β in cultured islets, and higher Con A response and biosynthetic activities in mesenteric lymphocytes than control rats fed the same diet. In control rats, the HC diet caused only minor changes in most variables, except for a decrease in oxidation of L-[U−C14]glutamine in Peyer''s patch (PP) cells and an increase in protein biosynthesis in mesenteric lymphocytes. In BBdp rats, however, the HC diet increased plasma insulin concentration, islet insulin/ protein ratio, and tended to normalize the basal and IL-1β-stimulated NO production by cultured islets. The HC diet decreased oxidation of L-[U−C14]glutamine in BBdp pancreatic islets, whereas oxidation of L-[U−C14]glutamine in PP cells was increased, and the basal [Methyl-H3] thymidine incorporation in mesenteric lymphocytes was decreased. These findings are compatible with the view that alteration of nutrient catabolism in islet cells as well as key cells of the gut immune system, particularly changes in mitotic and biosynthetic activities in mesenteric lymphocytes, as well as basal and IL-1β stimulated NO production, participate in the sequence of events leading to autoimmune diabetes in BB rats. Thus, the protection afforded by feeding a hydrolysed casein-based diet derives from alterations in both the target islet tissue and key cells of the gut immune system in this animal model of type 1 diabetes.     

Zinc inhibits the mixed lymphocyte culture

The mixed lymphocyte culture (MLC) is an established clinical method for bone marrow transplantation, as it serves as an in vitro model for allogenic reaction and transplantation. We previously showed that cytokine release into the supernatant is a more specific and sensitive parameter for cross-reactivity in the MLC than the common measurement of cell proliferation. Therefore we tried to find an inhibitor of the MLC in vitro with the least side effects in vivo, measuring interferon (IFN)-γ as one of the most important cytokines in posttransplant medicine. Earlier studies showed that zinc is an important trace element for immune function with both stimulatory and inhibitory effects on immune cells. We found that slightly elevated zinc concentrations (three to four times the physiological level), which do not decrease T-cell proliferation in vitro nor produce immunosuppressive effects in vivo, suppress alloreactivity in the mixed lymphocyte culture. In this report we analyzed the mechanism whereby zinc influences the MLC to possibly find a nontoxic way of immunosuppression.     

Bone marrow cells play only a very minor role in chronic liver regeneration induced by a choline-deficient, ethionine-supplemented diet

Liver progenitor (oval) cells have enormous potential in the treatment of patients with liver disease using a cell therapy approach, but their use is limited by their scarcity and the number of donor livers from which they can be derived. Bone marrow may be a suitable source. Previously the derivation of oval cells from bone marrow was examined in rodents using hepatotoxins and partial hepatectomy to create liver damage. These protocols induce oval cell proliferation; however, they do not produce the disease conditions that occur in humans. In this study we have used the choline-deficient, ethionine-supplemented (CDE) diet (which causes fatty liver) and viral hepatitis as models of chronic injury to evaluate the contribution of bone marrow cells to oval cells under conditions that closely mimic human liver disease pathophysiology. Following transplantation of lacZ-transgenic bone marrow cells into congenic mice, liver injury was induced and the movement of bone marrow cells to the liver monitored. Bone marrow-derived oval cells were observed in response to the CDE diet and viral injury but represented a minor fraction (0–1.6%) of the oval cell compartment, regardless of injury severity. In all situations only rare, individual bone marrow-derived oval cells were observed. We hypothesized that the bone marrow cells may replenish oval cells that are expended by protracted liver injury and regeneration; however, experiments involving a subsequent episode of chronic liver injury failed to induce proliferation of the bone marrow-derived oval cells that appeared as a result of the first episode. Bone marrow-derived hepatocytes were also observed in all injury models and controls at a frequency unrelated to that of oval cells. We conclude that during viral-and steatosis-induced liver disease the contribution of bone marrow cells to hepatocytes, either via oval cells or by independent mechanisms, is minimal and that the majority of oval cells responding to this injury are sourced from the liver.     

Recent advances in the immunological aspects of renal disease.

Anti-basement membrane antibodies and tissue deposition of immune complexes appear to be responsible for most glomerulonephritides and for some tubulo-interstitium injury accompanying glomerulonephritis or occuring primarily. Anti-tubular basement membrane antibodies complicate immunologic and toxic renal injury, including transplantation, and widespread tubulo-intersitial immune complex deposits are present in most patients with systemic immune complex disease, such as lupus erythematosus. Radioimmunoassay is now available for detecting and monitoring circulating anti-glomerular basement membrane antibodies. The effect of aggressive therapy with immunosuppression and plasma exchange is being studied to determine is value in minimizing tissue damage produced by the usual transient production of anti-glomerular basement membrane antibodies. Techniques are being explored to detect circulating immune complexes. Vigorous efforts are under way to identify antigen-antibody systems involved in the production of nephritogenic immune complexes, which may lead to antigen irradiation or specific manipulation of the immune response or its products.     

强啡肽A对烫伤大鼠免疫功能的影响

大鼠烫伤后24h血浆强啡肽A(Dyn A)的含量开始降低,120h仍未恢复到对照水平。烫伤后免疫功能也有明显的变化,表现为淋巴细胞转化功能降低,白细胞介素1,2(IL-1,IL-2)生成量减少。其变化过程与血浆Dyn A的变化基本一致。离体条件下,Dyn A与烫伤大鼠的脾淋巴细胞共同培养,可增强淋巴细胞转化及IL-2的生成。静脉注射Dyn A后,烫伤大鼠的淋巴细胞转化功能、IL-1和IL-2的生成都有不同程度的增加。本实验提示,血浆Dyn A水平的降低可能是烫伤大鼠免疫功能低下的原因之一。     

The effect of tumour bearing on skeletal muscle glutamine metabolism.

1. The effects of tumour bearing on glutamine metabolism in rat skeletal muscle were examined using the Walker 256 carcinosarcoma. 2. There was a rapid and marked decrease in skeletal muscle glutamine content, which was correlated with the size of the tumour, and a decrease in plasma glutamine concentration. 3. The rate of release of glutamine from EDL muscle in vitro was increased in cachectic, tumour bearing animals, but was unaffected from the soleus muscle of the same animals. 4. It is hypothesized that the increase in the rate of muscle glutamine release during cachexia represents a response of this tissue in order to satisfy the demand for glutamine by the tumour or by cells of the immune system.     

Transplantation osteoporosis

Transplantation provides a valuable, often life-saving, treatment for end-stage failure of many organs, including the heart, kidneys, liver, pancreas and lungs. It is also an important therapeutic option in diseases of the bone marrow and the immune system. Despite the undoubted benefits for transplant patients, it is associated with an increased risk of many complications. The potential causes include: poor general health of the patient, heavy burden of the surgery itself and the need for the long-term use of immunosuppression. In addition, the patients are also on numerous other medications, e.g. anti-coagulants, diuretics. Osteoporosis and high risk of fractures have emerged as frequent and devastating complications of the transplantation process. This article provides a review of the current literature on osteoporosis after transplantation, and the treatment options for this serious illness.     

添加丙氨酰谷氨酰胺的胃肠外营养对存在营养风险的胃癌根治术患者免 疫功能、营养状态及术后恢复的临床意义*

目的:本研究旨在探讨NRS评分大于5分的胃癌根治术患者围手术期应用丙氨酰谷氨酰胺(Ala-Gln)强化的肠外营养对免疫功能、营养状况及术后恢复情况的临价值。方法:NRS-2002评分大于5分的胃癌患者60例,随机分为两组,每组30例。术前开始给予肠外营养支持,5日后手术,手术方式为根治性胃切除,包括远端胃大部切除术和全胃切除术。术后继续给予常规肠外营养。只有实验组给予谷氨酰胺双肽每日20克。于入院时和手术后第6日测量CD4、CD8、CD4/CD8、IgG、IgA、IgM淋巴细胞计数等免疫指标,血清总蛋白、白蛋白、谷丙转氨酶、总胆红素、血肌酐等肝肾功能指标,观察手术恢复过程及术后并发症发生情况。结果:采用谷氨酰胺强化的试验组CD4、CD8等免疫指标恢复情况显著优于对照组。二者一过性肝功能损伤发生率无明显差异。但试验组白蛋白较对照组恢复迅速。试验组术后肠蠕动恢复较对照组快,术后腹泻发生率较低。两组在术后抗生素应用时间、术后感染等发病率方面未显示统计学差异。结论:对存在营养风险的胃癌患者进行围手术期静脉营养支持时添加谷氨酰胺制剂可明显改善患者的免疫状况,促进术后恢复减少手术并发症。     

Lidocaine depresses splenocyte immune functions following trauma-hemorrhage in mice

Traumatic and/or surgical injury as well as hemorrhage induces profound suppression of cellular immunity. Although local anesthetics have been shown to impair immune responses, it remains unclear whether lidocaine affects lymphocyte functions following trauma-hemorrhage (T-H). We hypothesized that lidocaine will potentiate the suppression of lymphocyte functions after T-H. To test this, we randomly assigned male C3H/HeN (6–8 wk) mice to sham operation or T-H. T-H was induced by midline laparotomy and 90 min of hemorrhagic shock (blood pressure 35 mmHg), followed by fluid resuscitation (4x shed blood volume in the form of Ringer lactate). Two hours later, the mice were killed and splenocytes and bone marrow cells were isolated. The effects of lidocaine on concanavalin A-stimulated splenocyte proliferation and cytokine production in both sham-operated and T-H mice were assessed. The effects of lidocaine on LPS-stimulated bone marrow cell proliferation and cytokine production were also assessed. The results indicate that T-H suppresses cell proliferation, Th1 cytokine production, and MAPK activation in splenocytes. In contrast, cell proliferation, cytokine production, and MAPK activation in bone marrow cells were significantly higher 2 h after T-H compared with shams. Lidocaine depressed immune responses in splenocytes; however, it had no effect in bone marrow cells in either sham or T-H mice. The enhanced immunosuppressive effects of lidocaine could contribute to the host's enhanced susceptibility to infection following T-H. shock; bone marrow cells