Pentoxifylline modulates meningeal inflammation in experimental bacterial meningitis

Sáez-Llorens, Xavier; Ramilo, Octavio; Mustafa, Mahmoud M.; Mertsola, Jussi; Alba, C. de; Hansen, Eric J.; McCracken, George H.

doi:10.1128/aac.34.5.837

Cited by 59 publications

(39 citation statements)

References 32 publications

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“…In the past few years, animal models of meningitis have added to the understanding of the pathophysiology of bacterial meningitis, including the role of bacterial components initiating the inflammatory response, the participation of chemical mediators, the role of polymorphonuclear neutrophils, and the altered physiology in the brain (4)(5)(6)(7). Both the bacterial cell wall and the capsule are involved in the virulence of Grampositive bacteria.…”

Section: Discussionmentioning

confidence: 99%

Biochemical Mediators of Meningeal Inflammatory Response to Group B Streptococcus in the Newborn Piglet Model

et al. 1995

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KACTThe meningeal inflammatory response to a heat-killed mutant unencapsulated strain of type I11 group B Streptococcus (GBS) was studied in a newborn piglet model. GBS (10" colonyforming unit equivalents) or saline (control) was inoculated intraventricularly. Serial cerebrospinal fluid measurements were done at baseline and over the course of the next 24 h for cytochemical changes and production of tumor necrosis factor (TNF) and prostaglandins. In separate experiments, we defined the time course of early changes during the first 6 h and dose response relationship over a range of inocula lo6 to 10" colonyforming unit equivalents. The intraventricular inoculation of the heat-killed unencapsulated GBS induced marked leukocytosis and increased protein by 6 h. These changes were preceded by a several hundredfold increase in TNF (maximum at 2 h) and prostaglandins (maximum at 2-4 h). The early and sharp rise in TNF suggests its pivotal role in initiating the inflammatory cascade. The magnitude of the inflammatory response increased with increasing bacterial dose over the range studied. To study the effect of encapsulation of GBS in the induction of meningeal inflammation, we compared the response to the unencapsulated mutant strain with that to the encapsulated parent strain. The encapsulated strain produced much smaller inflammatory changes, and only with high doses of bacteria. The GBS cell wall appeared to be the primary bacterial product triggering inflammation. Intraventricular injection of the heat-killed unencapsulated GBS with exposed cell wall can serve as a valid model for studying neonatal meningitis. ( Neonatal meningitis continues to be associated with high mortality and morbidity despite effective antibiotic therapy and advanced intensive care technology. The current incidence is 0.4-1.011 000 live births (1, 2), and current mortality is 20-40% with long-term neurologic sequelae in as many as onethird of the survivors (3). Over the past few years, studies on meningitis in human and in animal models have increased our understanding of the pathogenesis of infection and pathophysiology. It has been shown that bacterial products initiate a chain of inflammatory reactions with the formation of inflammatory cytokines and biochemical mediators (4-7). These events result in injury to the vascular lining of the brain and alteration in the CSF dynamics, brain metabolism, and the control of cerebral blood flow. Most animal models of bacterial meningitis use adult animals. It is important to develop a neonatal animal model to study the pathophysiologic consequences of meningeal inflammation on the immature brain. It is the objective of this study to develop an animal model of neonatal meningitis using a common neonatal pathogen. GBS is a common causative organism of neonatal sepsis and GBS type 111, in particular, is a common cause of neonatal meningitis (8).In Gram-positive organisms, the techoic acid-containing cell wall has been suggested to be responsible for the initiation of inflammation. In an adult rabbit ...

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Section: Discussionmentioning

confidence: 99%

Biochemical Mediators of Meningeal Inflammatory Response to Group B Streptococcus in the Newborn Piglet Model

et al. 1995

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“…Likewise, the transient enhancement of the host's inflammatory response that commonly follows initiation of antibiotic treatment has been significantly attenuated when agents have been used that selectively interfere with production of inflammatory mediators (e.g., dexamethasone, cyclooxygenase inhibitors) or with influx of leukocytes into the subarachnoid space (e.g., pentoxifylline, anti-CD 1 8 receptor antibodies) (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Enhanced attenuation of meningeal inflammation and brain edema by concomitant administration of anti-CD18 monoclonal antibodies and dexamethasone in experimental Haemophilus meningitis.

Sáez-Llorens¹,

Jafari²,

Severien³

et al. 1991

J. Clin. Invest.

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Antiinflammatory therapy has been shown to reduce the adverse pathophysiological consequences that occur in bacterial meningitis and to improve outcome from disease. In the present study, modulation of two principal steps of the meningeal inflammatory cascade was accomplished by concomitant administration of dexamethasone to diminish overproduction of cytokines in response to a bacterial stimulus and of a monoclonal antibody directed against adhesion-promoting receptors on leukocytes to inhibit recruitment of white blood cells into the subarachnoid space. Dexamethasone and antibody therapy produced a marked attenuation of all indices of meningeal inflammation and reduction of brain water accumulation after H.

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“…In experimental models of gram-negative infection or endotoxemia, pretreatment or early treatment with pentoxifylline increases survival and decreases lung injury (6,16,23). In the rabbit model of H. influenzae type b meningitis, pentoxifylline decreased protein and lactate concentrations in CSF when it was administered 30 min prior to ceftriaxone infusion (13).…”

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confidence: 99%

Effect of dexamethasone or HWA-138 in combination with antibiotics in experimental Haemophilus influenzae type b infection

Rodriguez

Kaplan

Hawkins

et al. 1991

Antimicrob Agents Chemother

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Modulation of the host's inflammatory response in bacterial meningitis may be beneficial. In this study, the effects of dexamethasone and HWA-138, an analog of pentoxifylline, on CSF cultures and cochlear inflammation in an infant rat model of Haemophilus influenzae type b were studied. Five-day-old infant rats were inoculated once intraperitoneally with 1 x 104 to 10 x i04 CFU of H. influenzae type b (strain 1406). Twenty-four hours later, infant rats were treated intraperitoneally with one dose of ampicillin (0.1 mg/g of body weight), cefotaxime (0.05 mg/g), or cefuroxime (0.05 mg/g) alone or in combination with one dose of dexamethasone (0.00015 mg/g) or HWA-138 (0.005 mg/g). Twenty-four hours after treatment with cefuroxime plus dexamethasone, animals had a significantly (P c 0.04) greater incidence of bacteremia and meningitis (eight of nine animals) than that in animals of the other treatment groups. Overall, dexamethasone was associated with less inflammation (P < 0.04) of the cochlear nerve compared with that from antibiotic treatment alone. In this model, when suboptimal antimicrobial therapy is administered, anti-inflammatory agents may be beneficial with respect to reducing cochlear inflammation. However, dexamethasone and cefuroxime lead to a higher rate of positive blood and cerebral spinal fluid cultures than cefuroxime alone.

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Pentoxifylline modulates meningeal inflammation in experimental bacterial meningitis

Cited by 59 publications

References 32 publications

Biochemical Mediators of Meningeal Inflammatory Response to Group B Streptococcus in the Newborn Piglet Model

Biochemical Mediators of Meningeal Inflammatory Response to Group B Streptococcus in the Newborn Piglet Model

Enhanced attenuation of meningeal inflammation and brain edema by concomitant administration of anti-CD18 monoclonal antibodies and dexamethasone in experimental Haemophilus meningitis.

Effect of dexamethasone or HWA-138 in combination with antibiotics in experimental Haemophilus influenzae type b infection

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