Inducible Nitric Oxide Synthase and the Effect of Aminoguanidine in Experimental Neonatal Meningitis

Leib, Stephen L.; Kim, Young S.; Black, Stephen M.; Tureen, Jay H.; Täuber, Martin G.

doi:10.1086/514226

Cited by 107 publications

(71 citation statements)

References 59 publications

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“…NO production in animal models of GBS infection has been shown to enhance meningeal inflammation (8), to mediate neuronal injury in brain cells (11), and to destroy lung surfactant (3). On the other hand, enhanced NO levels mediate beneficial hemodynamic effects in GBS infection by reducing pulmonary hypertension (2) and cerebral ischemia (15). The role of NO in septic shock and pulmonary hypertension in GBS infections of humans is controversial (5,27).…”

Section: Discussionmentioning

confidence: 99%

“…Early-onset GBS pneumonia is characterized by presence of numerous bacteria, an inflammatory exudate, and marked pulmonary epithelial and endothelial cell injury (1,10). Innate proinflammatory responses to GBS infection which may contribute to the respiratory pathology include the synthesis and release of cytokines (12,22), prostaglandins (16), and nitric oxide (NO) (6,15).…”

mentioning

confidence: 99%

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Cytokine Responses to Group B Streptococci Induce Nitric Oxide Production in Respiratory Epithelial Cells

Goodrum

Poulson-Dunlap

2002

Infect Immun

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Streptococcus agalactiae (group B streptococcus [GBS]) is a leading cause of neonatal pneumonia, sepsis, and meningitis. Early-onset GBS pneumonia is characterized by marked pulmonary epithelial and endothelial cell injury. Innate proinflammatory responses to GBS infection that may contribute to the respiratory pathology include the synthesis and release of cytokines, prostaglandins, and nitric oxide (NO). The hypothesis that NO is directly induced in lung epithelial cells by invading GBS or indirectly induced by cytokines released by GBS-infected mononuclear cells was tested. A549 transformed human respiratory epithelial cells were directly cultured with GBS, cocultured with GBS-infected human mononuclear cells or purified macrophages, or exposed to conditioned culture medium from human mononuclear cells infected by GBS. The culture medium of A549 cultures was assayed for NO secretion, and the cell lysates were tested for presence of inducible nitric oxide synthase (iNOS) mRNA by reverse transcriptase PCR (RT-PCR). GBS-treated A549 cells neither secreted detectable NO nor expressed iNOS mRNA. GBS interaction with human mononuclear cells, however, stimulated release of soluble factors that readily induced iNOS mRNA expression and NO secretion by A549 cells. Inflammatory mediator-induced nitric oxide (NO) production by alveolar epithelium may exceed that of other lung cell types such as macrophages, and induction during GBS infection may play a significant role in pulmonary defense or free-radical-mediated lung injury. Streptococcus agalactiae (group B streptococcus [GBS]) is a leading cause of neonatal pneumonia, sepsis, and meningitis (26). GBS is also an important pathogen in maternal infections and in infections of nonpregnant adults with risk factors such as older age and underlying disorders (25). Early-onset GBS pneumonia is characterized by presence of numerous bacteria, an inflammatory exudate, and marked pulmonary epithelial and endothelial cell injury (1, 10). Innate proinflammatory responses to GBS infection which may contribute to the respiratory pathology include the synthesis and release of cytokines (12,22), prostaglandins (16), and nitric oxide (NO) (6, 15).In the lung, alveolar macrophages, airway epithelial cells, endothelial cells, and inflammatory cells may be sources for NO (24). Though GBS, with or without cytokines, has been shown to induce NO production in cultured murine macrophages (3,6,20), human macrophages produce far less NO (5-to 100-fold less) in response to cytokine or microbial stimuli than do murine macrophages (31). An alternate source of alveolar NO are human lung epithelial cells, which possess a nitric oxide synthase (iNOS, NOS2) that is inducible by a mixture of cytokines (21) that should, based on in vitro data, be released locally by GBS-infected alveolar macrophages and mononuclear cells (12). Alternatively, direct GBS invasion of respiratory epithelial cells (23) might also induce NO production.In this report, human respiratory epithelial cells were directly cultured w...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cytokine Responses to Group B Streptococci Induce Nitric Oxide Production in Respiratory Epithelial Cells

Goodrum

Poulson-Dunlap

2002

Infect Immun

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“…Chronic nonsteroidal anti-inflammatory drug use, which inhibits prostaglandin synthesis, is associated with a decreased risk of developing Alzheimer's disease (McGeer and McGeer, 1995;Breitner, 1996). On the other hand, treatment with NOS inhibitors reduces the detrimental effects in some central nervous system inflammatory diseases (Boje, 1995b(Boje, , 1996Rose et al, 1998), but may exacerbate other disease processes (Campbell, 1996;Leib et al, 1998).…”

mentioning

confidence: 99%

Neuroinflammatory Role of Prostaglandins during Experimental Meningitis: Evidence Suggestive of an in Vivo Relationship between Nitric Oxide and Prostaglandins

Boje¹,

Jaworowicz²,

Raybon³

2003

J Pharmacol Exp Ther

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Nitric oxide (NO) and prostaglandins are inflammatory mediators produced during meningitis. The purpose of the present study was to pharmacologically inhibit cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) to 1) explore the prostaglandin contribution to blood-cerebrospinal fluid barrier permeability alterations and 2) elucidate the in vivo concentration relationship between prostaglandin E 2 (PGE 2 ) and NO during experimental meningitis. Intracisternal injection of lipopolysaccharides (LPSs, 200 g) induced neuroinflammation. Rats were dosed with nimesulide (COX-2 inhibitor), aminoguanidine (iNOS inhibitor), or vehicle. Evans blue was used to assess blood-cerebrospinal fluid barrier permeability. Meningeal NO and cerebrospinal fluid PGE 2 were assayed using conventional methods. ( ) on PGE 2 . The in vivo relationship between PGE 2 and NO was mathematically described by a biphasic, bell-shaped curve (r 2 ϭ 0.42; n ϭ 27 rats; p Ͻ 0.0001). Based on these results, inhibition of prostaglandin synthesis not only fails to prevent blood-cerebrospinal fluid barrier disruption during neuroinflammation and but also promotes increased meningeal NO production. The in vivo concentration relationship between PGE 2 and NO is biphasic, suggesting that inhibition of COX-2 alone may promote NO toxicity through enhanced NO synthesis.Blood-cerebrospinal fluid barrier and blood-brain barrier permeability alterations are suspected to contribute to the pathology of neurological diseases with a known inflammatory component, namely, Alzheimer's disease, multiple sclerosis, human immunodeficiency virus-1 dementia, cerebral ischemia, brain tumors, and meningitis (Boje, 1995a;Claudio et al

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“…Nitric oxide antagonists (7-nitroindazole and N-nitro-L-arginine) prevent early pial vasodilatation in experimental models, which suggests that nitric oxide is a potential therapeutic target (107). However, the early timing of inhibitor administration is crucial, because administration of the inhibitor later in the disease process exacerbates hypoperfusion (72,142).…”

Section: Conserve Cellular Function (I) Blood-brain Barrier and Incrmentioning

confidence: 99%

Reprogramming the Host Response in Bacterial Meningitis: How Best To Improve Outcome?

et al. 2003

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Despite effective antibiotic therapy, bacterial meningitis is still associated with high morbidity and mortality in both children and adults. Animal studies have shown that the host inflammatory response induced by bacterial products in the subarachnoid space is associated with central nervous system injury. Thus, attenuation of inflammation early in the disease process might improve the outcome. The feasibility of such an approach is demonstrated by the reduction in neurologic sequelae achieved with adjuvant dexamethasone therapy. Increased understanding of the pathways of inflammation and neuronal damage has suggested rational new targets to modulate the host response in bacterial meningitis, but prediction of which agents would be optimal has been difficult. This review compares the future promise of benefit from the use of diverse adjuvant agents. It appears unlikely that inhibition of a single proinflammatory mediator will prove useful in clinical practice, but several avenues to reprogram a wider array of mediators simultaneously are encouraging. Particularly promising are efforts to adjust combinations of cytokines, to inhibit neuronal apoptosis and to enhance brain repair

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Inducible Nitric Oxide Synthase and the Effect of Aminoguanidine in Experimental Neonatal Meningitis

Cited by 107 publications

References 59 publications

Cytokine Responses to Group B Streptococci Induce Nitric Oxide Production in Respiratory Epithelial Cells

Cytokine Responses to Group B Streptococci Induce Nitric Oxide Production in Respiratory Epithelial Cells

Neuroinflammatory Role of Prostaglandins during Experimental Meningitis: Evidence Suggestive of an in Vivo Relationship between Nitric Oxide and Prostaglandins

Reprogramming the Host Response in Bacterial Meningitis: How Best To Improve Outcome?

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