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Modulation of inflammatory mediators during experimental bacterial meningitis
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bacterial meningitis is a worldwide health problem with high morbidity and mortality mainly caused by Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae. It is an inflammatory disease of the central nervous system (eNS) initiated by cell wall or membrane components from the bacteria. This stimulates an accumulation of polymorphonuclear leukocytes (PMN) in the subarachnoid space, where they are further stimulated by bacterial products or by cytokines to release inflammatory mediators including nitric oxide (NO) and chemokines. The role of these mediators in the inflammatory response in vivo is not fully understood. The aim of present thesis was to investigate the role of these inflammatory mediators using Haemophilus influenzae type b (Hib) in an experimental model for meningitis.

Intraperitoneal inoculation of Hib into infant rats resulted in induction of iNOS mRNA that was detected in brain sections 12 hr post-inoculation (p.i). The number of iNOS mRNA-containing cells was gradually reduced and normalized by day 7 p.i. The numbers of intracerebral iNOS expressing cells was also detected after 12h p.i., but they were further elevated to a peak at 72h p.i. The iNOS positive brain sections also bound antibody specific for nitrotyrosine.

Brains of infant rats challenged intraperitoneally with Hib resulted in a time-dependent expression of MIP-2, MIP-1α MCP-1 and RANTES, which were detected with maximum levels at 24-48 h p.i. There were significant increases in the number of neutrophils and macrophages in the meninges, the ventricular system and the periventricular area. The kinetics of MIP-2, MIP-α, MCP-1 and RANTES mRNA expression paralleled those of the recruitment of inflammatory cells and disease severity. Administration of anti-MIP-2 or anti-MIP-1α antibodies (Abs) reduced the number of infiltrated neutrophils, anti-MCP-1 Abs reducing macrophage infiltration.

Hib infection resulted in 100% mortality by 72 h p.i. and pretreatment with CNI-1493, a tetravalent guanylhydrazone, resulted in 75% survival. This treatment also reduced the number of infiltrating granulocytes in the brain and reduced the number of cells producing TNF-α and IL-Iß in the spleen.

Macrophages (RAW 246.7) preincubated with CNI-1493 prior to activation with LPS/IFN- γ had decreased NO production and reduced iNOS expression. The production of reactive oxygen species (ROS) was increased in FMLP-stimulated granulocytes following CNI-1493-treatment, whereas their F-actin content, motility and chemotaxis were decreased under the same condition.

Conclusion: During experimental Hib meningitis iNOS was upregulated and associated with NO production. The chemokines MIP-2, MIP-1α MCP and RANTES were expressed and shown to be involved in neutrophil recruitment in vivo. Blockade of MIP-2 or MIP-1α bioactivity in vivo resulted in decreased neutrophil influx. CNI-1493 treatment increased animal survival by attenuating CNS inflammation and in vitro CNI-1493 had a direct effect on both macrophages and PMN.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2005. , 40 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 907
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-30081Local ID: 15546ISBN: 91-8529914-6 OAI: oai:DiVA.org:liu-30081DiVA: diva2:250902
Public defence
2005-06-09, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-26Bibliographically approved
List of papers
1. Expression of inducible nitric oxide synthases and nitrotyrosine during the course of Haemophilus influenzae type b meningitis in rat
Open this publication in new window or tab >>Expression of inducible nitric oxide synthases and nitrotyrosine during the course of Haemophilus influenzae type b meningitis in rat
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Bacterial meningitis continues to be a major health problem and despite great advances in antimicrobial therapy the fatality rate remains high. There is increasing evidence that leukocyte-endothelial interactions are involved in CNS damage during bacterial meningitis. Once leukocytes have entered the CSF they cause injury by releasing toxic molecules such as nitric oxide (NO) and reactive oxygen species (ROS). The induction of iNOS was examined by assessing intracerebral mRNA expression and protein production during the course of Haemophilus influenzae type b (Hib) meningitis in the rat. Induction of iNOS mRNA was detected 12h postinoculation (pi), followed by a gradual reduction. The increased number of intracerebral iN OS expressing cells was detected at 12h pi. followed by further elevation to peak expression at 72h pi. The iNOS positive tissue also bound antibodies specific for nitrotyrosine. The expression of iNOS and NO production, as shown by nitrotyrosine expression, correlated with disease severity, suggesting that activation of iNOS may play an important role in Haemophilus irifluenzae type b meningitis.

Keyword
iNOS, Hib, brain, bacterial meningitis, rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81944 (URN)
Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2012-09-26Bibliographically approved
2. Neutralization of macrophage inflammatory protein 2 (MIP-2) and MIP-1α attenuates neutrophil recruitment in the central nervous system during experimental bacterial meningitis
Open this publication in new window or tab >>Neutralization of macrophage inflammatory protein 2 (MIP-2) and MIP-1α attenuates neutrophil recruitment in the central nervous system during experimental bacterial meningitis
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1999 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 67, no 5, 2590-2601 p.Article in journal (Refereed) Published
Abstract [en]

Chemokines are low-molecular-weight chemotactic cytokines that have been shown to play a central role in the perivascular transmigration and accumulation of specific subsets of leukocytes at sites of tissue damage. Using in situ hybridization (ISH), we investigated the mRNA induction of macrophage inflammatory protein 2 (MIP-2), MIP-1α, monocyte chemoattractant protein 1 (MCP-1), and RANTES. Challenge of infant rats’ brains with Haemophilus influenzae type b intraperitoneally resulted in the time-dependent expression of MIP-2, MIP-1α, MCP-1, and RANTES, which was maximal 24 to 48 h postinoculation. Immunohistochemistry showed significant increases in neutrophils and macrophages infiltrating the meninges, the ventricular system, and the periventricular area. The kinetics of MIP-2, MIP-1α, MCP-1, and RANTES mRNA expression paralleled those of the recruitment of inflammatory cells and disease severity. Administration of anti-MIP-2 or anti-MIP-1α antibodies (Abs) resulted in significant reduction of neutrophils. Administration of anti-MCP-1 Abs significantly decreased macrophage infiltration. Combined studies of ISH and immunohistochemistry showed that MIP-2- and MIP-1α-positive cells were neutrophils and macrophages. MCP-1-positive cells were neutrophils, macrophages, and astrocytes. Expression of RANTES was localized predominantly to resident astrocytes and microglia. The present study indicates that blocking of MIP-2 or MIP-1α bioactivity in vivo results in decreased neutrophil influx. These data are also the first demonstration that the C-C chemokine MIP-1α is involved in neutrophil recruitment in vivo.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81946 (URN)10225925 (PubMedID)
Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2017-12-07Bibliographically approved
3. Suppression of macrophage activation with CNI-1493 increases survival in infant rats with systemic Haemophilus influenzae infection
Open this publication in new window or tab >>Suppression of macrophage activation with CNI-1493 increases survival in infant rats with systemic Haemophilus influenzae infection
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2000 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 68, no 9, 5329-5334 p.Article in journal (Refereed) Published
Abstract [en]

CNI-1493, a potent macrophage deactivator, was used to treat infant rats systemically infected with Haemophilus influenzae type b (Hib). CNI-1493 was injected 1 h prior to bacterial inoculation and 24 h later and resulted in a 75 percent increased rate of survival compared to that for untreated controls. The effect of CNI-1493 on the inflammatory response was studied by immunohistochemical detection of individual tumor necrosis factor alpha (TNF-α)-, interleukin 1 beta (IL-1β)-, and gamma interferon (IFN-γ)-producing cells in the spleen. A significant reduction of the incidence of TNF-α- and IL-1β-expressing cells was found for CNI-1493-treated animals. IFN-γ expression was not suppressed by CNI-1493, indicating that cytokine inhibition was specific in macrophages. CNI-1493 significantly reduced the number of infiltrating granulocytes in the brain from that for controls. This study provides evidence that CNI-1493 protects against lethal Hib infection by deactivating the inflammatory cascade in infant rats.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81948 (URN)10.1128/​IAI.68.9.5329-5334.2000 (DOI)
Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2017-12-07Bibliographically approved
4. Effects of CNI-1493 on human granulocyte functions
Open this publication in new window or tab >>Effects of CNI-1493 on human granulocyte functions
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2006 (English)In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 211, no 3, 191-197 p.Article in journal (Refereed) Published
Abstract [en]

During acute bacterial infections such as sepsis and meningitis, activation of inflammatory mediators such as nitric oxide (NO) plays a crucial role in both pathogenesis and host defense. We have previously reported that CNI-1493, a macrophage deactivator, reduced mortality in infant rats infected with Haemophilus influenzae type b (Hib) with associated decrease in the number of granulocytes in the infected tissue. The aim of the present study was to investigate how CNI-1493 affects granulocytes and macrophages in vitro. Murine macrophages (RAW 264.7) pre-incubated with CNI-1493 prior to activation with lipopolysaccharide (LPS)/interferon gamma (IFNγ) had decreased NO production measured as NO2/NO3 levels and reduction in inducible NO-synthase (iNOS) expression. Reactive oxygen species (ROS) production was increased in formylmethionyl-leucyl-phenylalanine (FMLP)-stimulated granulocytes following CNI-1493 treatment, whereas F-actin content, motility and chemotaxis were decreased under the same conditions. The effects of CNI-1493 on both NO production in LPS/IFNγ-activated macrophages and ROS production, F-actin content, motility and chemotaxis in granulocytes, may contribute to the reduced inflammatory response and increased survival in Hib-infected animals treated with CNI-1493.

Keyword
CNI-1493, Granulocytes, iNOS, Macrophages, ROS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-50239 (URN)10.1016/j.imbio.2005.09.006 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12Bibliographically approved

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