Neuroprotection by a caspase inhibitor in acute bacterial meningitis

Braun, Johann; Novak, Robert W.; Herzog, Karl-Heinz; Bodner, Sara M.; Cleveland, John L.; Tuomanen, Elaine

doi:10.1038/6514

Cited by 252 publications

(183 citation statements)

References 29 publications

(29 reference statements)

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“…Z-VAD-FMK, a pancaspase inhibitor (36)(37)(38)(39)(40)(41)(42), can inhibit cell death in response to mechanical injury. Interestingly, our results showed that Z-VAD-FMK could inhibit chondrocyte death more effectively in chondroitinase ABC-treated explants than in control explants.…”

Section: Discussionmentioning

confidence: 99%

The effect of glycosaminoglycan loss on chondrocyte viability: A study on porcine cartilage explants

Otsuki¹,

Brinson²,

Creighton³

et al. 2008

Arthritis & Rheumatism

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Objective. Loss of glycosaminoglycan (GAG) is an early event in osteoarthritis. Recent findings showed increased cell death in arthritic cartilage and linkage with extracellular matrix degradation. The aim of this study was to analyze the direct effect of GAG loss on chondrocyte survival and cell death following mechanical injury.Methods. In full-thickness cartilage explants from porcine knee joints, GAG was depleted by digestion with chondroitinase ABC. Explants were subjected to single-impact mechanical injury. Cell viability and the types of cell death were analyzed by Live/Dead cell assay, staining for active caspase 3, and sensitivity to caspase inhibitor.Results. GAG depletion did not directly lead to increased cell death. In chondroitinase ABC-treated explants, but not in control explants, mechanical injury caused an immediate reduction in cell viability (from 84.6% to 71.0%); the reduction was prominent in the superficial zone. This immediate cell death was not inhibited by the pancaspase inhibitor Z-VAD-FMK, suggesting cell necrosis. During subsequent culture, viability in these explants decreased further, to 50.5% on day 3. The second wave of cell death was reduced by the addition of Z-VAD-FMK in chondroitinase ABC-treated explants and was also associated with activation of caspase 3, suggesting apoptotic mechanisms of cell death.Conclusion. These results indicate that GAG loss alone does not directly lead to chondrocyte death. In response to mechanical injury, there is an immediate induction of necrotic cell death that is seen only in GAG-depleted explants and primarily in the superficial zone. During subsequent culture, cell death spreads via apoptotic mechanisms.

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Section: Discussionmentioning

confidence: 99%

The effect of glycosaminoglycan loss on chondrocyte viability: A study on porcine cartilage explants

Otsuki¹,

Brinson²,

Creighton³

et al. 2008

Arthritis & Rheumatism

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“…Therefore, during the past 15 years, investigations have focused on the pathogenesis of meningitis-associated CNS complications (4). It has become clear that the development of these complications is not simply dependent on the presence of viable bacteria, but rather occurs as a consequence of the host inflammatory reaction to the pathogen (5). Although the exact mechanisms of immune activation in pneumococcal meningitis are unknown, recent in vitro experiments provide a clue.…”

Section: B Acterial Meningitis Caused By Streptococcus Pneumoniaementioning

confidence: 99%

Toll-Like Receptor 2 Participates in Mediation of Immune Response in Experimental Pneumococcal Meningitis

Koedel¹,

Angele²,

Rupprecht³

et al. 2003

The Journal of Immunology

206

173

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Heterologous expression of Toll-like receptor (TLR)2 and CD14 in Chinese hamster ovary fibroblasts was reported to confer responsiveness to pneumococcal peptidoglycan. The present study characterized the role of TLR2 in the host immune response and clinical course of pneumococcal meningitis. Pneumococcal infection of mice caused a significant increase in brain TLR2 mRNA expression at both 4 and 24 h postchallenge. Mice with a targeted disruption of the TLR2 gene (TLR2−/−) showed a moderate increase in disease severity, as evidenced by an aggravation of meningitis-induced intracranial complications, a more pronounced reduction in body weight and temperature, and a deterioration of motor impairment. These symptoms were associated with significantly higher cerebellar and blood bacterial titers. Brain expression of the complement inhibitor complement receptor-related protein y was significantly higher in infected TLR2−/− than in wild-type mice, while the expression of the meningitis-relevant inflammatory mediators IL-1β, TNF-α, IL-6, macrophage-inflammatory protein (MIP)-2, inducible NO synthase, and C3 was similar in both genotypes. We first ectopically expressed single candidate receptors in HEK293 cells and then applied peritoneal macrophages from mice lacking TLR2 and/or functional TLR4 for further analysis. Overexpression of TLR2 and TLR4/MD-2 conferred activation of NF-κB in response to pneumococcal exposure. However, pneumococci-induced TNF-α release from peritoneal macrophages of wild-type and TLR2/functional TLR4/double-deficient mice did not differ. Thus, while TLR2 plays a significant role in vivo, yet undefined pattern recognition receptors contribute to the recognition of and initiation of the host immune defense toward Streptococcus pneumoniae infection.

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“…However, a growing body of animal studies supports the hypothesis that a major pathophysiologic mechanism in sepsis is lymphocyte apoptosis (8 -11, 27). Recently, Braun et al (28) showed that administration of caspase inhibitors, drugs that block apoptosis, provided excellent neuroprotection in a rabbit model of pneumococcal meningitis. Ayala et al (29) reported that septic mice deficient in FasL gld had decreased mucosal B lymphocyte apoptosis and improved survival compared with controls.…”

Section: Lymphocyte Apoptosis: a Key Pathophysiologic Mechanism In Sementioning

confidence: 99%

Sepsis-Induced Apoptosis Causes Progressive Profound Depletion of B and CD4+ T Lymphocytes in Humans

Kw²,

et al. 2001

The Journal of Immunology

799

624

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Patients with sepsis have impaired host defenses that contribute to the lethality of the disorder. Recent work implicates lymphocyte apoptosis as a potential factor in the immunosuppression of sepsis. If lymphocyte apoptosis is an important mechanism, specific subsets of lymphocytes may be more vulnerable. A prospective study of lymphocyte cell typing and apoptosis was conducted in spleens from 27 patients with sepsis and 25 patients with trauma. Spleens from 16 critically ill nonseptic (3 prospective and 13 retrospective) patients were also evaluated. Immunohistochemical staining showed a caspase-9-mediated profound progressive loss of B and CD4 T helper cells in sepsis. Interestingly, sepsis did not decrease CD8 T or NK cells. Although there was no overall effect on lymphocytes from critically ill nonseptic patients (considered as a group), certain individual patients did exhibit significant loss of B and CD4 T cells. The loss of B and CD4 T cells in sepsis is especially significant because it occurs during life-threatening infection, a state in which massive lymphocyte clonal expansion should exist. Mitochondria-dependent lymphocyte apoptosis may contribute to the immunosuppression in sepsis by decreasing the number of immune effector cells. Similar loss of lymphocytes may be occurring in critically ill patients with other disorders.

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Neuroprotection by a caspase inhibitor in acute bacterial meningitis

Cited by 252 publications

References 29 publications

The effect of glycosaminoglycan loss on chondrocyte viability: A study on porcine cartilage explants

The effect of glycosaminoglycan loss on chondrocyte viability: A study on porcine cartilage explants

Toll-Like Receptor 2 Participates in Mediation of Immune Response in Experimental Pneumococcal Meningitis

Sepsis-Induced Apoptosis Causes Progressive Profound Depletion of B and CD4+ T Lymphocytes in Humans

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