TNFMedicine

TNF-alpha and IL-8 in Acute Stroke

Note: U.S. patent 6,419,934 issued to Edward Tobinick, MD on July 16, 2002 describes the use of anti-TNF treatment for stroke
Title TNF-alpha and IL-8 in Acute Stroke and the Modulation of these Cytokines by Antiplatelet Agents.
Author(s) Al-Bahrani A, Taha S, Shaath H, Bakhiet M
Institution College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain. moiz@drmoiz.com.
Source Curr Neurovasc Res 2007 Feb; 4(1) :31-7.
Abstract Stroke is associated with elevation of several proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-8 that are correlated with central nervous system (CNS) injury. Anti-platelet therapies are important agents in stroke management. The role of antiplatelets as anti-inflammatory agents is not known in acute stroke patients. Furthermore, their effect on induction of potential cytokines as TNF-alpha and IL-8 in those patients is still not clear. Thus, we herein examined the induction of TNF-alpha and IL-8 in acute stroke patients and examined the effects of the antiplatelets drugs aspirin, clopidogrel and dipyridamole, and piracetam in their induction. Cytokines were detected intracellularly in leukocytes from patients who had first acute ischemic stroke and from matched controls by immunocytochemistry. The results showed significant increase of spontaneously produced TNF-alpha and IL-8 in patients compared to control. This induction was significantly inhibited differently by each drug and dual drug agents. The data of this work suggest that antiplatelets agents may have a role in inhibition of stroke mediated proinflammatory cytokine effects, which may initiate a new aspect of the role of antiplatelets in the treatment of acute ischemic stroke.
Language eng
Pub Type(s) Journal Article
PubMed ID 17311542

Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients.

Title Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients.
Author(s) Intiso D, Zarrelli MM, Lagioia G, Di Rienzo F, Checchia De Ambrosio C, Simone P, Tonali P, Cioffi Dagger RP
Institution Department of Neurology, IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini 1, I-71013, San Giovanni Rotondo (FG), Italy. do.intiso@tiscali.it
Source Neurol Sci 2004 Feb; 24(6) :390-6.

Abstract Experimental evidence indicates that tumor necrosis factor alpha (TNF-alpha) is involved in brain damage following ischemic injury. The present study was designed to monitor serum TNF-alpha levels in acute stroke patients and to correlate TNF-alpha levels with lesion size, neurological impairment and vascular risk factors. In 41 patients with ischemic stroke, serum TNF-alpha levels were serially measured by a solid enzyme amplified sensitivity immunoassay (EASIA) in the first 10 days after stroke onset. Serum fibrinogen and C-reactive protein (CRP), white blood cell (WBC) and neutrophil counts were determined on the same days to monitor acute phase response changes. Lesion size was calculated on computed tomograms by a computer-assisted procedure. Neurological impairment was evaluated on the Canadian Neurological Scale. Forty age-matched subjects were used as controls. Compared to baseline, TNF-alpha levels significantly increased during the study ( p=0.0001), peaking on day 7. Peak TNF-alpha levels did not correlate with neurological impairment or lesion size. Multivariate analysis showed that sex, age, vascular risk factors and infectious complications did not influence TNF-alpha levels. Fibrinogen, CRP, WBC and neutrophil concentrations increased, indicating an acute phase response occurred after stroke. In conclusion, serum TNF-alpha levels showed an early and prolonged increase after stroke onset, unrelated to lesion size, neurological impairment, age, sex, vascular risk factors or infectious complications. Serum increase of TNF-alpha may be explained as part of the acute phase response occurring in stroke patients.
Language eng
Pub Type(s) Journal Article
PubMed ID 14767684

Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-alpha theory.

Title Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-alpha theory.
Author(s) Odeh M
Institution Bnai Zion Medical Centre, and Faculty of Medicine, Technion, Haifa, Israel.
Source Eur J Clin Invest 2007 Apr; 37(4) :291-304.
Abstract Hepatic encephalopathy (HE) is a major complication for acute and chronic liver failure. Despite several decades of intensive clinical and basic research, the pathogenesis of HE is still incompletely understood, and the precise mechanisms causing brain dysfunction in liver failure are still not fully established. Several theories concerning the pathogenesis of HE have been previously suggested, including the ammonia theory, which received the most attention. These theories are not mutually exclusive and the validity of none of them has been definitely proved experimentally. In this review article, an attractive theory concerning the pathogenesis of HE, the tumour necrosis factor-alpha (TNF) theory, is presented and comprehensively discussed after accumulation of sufficient data which indicate that the pro-inflammatory cytokine, TNF, is strongly involved in the pathogenesis of HE associated with both acute and chronic liver failure. This theory seems to be superior to all other previous theories in the pathogenesis of HE, and may induce development of other beneficial therapeutical modalities for HE directed towards inhibition of TNF production and/or action, and towards enhancement of its degradation.
Language eng
Pub Type(s) Journal Article
PubMed ID 17373965

Increased Tumor Necrosis Factor-{alpha} and Prostaglandin E2 Concentrations in the Cerebrospinal Fluid of Rats with Inflammatory Hyperalgesia: The Effects of Analgesic Drugs.

Bianchi M, Martucci C, Ferrario P, Franchi S, Sacerdote P
Increased Tumor Necrosis Factor-{alpha} and Prostaglandin E2 Concentrations in the Cerebrospinal Fluid of Rats with Inflammatory Hyperalgesia: The Effects of Analgesic Drugs. [Journal Article]
Anesth Analg 2007 Apr; 104(4) :949-54.

BACKGROUND: We examined the changes in cerebrospinal fluid (CSF) concentrations of prostaglandin E(2) (PGE(2)) and tumor necrosis factor-alpha (TNF-alpha) after intraplantar administration of complete Freund's adjuvant (CFA) in rats. In addition, we investigated whether different analgesic drugs orally administered at antihyperalgesic doses were able to prevent the changes in PGE(2) and TNF-alpha spinal levels associated with hindpaw inflammation.
METHODS: The Randall-Selitto paw-withdrawal test was used to measure inflammatory hyperalgesia. Tramadol (7.5 mg/kg), paracetamol (65 mg/kg), tramadol plus paracetamol and nimesulide (5 mg/kg) were administered orally twice a day, starting from the first day after the CFA injection. PGE(2) in the CSF was measured by enzyme immunoassay, and TNF-alpha by ELISA. Behavioral and biochemical parameters were measured on Day 7 after intraplantar injection of CFA or saline.
RESULTS: Withdrawal thresholds to mechanical stimuli decreased markedly in the CFA-treated paw. In these animals the quantification of proinflammatory mediators in the CSF revealed a significant increase in both PGE(2) and TNF-alpha concentrations. All the pharmacological treatments prevented the development of the hyperalgesia as well as the PGE(2) increase in the CSF. Conversely, a prevention of the increase in TNF-alpha levels was observed only in rats treated with nimesulide or tramadol and paracetamol in combination.
CONCLUSIONS: Our results demonstrate that peripheral inflammatory hyperalgesia is associated with significant changes of proinflammatory mediators in the CSF. It is important to note, however, that spinal PGE(2) and TNF-alpha proved to be differently affected by pharmacological treatments able to fully abolish the hyperalgesia.

Induction of tumor necrosis-α, p38 and JNK in the spinal cord following acute heart injury in the rat model

Induction of tumor necrosis-α, p38 and JNK in the spinal cord following acute heart injury in the rat model
R.-P. Dai1,
J.-M Xu1,
L.-J. Tao2,
L. Li1,
Z.-P. Li1
J.-Y. Zhang3
1Department of Anesthesia, Second Xiang-Ya Hospital, 2Department of Medicine, Xiang-Ya Hospital and 3Department of Anatomy, Xiang-Ya College of Medicine, Central South University, Changsha, China
Dr Ru-Ping Dai
Department of Anesthesia
Second Xiang-Ya Hospital
Central South University
Ren-Min Road
Changsha 410008
China
e-mail: jmxu001@yahoo.com.cn
Abstract
Background: It is still not known whether the spinal cytokine signaling pathways are involved in the pathophysiologic mechanism of the acute phase of heart disease. This study examines the expression pattern of tumor necrosis factor-α (TNF-α) and its two related mitogenic-activated protein kinases, p38 and Jun-N-terminal kinase (JNK), in the spinal cord in response to acute cardiac injury (ACI).
Methods: The ACI rat model was established by intra-myocardial injection of formalin. At the indicated times after the establishment of ACI, the thoracic segments of the spinal cord were harvested and Western blot was performed to determine the expression of TNF-α, p38 and JNK. The localization of the cytokine and the kinases was determined by immunohistochemistry and double immunofluorescence.
Results: In response to ACI, TNF-α protein was up-regulated and reached a peak level at 6 h after ACI. The up-regulated TNF-α was distributed in all the laminae in the spinal cord and mainly localized in the neurons, as determined by immunohistochemistry and double immunofluorescence. In response to ACI, p38 and JNK were also up-regulated in the spinal cord. The expression profiles of p38 and JNK were similar to that of activated TNF-α following ACI.
Conclusions: This study shows that cardiac injury can induce the activation of spinal TNF-α, p38 and JNK. The activated spinal cytokine signaling may contribute to disease progression in the acute phase of cardiac injury in clinical practice.

[Lack of] Intravitreal toxicity of high-dose etanercept.

U.S. patent 6,428,787, issued to Edward Tobinick, MD on August 6, 2002, entitled "TNF inhibitors for the treatment of retinal disorders", details the use of etanercept for the treatment of retinitis pigmentosa, macular degeneration, and diabetic retinopahy.

Intravitreal toxicity of high-dose etanercept.
J Ocul Pharmacol Ther. 2007 Feb;23(1):57-62.
Kivilcim M,
Peyman GA,
Kazi AA,
Dellacroce J,
Ghobrial RN,
Monzano R.
Department of Ophthalmology, University of Arizona, Arizona Health Sciences Center, Tucson, AZ.
Purpose: The aim of this study was to evaluate the retinal toxicity of high-dose intravitreal etanercept, a U.S. Food and Drug Administration-approved anti-inflammatory drug, in the rabbit model. Methods: Twenty (20) New Zealand albino rabbits were divided into 5 groups (n = 4); eyes in each group were intravitreally injected with one of the following doses of etanercept: 125 mug, 250 mug, 500 mug, 1 mg, or 2.5 mg. One (1) eye in each animal was used for the study dose; the fellow eye was injected with buffered sterile saline as a control. All animals were examined using indirect ophthalmoscopy and slit-lamp biomicroscopy before and after intravitreal injection and at days 1, 7, and 14. Electroretinography (ERG) was performed on all animals before intravitreal injection and 14 days after injection. The animals were euthanized on day 14. Histological preparations of the enucleated eyes were examined with light microscopy for retinal toxicity. Results: Clinical examination, histological evaluation, and ERG results of all 5 groups demonstrated no signs of retinal toxicity. Conclusions: Intravitreal doses as high as 2.5 mg of etanercept did not cause retinal toxicity. Intravitreal doses of up to 2.5 mg of etanercept may provide a more potent, prolonged effect than the lower doses previously recommended.
PMID: 17341152 [PubMed - in process]

Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling

Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling.
Cardiovasc Res. 2005 Jul 1;67(1):106-15. Epub 2005 Mar 23.
Gurantz D,
Yndestad A,
Halvorsen B,
Lunde OV,
Omens JH,
Ueland T,
Aukrust P,
Moore CD,
Kjekshus J,
Greenberg BH.
Department of Medicine, Division of Cardiology, University of California, San Diego, Medical Center, 200 W Arbor Drive, San Diego, California, CA 92103-8411, USA.
OBJECTIVE: Persistently elevated levels of inflammatory cytokines such as tumor necrosis factor (TNF)alpha after acute myocardial infarction (MI) may contribute to maladaptive ventricular remodeling. The aim of the present study was to examine the effects of immunomodulatory therapy with recombinant soluble TNF receptor (TNFR:Fc) or intravenous immunoglobulin (IVIg) on left and right ventricular post-MI remodeling in rats. METHODS AND RESULTS: Adult male Sprague-Dawley rats were subjected to MI by left coronary artery ligation and randomized to treatment with vehicle, TNFR:Fc, or IVIg and sacrificed after 7 days. The main findings were that: (i) TNFR:Fc- and IVIg-treated rats developed less right ventricular (RV) hypertrophy compared to vehicle-treated controls. (ii) LV and arterial pressures in post-MI rats were not affected by the TNFR:Fc or IVIg treatment. (iii) As determined by real-time RT-PCR, both treatments reduced the expression of the hypertrophy-related genes, atrial natriuretic peptide and the ratio of beta/alpha-myosin heavy chains, and genes related to extracellular matrix remodeling (i.e., collagens I and III, matrix metalloproteinase [MMP]-2 and its tissue inhibitor TIMP-1) in the non-ischemic segment of LV and, in particular, in the RV. (iv) Treatment with IVIg, but not TNFR:Fc, reduced MMP-2 zymographic activity in the RV and the expression of genes for TNFalpha and monocyte chemoattractant protein-1. CONCLUSION: Therapy targeted directly against TNFalpha (i.e., TNFR:Fc) and a more general immunomodulatory approach (i.e., IVIg) in the acute phase of MI attenuates the cardiac remodeling process and expression of genes that are involved. These findings raise the possibility that initiation of immunomodulatory therapy post-MI could be beneficial in preventing the later development of heart failure.
PMID: 15949474 [PubMed - indexed for MEDLINE]

Comparative study of the anti-inflammatory effect of two intravenous immunoglobulin preparations manufactured by different processes

Comparative study of the anti-inflammatory effect of two intravenous immunoglobulin preparations manufactured by different processes.
Immunol Lett. 2006 Sep 15;107(1):58-62. Epub 2006 Aug 22.
Elluru S,
Van Huyen JP,
Prost F,
Delignat S,
Bayry J,
Ephrem A,
Siberil S,
Misra N,
Lacroix-Desmzes S,
Kazatchkine MD,
Kaveri SV.
INSERM U681, Universite Pierre et Marie Curie, UPMC, Paris 6, Institut des Cordeliers, 15 Rue de l'Ecole de Medecine, 75006 Paris, France.
Intravenous immunoglobulin (IVIG) is increasingly used in the treatment of diverse immune-mediated disorders. Since several preparations of IVIG are available for therapy, it is possible that different manufacturing processes might influence clinical efficacy of IVIG. An insight into the mechanisms of action of such different IVIG preparations is therefore necessary that will provide further guidelines for the utility of IVIG preparations in autoimmune and inflammatory diseases. Since endothelial cells (EC) influence the inflammatory process via production of cytokines, chemokines and expression of adhesive molecules, we analyzed the anti-inflammatory effect on EC of two IVIG preparations: caprylated IVIG (IVIG-C) versus solvent/detergent-treated IVIG (IVIG-SD) preparation. We found that both IVIG preparations inhibit in an equivalent manner, the expression of different pro-inflammatory factors such as IL-6, IL-8, GM-CSF, IL-1beta and TNF-alpha and the adhesion molecules ICAM-1 and VCAM-1. Our results thus suggest that the caprylate while inactivating the virus and enhancing the yield of IgG during IVIG formulation, does not modulate the immunomodulatory properties of IVIG at EC level and that the two preparations show similar anti-inflammatory effects.
PMID: 16952403 [PubMed - indexed for MEDLINE]

Post-polio syndrome patients treated with intravenous immunoglobulin: a double-blinded randomized controlled pilot study

Post-polio syndrome patients treated with intravenous immunoglobulin: a double-blinded randomized controlled pilot study.
Eur J Neurol. 2007 Jan;14(1):60-5.
Farbu E,
Rekand T,
Vik-Mo E,
Lygren H,
Gilhus NE,
Aarli JA.
Department of Neurology, Haukeland University Hospital, Bergen, Norway. elfa@sir.no
Post-polio syndrome (PPS) is characterized by new muscle weakness, atrophy, fatigue and pain developing several years after the acute polio. Some studies suggest an ongoing inflammation in the spinal cord in these patients. From this perspective, intravenous immunoglobulin (IvIg) could be a therapeutic option. We performed a double-blinded randomized controlled pilot study with 20 patients to investigate the possible clinical effects of IvIg in PPS. Twenty patients were randomized to either IvIg 2 g/kg body weight or placebo. Primary endpoints were changes in pain, fatigue and muscle strength 3 months after treatment. Surrogate endpoints were changes in cerebrospinal fluid (CSF) cytokine levels. Secondary endpoints were pain, fatigue and isometric muscle strength after 6 months. Patients receiving IvIg reported a significant improvement in pain during the first 3 months, but no change was noted for subjective fatigue and muscle strength. CSF levels of tumour necrosis factor-alpha (TNF-alpha) were increased compared with patients with non-inflammatory neurological disorders. In conclusion, in this small pilot study no effect was seen with IvIg treatment on muscle strength and fatigue, however IvIg treated PPS patients reported significantly less pain 3 months after treatment. TNF-alpha was increased in the CSF from PPS patients. The results are promising, but not conclusive because of the low number of patients studied.
PMID: 17222115 [PubMed - in process]

Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production

Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production.
BMC Neurol. 2007 Feb 28;7(1):5 [Epub ahead of print]
Emsley HC,
Smith CJ,
Gavin CM,
Georgiou RF,
Vail A,
Barberan EM,
Illingworth K,
Scarth S,
Wickramasinghe V,
Hoadley ME,
Rothwell NJ,
Tyrrell PJ,
Hopkins SJ.
ABSTRACT: Background As critical mediators of local and systemic inflammatory responses, cytokines are produced in the brain following ischaemic stroke. Some have been detected in the circulation of stroke patients, but their role and source is unclear. Focusing primarily on interleukin(IL)-1-related mechanisms, we serially measured plasma inflammatory markers, and the production of cytokines by whole blood, from 36 patients recruited within 12h and followed up to 1 year after acute ischaemic stroke (AIS). Results Admission plasma IL-1 receptor antagonist (IL-1ra) concentration was elevated, relative to age-, sex-, and atherosclerosis-matched controls. IL-1beta, soluble IL-1 receptor type II, tumour necrosis factor (TNF)-alpha, TNF-RII, IL-10 and leptin concentrations did not significantly differ from controls, but peak soluble TNF receptor type I (sTNF-RI) in the first week correlated strongly with computed tomography infarct volume at 5-7 days, mRS and BI at 3 and 12 months. Neopterin was raised in patients at 5-7d, relative to controls, and in subjects with significant atherosclerosis. Spontaneous IL-1beta, TNF-alpha and IL-6 gene and protein expression by blood cells was minimal, and induction of these cytokines by lipopolysaccharide (LPS) was significantly lower in patients than in controls during the first week. Minimum LPS-induced cytokine production correlated strongly with mRS and BI, and also with plasma cortisol. Conclusions Absence of spontaneous whole blood gene activation or cytokine production suggests that peripheral blood cells are not the source of cytokines measured in plasma after AIS. Increased plasma IL-1ra within 12h of AIS onset, the relationship between sTNF-RI and stroke severity, and suppressed cytokine induction suggests early activation of endogenous immunosuppressive mechanisms after AIS.
PMID: 17328808 [PubMed - as supplied by publisher]