scholarly journals Blockade of Endogenous Leukotrienes Exacerbates Pulmonary Histoplasmosis

2004 ◽  
Vol 72 (3) ◽  
pp. 1637-1644 ◽  
Author(s):  
Alexandra I. Medeiros ◽  
Anderson Sá-Nunes ◽  
Edson G. Soares ◽  
Camila M. Peres ◽  
Célio L. Silva ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Histoplasma Capsulatum ◽  
Interleukin 1 ◽  
Lung Parenchyma ◽  
Synthesis Inhibitor ◽  
Necrosis Factor Alpha ◽  
Pulmonary Histoplasmosis ◽  
Cytokine Levels ◽  
New Strategy ◽  
Factor Alpha

ABSTRACT Leukotrienes are classical mediators of inflammatory response. New aspects of leukotriene function have recently been described. We examine here the previously unreported role that leukotrienes play in the regulation of cytokines in a murine model of histoplasmosis. We demonstrate that administration of MK 886, a leukotriene synthesis inhibitor, caused Histoplasma capsulatum-infected mice to die by the day 15 of infection, whereas the correlating death rate in untreated infected mice was 0%. Treating infected animals with MK 886 inhibited leukotriene synthesis but increased leukocyte recruitment to the lungs. Subsequent to this phenomenon, levels of tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and KC chemoattractant cytokines and fungi in the lung parenchyma increased, as did inflammatory response. In contrast, IL-2, IL-5, IL-12, and gamma interferon cytokine levels actually decreased. Thus, murine response to pulmonary histoplasmosis may be leukotriene modulated. This finding may enable us to alter the course of the immune response and inflammation caused by histoplasmosis. The data from the present study suggest an important new strategy for immunologic or drug intervention in human patients.

scholarly journals Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rachel A. Brown ◽  
Fatima Barbar-Smiley ◽  
Cagri Yildirim-Toruner ◽  
Monica I. Ardura ◽  
Stacy P. Ardoin ◽  
...  
Keyword(s):  
Rheumatic Disease ◽  
Lupus Erythematosus ◽  
Histoplasma Capsulatum ◽  
Case Series ◽  
Organ Damage ◽  
Necrosis Factor Alpha ◽  
Pulmonary Histoplasmosis ◽  
Immunosuppressive Medications ◽  
Biologic Dmard ◽  
Factor Alpha

Abstract Background Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD. Case presentation We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months). Conclusions In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.

scholarly journals Local and systemic influence of toxic levels of airborne ozone on the inflammatory response in rats

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Małgorzata Chmielewska-Krzesińska ◽  
Krzysztof Wąsowicz
Keyword(s):  
Inflammatory Response ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Genes Expression ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

Abstract Introduction Ozone is not harmful itself; however, it directly oxidises biomolecules and produces radical-dependent cytotoxicity. Exposure to ozone is by inhalation and therefore the lungs develop the main anti-inflammatory response, while ozone has an indirect impact on the other organs. This study investigated the local and systemic effects of the ozone-associated inflammatory response. Material and Methods Three groups each of 5 Wistar Han rats aged 6 months were exposed for 2h to airborne ozone at 0.5 ppm and a fourth identical group were unexposed controls. Sacrifice was at 3h after exposure for control rats and one experimental group and at 24 h and 48 h for the others. Lung and liver samples were evaluated for changes in expression of transforming growth factor beta 1, anti-inflammatory interleukin 10, pro-inflammatory tumour necrosis factor alpha and interleukin 1 beta and two nuclear factor kappa-light-chain-enhancer of B cells subunit genes. Total RNA was isolated from the samples in spin columns and cDNA was synthesised in an RT-PCR. Expression levels were compared to those of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and analysed statistically. Results All variables changed non-linearly over time comparing experimental groups to the control. Conspicuous expression changes in the subunit genes and cytokines were observed in both evaluated organs. Conclusion Locally and systemically, inflammation responses to ozone inhalation include regulation of certain genes’ expression. The mechanisms are unalike in lungs and liver but ozone exerts a similar effect in both organs. A broader range of variables influential on ozone response should be studied in the future.

scholarly journals Interaction of Neisseria meningitidis with Human Dendritic Cells

2001 ◽  
Vol 69 (11) ◽  
pp. 6912-6922 ◽  
Author(s):  
Annette Kolb-Mäurer ◽  
Alexandra Unkmeir ◽  
Ulrike Kämmerer ◽  
Claudia Hübner ◽  
Thomas Leimbach ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Neisseria Meningitidis ◽  
Proinflammatory Cytokines ◽  
Interleukin 1 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Factor Alpha ◽  
Human Dendritic Cells ◽  
Necrosis Factor

ABSTRACT Infection with Neisseria meningitidis serogroup B is responsible for fatal septicemia and meningococcal meningitis. The severity of disease directly correlates with the production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-6, and IL-8. However, the source of these cytokines has not been clearly defined yet. Since bacterial infection involves the activation of dendritic cells (DCs), we analyzed the interaction of N. meningitidis with monocyte-derived DCs. Using N. meningitidis serogroup B wild-type and unencapsulated bacteria, we found that capsule expression significantly impaired neisserial adherence to DCs. In addition, phagocytic killing of the bacteria in the phagosome is reduced by at least 10- to 100-fold. However, all strains induced strong secretion of proinflammatory cytokines TNF-α, IL-6, and IL-8 by DCs (at least 1,000-fold at 20 h postinfection [p.i.]), with significantly increased cytokine levels being measurable by as early as 6 h p.i. Levels of IL-1β, in contrast, were increased only 200- to 400-fold at 20 h p.i. with barely measurable induction at 6 h p.i. Moreover, comparable amounts of cytokines were induced by bacterium-free supernatants of Neisseria cultures containing neisserial lipooligosaccharide as the main factor. Our data suggest that activated DCs may be a significant source of high levels of proinflammatory cytokines in neisserial infection and thereby may contribute to the pathology of meningococcal disease.

scholarly journals Features of cytokine profile in patients with local and generalized soft tissue infections

2013 ◽  
Vol 94 (4) ◽  
pp. 455-459
Author(s):  
N A Barkhatova
Keyword(s):  
Tumor Necrosis Factor ◽  
Inflammatory Response ◽  
Receptor Antagonist ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Necrosis Factor Alpha ◽  
Interleukin 1 Receptor Antagonist ◽  
Factor Alpha ◽  
Necrosis Factor

Aim. To determine the features of cytokine profile in patients with local and generalized soft tissue infections. Methods. The treatment results of 2350 patients with soft tissues infections since 1998 to 2012 were analyzed. ELISA test was used to measure tumor necrosis factor alpha and interleukin-1 receptor antagonist levels in 300 randomly picked patients with local (75 patients, comparison group) and generalized (225 patients, main group) forms of soft tissue infections. Results. In patients with generalized infections, tumor necrosis factor alpha level was 1.5 times higher in patients with mild systemic inflammatory response, 3.5 times higher - in patients with moderate and 6.7 times higher in patients with severe systemic inflammatory response compared to healthy controls. Interleukin-1 receptor antagonist levels were also elevated and related to the degree of inflammatory response, thus, it was the highest (2 times higher compared to controls) in patients with moderate systemic inflammatory response, while in patients with mild and severe inflammation it was only 30-40% higher. The significant increase in tumor necrosis factor alpha level associated with normal interleukin-1 receptor antagonist level is characteristic for different forms of sepsis. At the same time, increase in interleukin-1 receptor antagonist level associated with minimal changes in tumor necrosis factor alpha level can be used as a diagnostic criteria for compensated inflammatory response I patients with local infections cytokine profile was normal. The severity of systemic inflammation and clinical course of generalized infection depended not only on the absolute increase of cytokine levels, but on pro-inflammatory (tumor necrosis factor alpha) and anti-inflammatory (interleukin-1 receptor antagonist) cytokine levels misbalance. Conclusion. Examining the serum cytokine levels allows to confirm the diagnosis of generalized infection on early stages and to differentiate between compensated and non-ompensated systemic inflammatory response.

Triterpenoid CDDO-IM protects against lipopolysaccharide-induced inflammatory response and cytotoxicity in macrophages: The involvement of the NF-κB signaling pathway

2022 ◽  
pp. 153537022110669
Author(s):  
Hassan Ahmed ◽  
Urooj Amin ◽  
Xiaolun Sun ◽  
Demetrius R Pitts ◽  
Yunbo Li ◽  
...  
Keyword(s):  
Septic Shock ◽  
Inflammatory Cytokine ◽  
Interleukin 1 ◽  
Severe Form ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Factor Alpha ◽  
Gene Expression Levels

Lipopolysaccharide (LPS), also known as endotoxin, can trigger septic shock, a severe form of inflammation-mediated sepsis with a very high mortality rate. However, the precise mechanisms underlying this endotoxin remain to be defined and detoxification of LPS is yet to be established. Macrophages, a type of immune cells, initiate a key response responsible for the cascade of events leading to the surge in inflammatory cytokines and immunopathology of septic shock. This study was undertaken to determine whether the LPS-induced inflammation in macrophage cells could be ameliorated via CDDO-IM (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline), a novel triterpenoid compound. Data from this study show that gene expression levels of inflammatory cytokine genes such as interleukin-1 beta (IL-1β), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) were considerably increased by treatment with LPS in macrophages differentiated from ML-1 monocytes. Interestingly, LPS-induced increase in expression of pro-inflammatory cytokine levels is reduced by CDDO-IM. In addition, endogenous upregulation of a series of antioxidant molecules by CDDO-IM provided protection against LPS-induced cytotoxicity in macrophages. LPS-mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) transcriptional activity was also noted to decrease upon treatment with CDDO-IM in macrophages suggesting the involvement of the NF-κB signaling. This study would contribute to improve our understanding of the detoxification of endotoxin LPS by the triterpenoid CDDO-IM.

scholarly journals Local production of tumor necrosis factor alpha, interleukin 1, and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response.

1989 ◽  
Vol 170 (6) ◽  
pp. 1859-1867 ◽  
Author(s):  
A Waage ◽  
A Halstensen ◽  
R Shalaby ◽  
P Brandtzaeg ◽  
P Kierulf ◽  
...  
Keyword(s):  
Septic Shock ◽  
Inflammatory Response ◽  
Subarachnoid Space ◽  
Interleukin 1 ◽  
Systemic Circulation ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Local Inflammatory Response ◽  
Glucose Ratio ◽  
Factor Alpha

We examined the cerebrospinal fluid (CF) taken on admission from 60 patients with infections caused by Neisseria meningitidis for presence of TNF-alpha, IL-1, and IL-6. TNF-alpha was detected in CF in 55 and 19% (p = 0.03), IL-1 in 50 and 15% (p = 0.05), and IL-6 in 98 and 100% of patients with meningitis and septic shock/bacteremia, respectively. The median IL-6 concentration in CF in patients with meningitis was 154 ng/ml, and in patients with septic shock/bacteremia it was 42 ng/ml (p = 0.001). The level of LPS in CF correlated with the level of TNF-alpha (r = 0.91, p less than 0.001), but not with the level of IL-1 and IL-6. CF levels of TNF-alpha, IL-1, and IL-6 correlated with each other (r = 0.34-0.54, p less than 0.01), with the protein concentration (r = 0.34-0.62, p less than 0.01) and inversely with the CF/blood glucose ratio (r = -0.34 to -0.67, p less than 0.01). Only the Il-6 level correlated with the leukocyte count (r = 0.37, p less than 0.01). In rabbits TNF-alpha, IL-1, and IL-6 activities sequentially appeared in CF within 3 h of injection of meningococcal LPS or viable meningococci, whereas the main infiltration of granulocytes started after 4 h. TNF-alpha was detected in serum at concentrations less than 1/100 of those in CF after administration of LPS into the subarachnoid space, and conversely, TNF-alpha was detected in CF at concentrations 1/100 of those in serum after intravenous injection of LPS. The results demonstrate that TNF-alpha, IL-1, and IL-6 are sequentially produced in the initial phase of the local inflammatory response caused by meningococci, and that the subarachnoid space and systemic circulation are separate compartments with respect to production of TNF-alpha, IL-1, and IL-6.

scholarly journals The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Shinrye Lee ◽  
Seyeon Kim ◽  
Ha-Young Kang ◽  
Hye Ryeong Lim ◽  
Younghwi Kwon ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cortical Neurons ◽  
Interleukin 1 ◽  
Immunoblot Analysis ◽  
Necrosis Factor Alpha ◽  
Cytoplasmic Inclusions ◽  
Coculture System ◽  
Tnf Α ◽  
Factor Alpha ◽  
Primary Astrocytes

Abstract Background Cytoplasmic inclusions of transactive response DNA binding protein of 43 kDa (TDP-43) in neurons and astrocytes are a feature of some neurodegenerative diseases, such as frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). However, the role of TDP-43 in astrocyte pathology remains largely unknown. Methods To investigate whether TDP-43 overexpression in primary astrocytes could induce inflammation, we transfected primary astrocytes with plasmids encoding Gfp or TDP-43-Gfp. The inflammatory response and upregulation of PTP1B in transfected cells were examined using quantitative RT-PCR and immunoblot analysis. Neurotoxicity was analysed in a transwell coculture system of primary cortical neurons with astrocytes and cultured neurons treated with astrocyte-conditioned medium (ACM). We also examined the lifespan, performed climbing assays and analysed immunohistochemical data in pan-glial TDP-43-expressing flies in the presence or absence of a Ptp61f RNAi transgene. Results PTP1B inhibition suppressed TDP-43-induced secretion of inflammatory cytokines (interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α)) in primary astrocytes. Using a neuron-astrocyte coculture system and astrocyte-conditioned media treatment, we demonstrated that PTP1B inhibition attenuated neuronal death and mitochondrial dysfunction caused by overexpression of TDP-43 in astrocytes. In addition, neuromuscular junction (NMJ) defects, a shortened lifespan, inflammation and climbing defects caused by pan-glial overexpression of TDP-43 were significantly rescued by downregulation of ptp61f (the Drosophila homologue of PTP1B) in flies. Conclusions These results indicate that PTP1B inhibition mitigates the neuronal toxicity caused by TDP-43-induced inflammation in mammalian astrocytes and Drosophila glial cells.

scholarly journals Reintroduction of Immunosuppressive Medications in Pediatric Rheumatology Patients With Histoplasmosis: A Case Series

2021 ◽  
Author(s):  
Rachel Brown ◽  
Fatima Barbar-Smiley ◽  
Cagri Yildirim-Toruner ◽  
Monica I. Ardura ◽  
Stacy P. Ardoin ◽  
...  
Keyword(s):  
Rheumatic Disease ◽  
Lupus Erythematosus ◽  
Histoplasma Capsulatum ◽  
Case Series ◽  
Organ Damage ◽  
Necrosis Factor Alpha ◽  
Pulmonary Histoplasmosis ◽  
Immunosuppressive Medications ◽  
Biologic Dmard ◽  
Factor Alpha

Abstract Background: Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD.Case Presentation: We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months).Conclusions: In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.

scholarly journals Tumor necrosis factor alpha/cachectin and interleukin 1 beta initiate meningeal inflammation.

1990 ◽  
Vol 172 (2) ◽  
pp. 497-507 ◽  
Author(s):  
O Ramilo ◽  
X Sáez-Llorens ◽  
J Mertsola ◽  
H Jafari ◽  
K D Olsen ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Inflammatory Response ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Interleukin 1 Beta ◽  
Necrosis Factor Alpha ◽  
Meningeal Inflammation ◽  
Factor Alpha ◽  
Necrosis Factor

Although previous studies using human cytokines in rabbits and rats have provided evidence of the participation of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) in the meningeal inflammatory cascade, the results obtained by several groups of investigators have been discordant or, at times, contradictory. In the present study, homologous cytokines were applied to the rabbit meningitis model. Intracisternal administration of 10(2)-10(5) IU of purified rabbit TNF-alpha (RaTNF-alpha) produced significant cerebrospinal fluid (CSF) inflammation. A similar response was observed after intracisternal inoculation of 5-200 ng of rabbit recombinant IL-1 beta (rrIL-1 beta). Preincubation of these two mediators with their specific antibodies resulted in an almost complete suppression of the CSF inflammatory response. In animals with Haemophilus influenzae type b lipooligosaccharide-induced meningitis, intracisternal administration of anti-rrIL-1 beta, anti-RaTNF-alpha, or both resulted in a significant modulation of meningeal inflammation. Simultaneous administration of 10(3) IU of RaTNF-alpha and 5 ng of rrIL-1 beta resulted in a synergistic inflammatory response manifested by a more rapid and significantly increased influx of white blood cells into the CSF compared with results after each cytokine given alone. These data provide evidence for a seminal role of TNF-alpha and IL-1 beta in the initial events of meningeal inflammation.

scholarly journals Effects of Polysaccharide Fucoidin on Cerebrospinal Fluid Interleukin-1 and Tumor Necrosis Factor Alpha in Pneumococcal Meningitis in the Rabbit

1999 ◽  
Vol 67 (5) ◽  
pp. 2071-2074 ◽  
Author(s):  
Carl Granert ◽  
Johan Raud ◽  
Anders Waage ◽  
Lars Lindquist
Keyword(s):  
Cerebrospinal Fluid ◽  
Tumor Necrosis Factor ◽  
Bacterial Meningitis ◽  
Inflammatory Response ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The inflammatory response in bacterial meningitis is mediated by cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1), which are produced in the subarachnoid space by different cells, e.g., leukocytes, astrocytes, and microglia. The recruitment of leukocytes into the cerebrospinal fluid (CSF) has been shown to contribute to the neurological damage in this disease, a process which could be enhanced by treatment with antibiotics. In this study, we have used a rabbit meningitis model for two sets of experiments with intracisternal (i.c.) injections ofStreptococcus pneumoniae. First, pneumococcal cell wall (PCW) components were injected i.c., inducing an inflammatory response with pleocytosis and increased levels of CSF TNF-α) and IL-1 at 6 and 12 h after PCW injection. Treatment with fucoidin, known to inhibit leukocyte rolling, abolished pleocytosis and inhibited the release of TNF-α and IL-1. In the second experiment, live pneumococcal bacteria were injected i.c. and treatment with one dose of ampicillin (40 mg/kg of body weight intravenously) was given 16 h after induction of meningitis, causing a sevenfold increase in CSF leukocytes over a 4-h period. CSF IL-1 levels at 16 h were high but did not increase further at 20 h. Also, CSF TNF-α levels were high at 16 h and tended to increase at 20 h. Fucoidin treatment prevented the antibiotic-induced increase of CSF leukocytes but had no effect on the TNF-α and IL-1 levels. Taken together, fucoidin reduced CSF TNF-α and IL-1 levels in acute bacterial meningitis induced by PCW fragments but had no effect later in the course of the disease, when live bacteria were used and an inflammatory increase was caused by a dose of antibiotics.

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