Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha

OBJECTIVES: This study sought to assess the role of tumor necrosis factor-alpha (TNF-alpha) in myocardial ischemia/reperfusion (I/R) injury using TNF-alpha knockout (KO) mice. BACKGROUND: Tumor necrosis factor-alpha is thought to be involved in the pathogenesis of myocardial I/R injury by promoting leukocyte infiltration of the myocardium. However, the precise role of TNF-alpha in I/R injury is still unknown. METHODS: The hearts in TNF-alpha KO and wild-type (WT) mice were exposed by left lateral thoracotomy, and the left coronary artery was occluded for 30 min then reperfused for 120 min. RESULTS: The infarct size in TNF-alpha KO mice was significantly reduced compared with WT mice. The frequency of arrhythmia was decreased, and cardiac function during reperfusion was significantly improved in TNF-alpha KO mice compared with WT mice. The activation of nuclear factor-kappaB (NF-kappaB), the expression of chemokines and adhesion molecules and the infiltration of leukocytes were also significantly reduced in TNF-alpha KO mice, compared with WT mice. These findings provide evidence that TNF-alpha aggravates I/R injury. CONCLUSIONS: Tumor necrosis factor-alpha exacerbates myocardial I/R injury at an early stage of reperfusion by activating NF-kappaB, thereby inducing chemokines and adhesion molecules and facilitating leukocyte infiltration.     

Acute hematologic effects of interferon alpha,interferon gamma,tumor necrosis factor alpha and Interleukin 2

Summary This study was designed to investigate acute effects of various doses of the cytokines IFN-alpha, IFN-gamma Interleukin 2 and tumor necrosis factor alpha on white blood cell differential counts. Before initiation of phase II trials, a dose-determination phase was performed, where three different dose levels of each cytokine were applied as a single dose. White blood cell differential counts were assessed immediately before and 2, 12, 24, 48 and 168 h after injection. Patients enrolled suffered from metastatic cancer or chronic active hepatitis. In addition, IFN-alpha was administered to five healthy volunteers. Results indicate that cytokines cause rapid and transient changes in the numbers of leukocyte subsets. Hematologic changes were cell-type- and cytokine-specific: transient lymphopenia was observed after administration of all four cytokines, reaching a nadir 12 to 24 h after subcutaneous injection. Administration of TNF-alpha and IFN-gamma also caused transient monocytopenia. Neutrophilia developed after administration of Interleukin 2, IFN-alpha and TNF-alpha. We conclude that cytokines play a key role in the regulation of peripheral blood cell traffic by their capacity to influence homing patterns of peripheral blood leukocytes.     

Expression and functional role of tumor necrosis factor receptors on leukemic cells from patients with type B chronic lymphoproliferative disorders

Two receptors for tumor necrosis factor (TNF) with different molecular weight (75-Kd and 55-Kd) and binding affinity have been recently discovered. To investigate the distribution and the functional role of these receptors on leukemic B cells from hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia (B-CLL) patients, we evaluated: (1) the cytofluorimetric pattern of uncultured and cultured leukemic B cells incubated with utr-1 and htr-9 monoclonal antibodies (MoAbs), which specifically recognize the 75-Kd and 55-Kd TNF receptors (TNFR), respectively; (2) the effect of TNF-alpha and TNF-beta on leukemic B cells in an in vitro proliferation assay; (3) the role of anti-TNFR MoAbs on TNF-alpha and TNF-beta-driven B-cell growth; and (4) the proliferative effect of utr-1 and htr-9 MoAbs on in vitro cultured leukemic cells. Our study shows that the high affinity (75-Kd) but not the low affinity (55-Kd) TNFR molecules are expressed on freshly isolated leukemic B cells recovered from HCL and B-CLL patients. The expression of these receptors was neither upregulated nor downregulated by different stimuli, including TNF-alpha, TNF-beta, B-cell growth factor, and interleukin-2. TNF-alpha efficiently triggers the proliferation of HC and, to a lesser extent, the growth of B-CLL cells. TNF-beta was also able to transduce the proliferative signal in HCL, but not in B-CLL patients. TNF-alpha- and TNF-beta-driven B-cell proliferation was inhibited by the preincubation of leukemic B cells with utr-1 but not htr-9 MoAb. Moreover, anti-75-Kd, but not anti-55-Kd TNFR MoAb, was able to trigger the proliferation of leukemic B cells, and in particular of HC. These results show that leukemic B cells from patients with HCL and B-CLL are equipped with a fully functional high affinity TNFR.     

Kinetics of tumor necrosis factor alpha in plasma and the cardioprotective effect of a monoclonal antibody to tumor necrosis factor alpha in acute myocardial infarction.

BACKGROUND: Inflammation plays a critical role in acute myocardial infarction (AMI) and tumor necrosis factor alpha (TNF-alpha) is a potent inflammatory trigger. This study was designed to examine the kinetics of TNF-alpha in plasma in patients with AMI and the potential benefit of inhibition of TNF-alpha monoclonal antibody in AMI. METHODS AND RESULTS: TNF-alpha levels in plasma were measured in 42 patients with AMI. TNF-alpha levels were elevated at 4 hours after onset of chest pain and declined to control values at 48 hours. TNF-alpha levels were higher in patients with Killip III and IV than in those with Killip I and II (P <.01). To examine the pathogenic role of TNF-alpha, New Zealand White rabbits were treated with buffer or a TNF-alpha monoclonal antibody before left anterior descending artery (LAD) ligation. Treatment with the TNF-alpha monoclonal antibody decreased area of necrosis, number of circulating endothelial cells, and lipid peroxidation product malonaldehyde bis(dimethyl acetal). There was a significant correlation of TNF-alpha levels with peak CK-MB in AMI patients, and area of necrosis, MDA, and circulating endothelial cells in rabbits (all P <.05). CONCLUSIONS: TNF-alpha release early in the course of AMI contributes to myocardial injury and dysfunction. Treatment with the monoclonal antibody against TNF-alpha can be cardioprotective, particularly in the setting of heart failure in patients with AMI.     

Aplastic anemia following administration of a tumor necrosis factor-alpha inhibitor

Upregulation of tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of several inflammatory conditions, including rheumatoid arthritis. Therapeutic agents such as antibodies or soluble TNF-alpha receptor analogs, which block TNF-alpha activity are a recent addition to the therapeutic armamentarium for the conditions. We describe a patient who developed aplastic anemia complicated by sepsis after receiving etanercept, a TNF-alpha receptor analog, for the treatment of rheumatoid arthritis. Pancytopenia resolved within 3 wk of discontinuing etanercept. To our knowledge, this is the first report of aplastic anemia associated with TNF-alpha blockade.     

The role of vascular endothelial growth factor, tumor necrosis factor alpha and interleukin-6 in pathogenesis of diabetic retinopathy

The aim of the study was to analyze the relation between early diabetic retinopathy and the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) in children with diabetes mellitus type 1. Two hundred and two children with diabetes mellitus type 1 aged 13.2+/-3.83 years and 85 healthy controls were analyzed. Patients were divided into two subgroups: children with retinopathy (Group 1, n=39) and children without retinopathy (Group 2, n=163). All the children had 24h urine albumin secretion rate, glycosylated hemoglobin HbA1c level, and C-reactive protein level measured, underwent 24h blood pressure monitoring and had ophthalmologic examination performed. Additionally, all the children had serum TNF-alpha, IL-6 and VEGF level measured using an ELISA test (Quantikine High Sensitivity Human). Statistically significant higher blood serum levels of HbA1c, VEGF, TNF-alpha and IL-6 were found in the Group 1 in comparison with the Group 2. Additionally, the children of the Group 1 showed statistically significant correlation between serum VEGF and serum TNF-alpha (R=0.35, p=0.000), CRP level (R=0.23, p=0.006), 24h albumin urine secretion rate (R=0.45, p=0.000) and duration of the disease (R=0.26, p=0.002). The results of the current study suggest that there is a relationship between VEGF, TNF-alpha, IL-6 and the development of the diabetic retinopathy in children with diabetes mellitus type 1.     

Selective inhibition of spontaneous IgE and IgG4 production by interleukin-8 in atopic patients

The effects of interleukin (IL)-8 on spontaneous IgE and IgG4 production in atopic patients were studied. IL-8 inhibited IgE and IgG4 production by purified surface (s) IgE+ and sIgG4+ B cells, respectively, while it had no effect on IgG1, IgG2, IgG3, IgM, IgA1, and IgA2 production by corresponding sIg+ B cells. The IL-8-induced inhibition was counteracted by IL-6 and tumor necrosis factor-alpha (TNF-alpha) and was blocked by anti-IL-8 monoclonal antibody (MoAb). Conversely, the addition of anti-IL-6 MoAb and anti-TNF-alpha MoAb, in the absence of IL-8, inhibited IgE and IgG4 production by sIgE+ and sIgG4+ B cells, respectively. Purified sIgE+ and sIgG4+ B cells expressed IL-6 receptors (R), TNF-alpha R, and IL-8R, and they produced IL-6 and TNF-alpha, but not IL-8. IL-8 had no effect on IL-6R or TNF- alpha R, while it abrogated IL-6 and TNF-alpha production in these cells. In contrast, slgG1+, slgG2+, slgG2+, slgG3+, slgM+, slgA1+, and slgA2+ B cells expressed IL-6R and TNF-alpha R but not IL-8R, and they produced IL-6 and TNF-alpha. IL-8 had no effect on IL-6R and TNF-alpha R, or on TNF-alpha and IL-6 production in these cells. These results indicate that IL-8 inhibits spontaneous IgE and IgG4 production in slgE+ and slgG4+ B cells, respectively, by inhibiting the endogenous production of IL-6 and TNF-alpha.     

糖皮质激素对非IgA系膜增殖性肾炎患者肿瘤坏死因子的影响

目的观察非ＩｇＡ系膜增殖性肾炎患者应用激素前后血清肿瘤坏死因子－α（ＴＮＦ－α）的变化及其与尿蛋白的相关关系。方法３０例非ＩｇＡ系膜增殖性肾炎表现为肾病综合征的患者按病理增生程度不同分为轻度增生组和中重度增生组，两组均在用激素前及用激素后４周及８周测定血清ＴＮＦ－α及２４小时尿蛋白定量。结果两组患者治疗前血清ＴＮＦ－α明显升高，且ＴＮＦ－α水平与系膜增生程度有关，激素治疗后ＴＮＦ－α下降，疗效与系膜增生程度及ＴＮＦ－α水平有关。ＴＮＦ－α与２４小时尿蛋白存在显著正相关。结论对非ＩｇＡ系膜增殖性肾炎患者测定血清ＴＮＦ－α可作为判断组织学损伤的非创伤性参考指标及判断激素疗效与预后的参考指标。     

Psoriasis induced by tumor necrosis factor-alpha antagonist therapy: a case series

OBJECTIVE: Although tumor necrosis factor-alpha (TNF-alpha) antagonists are effective in the treatment of refractory psoriasis, some cases have suggested that psoriasis might be induced as a result of treatment prescribed mainly for rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. To investigate anti-TNF-alpha induced psoriasis, we conducted a systematic analysis of the 6 cases we observed among our inflammatory patient cohort treated with anti-TNF-alpha (infliximab or etanercept). METHODS: We report 6 cases of psoriasis with onset during TNF-alpha antagonist therapy (infliximab and etanercept); characteristics and skin lesions are described. RESULTS: No patient had a personal or family history of psoriasis. The development of psoriasis was seen in all the types of inflammatory diseases we treated with TNF-alpha antagonists. There was great variation in the age of affected patients and in the onset of psoriasis after initiation of TNF-alpha antagonists. Both TNF-alpha antagonists studied were associated with development of psoriasis. In 2 cases psoriasis was associated with 2 different TNF-alpha antagonists in the same patient. In half our patients, skin lesions started in the inguinal and pubic regions, but palmoplantar pustulosis was also common. In half the cases, skin lesions responded favorably with topical agents despite continuation of TNF-alpha antagonist therapy. CONCLUSION: In light of previously published cases describing psoriasis or psoriasiform lesions after TNF-alpha antagonist therapy, our series strongly confirms that TNF-alpha antagonists may induce psoriasis in some patients. Further studies are needed to identify risk factors for TNF-alpha antagonist induced psoriasis.     

The role of soluble tumor necrosis factor receptor types I and II and tumor necrosis factor-alpha in malaria during pregnancy

In a prospective study of rhesus monkeys inoculated with Plasmodium coatneyi or saline on an infection/gestational timeline, we determined the serum levels of tumor necrosis factor-alpha (TNF-alpha), soluble tumor necrosis factor receptor type I (sTNFR-I), and soluble tumor necrosis factor receptor type II (sTNFR-II) in peripheral blood throughout primigravid pregnancy, malaria infection, and a combination of the two. Our goal was to determine the association between levels of TNF-alpha and of its 2 soluble receptors and the course of pregnancy and/or malaria and infant outcome. We found that any detectable level of TNF-alpha was always associated with fetal death and that the sTNFRs may be important for fetal protection, possibly through neutralizing the toxic effects of TNF-alpha. Our findings also showed that increased levels of sTNFR-II were associated specifically with malaria and not with normal pregnancy or even pregnancy with low birth weight due to other causes. In contrast, increases in sTNFR-I levels during the later half of normal pregnancies indicate that sTNFR-I may be important in regulating TNF-alpha levels in preparation for normal labor and delivery.     

Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents

OBJECTIVE: To describe the clinical features of leukocytoclastic vasculitis (LCV) associated with the use of tumor necrosis factor-alpha (TNF-alpha) blockers. METHODS: The Adverse Events Reporting System (AERS) of the US Food and Drug Administration (FDA) was queried for reports of patients who developed LCV during or after starting etanercept or infliximab from date of approval of each agent through September 6, 2002. RESULTS: Thirty-five cases of LCV were identified, 20 following etanercept administration and 15 following infliximab administration. Seventeen of the 35 (48.5%) were biopsy-proven cases and the others had skin lesions that were clinically typical for LCV. Twenty-two of 35 (62.8%) patients had complete or marked improvement of skin lesions upon stopping the TNF-alpha blocker. Three patients who had received etanercept had continuing lesions despite discontinuation of the drug; one of these patients improved when switched to infliximab. One patient who received infliximab was reported to have continuing lesions despite discontinuation of the drug and treatment with prednisone and antihistamines. Six patients experienced a positive rechallenge (recurrence of LCV on restarting therapy with a TNF-alpha blocker) and 3 patients a negative rechallenge phenomenon. LCV lesions improved in patients despite continuing use of concomitant medications reportedly associated with LCV. CONCLUSION: Therapy with TNF-alpha blocking agents may be associated with the development of LCV. Skin lesions improved on discontinuation of anti-TNF-alpha therapy in most patients. Other causes of LCV should be excluded, and evaluation for systemic involvement with appropriate investigations is recommended.     

Relationship between tumor necrosis factor-alphaand liver fibrosis

INTRODUCTION:To intrestigate the relationship between tumor necrosis factor-alphaand liver fibrosis in patients with chronic liver disease.METHODS:Radioimmunoassay was made in 20 patients with mild chronic hepatitis(CMH),20 patients with severe chronic hepatitis(CSH),51 patients with liver cirrhosis(LC)and 32-normal persons to determine the contents of tumor necrosis factor-alpha(TNF-alpha),laminin-(LN) and hyaluronate (HA) in serum.The changes in and relationship between TNF-alpha,LN and HA were analyzed.The TNF-alphaand collagen III were determined using mmunohistochemical studies in liver tissues from 32 persons including 7 normal persons,3 patients with MCH,5 patients with SCH and 17 with LC.RESULTS:TNF-alpha,LN and HA levels in serum of CSH and LC patients were significantly higher than those in healthy controls (SCH:1.11plus minus0.59 130.7plus minus17.2,219.1plus minus121.3;LC:0.92plus minus0.66,156.8plus minus31.7,400.5plus minus183.7,P<0.05-0.01),which increased gradually,and correlated positively with each other in all patients with liver diseases (n=91,gamma=0.3149 P <0.01).TNF-alpha contents-showed a remarkably positive correlation with HA and LN levels in CMH and CSH (LN:n=40,gamma=0.3404,P <0.05 HA n=40,gamma=0.3847 P <0.05).The total collagen content of MCH,SCH and LC increased gradually in liver biopsy specimens.The number of TNF-alphapositive cells increased significantly in liver tissues from patients with SCH and LC (62%;45%;P <0.01).TNF-alphapositive cells were mainly located in the periportal areas.CONCLUSION:TNF-alphamay be related to liver fibrosis,and might promote liver fibrosis.     

C-reactive protein and tumor necrosis factor-alpha in gestational hyperglycemia

OBJECTIVES AND STUDY DESIGN: Increasing evidences support an inflammatory origin for gestational hyperglycemia. This paper aims at investigating, cross-sectionally and prospectively, the relationships between tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP) levels in normoglycemic and hyperglycemic pregnancies of women with and without conventional risk factors for gestational diabetes (GDM). RESULTS: Both at simple and multiple correlations TNF-alpha levels are associated to fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR) values and gestational hyperglycemia, while high sensitivity CRP (hsCRP) levels to body mass index (BMI). Furthermore, the TNF-alpha levels of the second trimester and their increments in the third trimester are significant predictors of insulin levels measured at 32-36 weeks in the subgroup of hyperglycemic women with < or = 35 yr, BMI <25 kg/m2 and the absence of a first-degree relative with Type 2 diabetes (respectively, beta=1.1; 95%CI 0.66-1.48; p=0.002 and beta=1.0; 95%CI 0.36-1.66; p=0.02), in a multiple regression model, after multiple adjustments. In a second cohort of women at low risk for GDM (<25 yr, BMI <25 kg/m2 and absence of a first-degree relative with Type 2 diabetes), 24-28 weeks TNF-alpha levels are highly associated with corresponding insulin and HOMA values in the same model (respectively, beta=0.27; 95%CI 0.11-0.43; p=0.001 and beta=0.30; 95%CI 0.14-0.46; p<0.001). CONCLUSIONS: The data support the developing hypothesis that low-grade systemic inflammation is associated to GDM, in particular for pregnant women without conventional risk factors for gestational hyperglycemia, whose insulin resistance seems less explainable.     

Comparison of circulating levels of interleukin-6 and tumor necrosis factor-alpha in hypertrophic cardiomyopathy and in idiopathic dilated cardiomyopathy

It is known from the literature that the circulating levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are elevated in heart failure and idiopathic dilated cardiomyopathy (IDC). Few convincing data are available on the production of cytokines in hypertrophic cardiomyopathy (HC). The levels of circulating IL-6, the soluble form of the IL-6 receptor (sIL-6R), and TNF-alpha in 19 patients with HC, 31 patients with IDC, and 20 healthy subjects (control group) were examined and compared with their clinical parameters. The levels of TNF-alpha and circulating IL-6 proved to be elevated in the sera of patients with IDC. In contrast, the level of TNF-alpha was not elevated in HC, although the levels of IL-6 and sIL-6R were significantly higher than those in the sera of patients with IDC. Although elevated levels of IL-6 may correlate with the extent of left ventricular dysfunction in IDC, the markedly elevated IL-6 levels did not correlate with left ventricular function in HC. The markedly elevated TNF-alpha levels in IDC were associated with the elevated IL-6 levels, probably because of an inflammatory process and/or heart failure. In contrast, in HC, in which the New York Heart Association functional class was actually good, the even higher IL-6 and sIL-6R levels were not associated with a TNF-alpha elevation. In HC, the IL-6 and sIL-6R elevations were due to another mechanism, probably by way of the cardiotrophin-associated gp130 receptor. The sources of IL-6 production in HC are not clear yet.     

Bone marrow necrosis.

The clinical findings of bone marrow necrosis in 13 patients undergoing bone marrow examination to investigate a peripheral blood cytopenia or leukoerythroblastic blood smear were reviewed and compared to those in the literature. Excluding sickle cell disease, all cases of bone marrow necrosis diagnosed during life were associated with a neoplastic process involving the marrow. A myeloproliferative disorder was found in five patients, metastatic carcinoma in five patients, a lymphoma in two patients, and both a myeloproliferative disorder and metastatic carcinoma in one patient. Marrow necrosis was found to involve the marrow at multiple sites in a piecemeal fashion with areas of necrotic marrow and structurally intact marrow adjacent to each other. Severe bone pain without roentgenographic abnormality was the major symptom in 85% of the patients. Marrow and fat emboli, hypercalcemia and peripheral blood cytopenias were identified as direct complications of marrow necrosis. The prognosis of patients with marrow necrosis secondary to neoplastic disease was found to be extremely poor with a median survival of less than one month. However, one patient responded to antineoplastic chemotherapy and showed healing of the bone marrow.     

Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection

Serum samples of 120 patients in different stages of chronic human immunodeficiency virus type 1 (HIV-1) infection, 11 patients with primary HIV-1 infection (PHI), and 49 HIV-1 seronegative homosexual men were analyzed for tumor necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha), and HIV-1 p24 antigen. Increased levels of IFN-alpha and TNF-alpha were found in some, but not all, cases with PHI. During progressing disease IFN-alpha occurred in serum with increasing frequency and concentration. Raised levels of TNF-alpha were found in all stages of chronic infection, but were less common in patients with AIDS than were raised levels of IFN-alpha. The levels of the two substances were not correlated. There was a correlation between IFN-alpha, but not TNF-alpha, and the occurrence of HIV-1 p24 antigen in serum. These results suggest that IFN-alpha and TNF-alpha are induced by different agents during HIV-1 infection. The findings would be consistent with the hypothesis that IFN-alpha and TNF-alpha are counteracting forces that have important down- and upregulatory effects, respectively, on HIV-1 replication in vivo.     

Combined liver and pancreas resection with biochemotherapy for metastatic ocular melanoma

Systemic therapy alone for metastatic melanoma is relatively ineffective, and surgical resection of metastases to a solitary site remains the best single treatment to improve survival. While cytoreductive surgery plus chemotherapy play a significant role in the management of advanced ovarian cancer, the precise role of surgery as an adjunct to systemic therapy for melanoma metastatic to multiple sites is not well defined. We report a patient with ocular melanoma metastatic to liver and pancreas treated by cytoreductive surgery consisting of mesohepatic resection, distal pancreatectomy, and portal node dissection, followed by biochemotherapy with dacarbazine and interferon alpha. The concept of cytoreductive surgery is reviewed, with particular attention to its use in the management of metastatic melanoma. The patient's postoperative course was unremarkable and she remains alive and asymptomatic with no detectable disease at 20 months' follow‐up. Cytoreductive surgery as a part of an aggressive multidisciplinary approach may play a role in the treatment of cutaneous and ocular melanoma metastatic to multiple visceral sites. Data from well‐designed, innovative clinical trials of cytoreductive surgery and biochemotherapy are required to determine the effectiveness of this multidisciplinary approach.