Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza

Budd, Alison; Alleva, Lisa M.; Alsharifi, Mohammed; Koskinen, Aulikki; Smythe, Victoria; Müllbacher, Arno; Wood, Jeffrey; Clark, Ian A.

doi:10.1128/aac.00219-07

Cited by 87 publications

(70 citation statements)

References 26 publications

(21 reference statements)

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“…Ethyl pyruvate was given either daily, from days 4 to 10 post infection (p.i.) as we have done previously for the drug gemfibrozil (20), or prophylactically, from 1 h before infection, and then daily, until day 10 p.i. …”

Section: Treatment With Ethyl Pyruvatementioning

confidence: 73%

Systemic Release of High Mobility Group Box 1 Protein during Severe Murine Influenza

Alleva

Budd

Clark

2008

The Journal of Immunology

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Hypercytokinemia is gaining recognition as the mechanism of fatality from influenza. No work to date has addressed the role of high mobility group box 1 protein (HMGB1) in influenza, the parallel being that in other severe proinflammatory cytokine syndromes (e.g., sepsis and malaria) levels of circulating HMGB1 are elevated and may correlate with death. Using a commercially available ELISA for HMGB1, we found that HMGB1 was not increased in the plasma of influenza virus-infected mice (A/Japan/305/57) on day 7 post infection, about the time of peak mortality, and peak levels of HMGB1 in the plasma did not occur until relatively late in infection, on day 9 post infection. In keeping with the late peak of HMGB1 being unassociated with mortality, administration of ethyl pyruvate, which inhibits active secretion but not passive release of HMGB1, to influenza virus-infected mice, did not affect their survival. Further work is required to determine whether influenza virus infection induces passive release of HMGB1, and whether HMGB1 neutralization with a specific Ab would improve survival.

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Section: Treatment With Ethyl Pyruvatementioning

confidence: 73%

Systemic Release of High Mobility Group Box 1 Protein during Severe Murine Influenza

Alleva

Budd

Clark

2008

The Journal of Immunology

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“…Viral stock and infection procedures were as described previously (39). Briefly, stocks of influenza virus A/Japan/305/57 (A/Jap, H2N2), a negative ssRNA virus, were grown in embryonated eggs.…”

Section: Influenza Virus Infection Of Balb/c Mice and Localization Ofmentioning

confidence: 99%

IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA

Endoh¹,

Chung²,

Clark

et al. 2009

The Journal of Immunology

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The S100 calcium-binding proteins S100A8 and S100A9 are elevated systemically in patients with viral infections. The S100A8-S100A9 complex facilitated viral replication in human CD4+ T lymphocytes latently infected with HIV-1- and S100A8-induced HIV-1 transcriptional activity. Mechanisms inducing the S100 genes and the potential source of these proteins following viral activation are unknown. In this study, we show that S100A8 was induced in murine macrophages, and S100A8 and S100A9 in human monocytes and macrophages, by polyinosinic:polycytidylic acid, a dsRNA mimetic. Induction was at the transcriptional level and was IL-10 dependent. Similar to LPS-induced S100A8, induction by dsRNA was dependent on p38 and ERK MAPK. Protein kinase R (PKR) mediates antiviral defense and participates in MyD88-dependent/independent signaling triggered by TLR4 or TLR3. Like IL-10, S100 induction by polyinosinic:polycytidylic acid and by LPS was inhibited by the specific PKR inhibitor 2-aminopurine, indicating a novel IL-10, PKR-dependent pathway. Other mediators such as IFN-β, which synergized with dsRNA, may also be involved. C/EBPβ bound the defined promoter region in response to dsRNA. S100A8 was expressed in lungs of mice infected with influenza virus and was maximal at day 8 with strong immunoreactivity in epithelial cells lining the airways and in mononuclear cells and declined early in the recovery phase, implying down-regulation by mediator(s) up-regulated during resolution of the infection. IL-10 is implicated in viral persistence. Since S100A8/S100A9 levels are likely to be maintained in conditions where IL-10 is raised, these proteins may contribute to viral persistence in patients infected by some RNA viruses.

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“…83 A limited number of laboratory studies have shown the effectiveness of other immunomodulatory agents in mouse models of influenza. Post-infection treatment with resveratrol (a plant polyphenol with immunomodulatory activities) 84 and gemfibrozil 85 significantly improved survival in influenza virus-infected mice, and similar improvements have been demonstrated for pre-infection treatment with pioglitazone 86 and pioglitazone combined with AICAR, a metformin-like drug. 87 In two studies that evaluated the effects of treatment on virus replication, pulmonary virus levels were either unchanged 86 or reduced.…”

Section: The Host Response To Influenzamentioning

confidence: 60%

“…Influenza virologists usually use either inbred BALB/c or C57Bl/6 mice, 115 and these two strains have been used in all experimental studies of immunomodulatory agents. [84][85][86][87][88][89] These strains might not be optimal for determining which agent might best counteract the more intense inflammatory response in man. For example, in a study of host factors involved in the pathogenesis of pH1N1 virus influenza, BALB/c mice, which have a Th-2 bias, were shown to be less suitable than C57Bl/6 mice, which have a Th-1 bias.…”

Section: Acknowledgmentsmentioning

confidence: 99%