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Intranasal rapamycin rescues mice from staphylococcal enterotoxin B-induced shock.

Krakauer T, Buckley M - Toxins (Basel) (2012)

Bottom Line: Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively.Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock.Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window.

View Article: PubMed Central - PubMed

Affiliation: Integrated Toxicology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. marilyn.buckley@us.army.mil

ABSTRACT
Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window.

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Chemokine and cytokine assessment at 42 h in lungs of mice treated with intranasal rapamycin after SEB challenge. Values represent the mean ± SE for five mice and results are statistically significant (p < 0.05) between SEB and SEB + rapamycin group.
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toxins-04-00718-f004: Chemokine and cytokine assessment at 42 h in lungs of mice treated with intranasal rapamycin after SEB challenge. Values represent the mean ± SE for five mice and results are statistically significant (p < 0.05) between SEB and SEB + rapamycin group.

Mentions: Proinflammatory cytokines mediate the lethal and pathological effects of SEB and monocyte chemoattractant protein (MCP-1), interleukin 2 (IL-2), IL-6 and gamma interferon (IFNγ) are critical mediators in various mouse models of SEB-induced shock [19,23,26,28,32]. We next examined the effect of intranasal rapamycin on these pulmonary mediators. Figure 4 shows that high levels of MCP-1, IL-2, IL-6, and IFNγ were present in lung tissue at 42 h post-SEB treatment. In contrast, mice treated with rapamycin at 15 h followed by two additional doses at 21 and 39 h after SEB attenuated MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. These findings indicate a protective regimen of rapamycin is also effective in reducing the pulmonary mediators critical in initiating cell migration, cell activation, inflammation culminating in lung injury.


Intranasal rapamycin rescues mice from staphylococcal enterotoxin B-induced shock.

Krakauer T, Buckley M - Toxins (Basel) (2012)

Chemokine and cytokine assessment at 42 h in lungs of mice treated with intranasal rapamycin after SEB challenge. Values represent the mean ± SE for five mice and results are statistically significant (p < 0.05) between SEB and SEB + rapamycin group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475225&req=5

toxins-04-00718-f004: Chemokine and cytokine assessment at 42 h in lungs of mice treated with intranasal rapamycin after SEB challenge. Values represent the mean ± SE for five mice and results are statistically significant (p < 0.05) between SEB and SEB + rapamycin group.
Mentions: Proinflammatory cytokines mediate the lethal and pathological effects of SEB and monocyte chemoattractant protein (MCP-1), interleukin 2 (IL-2), IL-6 and gamma interferon (IFNγ) are critical mediators in various mouse models of SEB-induced shock [19,23,26,28,32]. We next examined the effect of intranasal rapamycin on these pulmonary mediators. Figure 4 shows that high levels of MCP-1, IL-2, IL-6, and IFNγ were present in lung tissue at 42 h post-SEB treatment. In contrast, mice treated with rapamycin at 15 h followed by two additional doses at 21 and 39 h after SEB attenuated MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. These findings indicate a protective regimen of rapamycin is also effective in reducing the pulmonary mediators critical in initiating cell migration, cell activation, inflammation culminating in lung injury.

Bottom Line: Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively.Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock.Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window.

View Article: PubMed Central - PubMed

Affiliation: Integrated Toxicology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. marilyn.buckley@us.army.mil

ABSTRACT
Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window.

Show MeSH
Related in: MedlinePlus