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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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Related in: MedlinePlus

Intranasal rapamycin prevented weight loss in mice treated with SEB. Weights of mice (n = 9 or n = 10) exposed to SEB and SEB plus rapamycin (0.16 mg/kg) at different time points after SEB exposure. Group identifiers are identical to those in Table 1. Points represent the average % weight change ± SD for each group. Grey arrow indicates time of SEB exposure and black arrows represent time of rapamycin administration for the SEB + R17h3d group.
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toxins-04-00718-f003: Intranasal rapamycin prevented weight loss in mice treated with SEB. Weights of mice (n = 9 or n = 10) exposed to SEB and SEB plus rapamycin (0.16 mg/kg) at different time points after SEB exposure. Group identifiers are identical to those in Table 1. Points represent the average % weight change ± SD for each group. Grey arrow indicates time of SEB exposure and black arrows represent time of rapamycin administration for the SEB + R17h3d group.

Mentions: Weight loss is another prominent indicator of SEB-induced shock in other animal models of superantigen-induced disease [16]. We therefore examined the effect of rapamycin on the weight of animals after intranasal SEB. SEB-exposed mice experienced weight loss of 3%–7% at 53 h with drastic weight reduction over time. Most of the rapamycin-treated, SEB-exposed mice had 1% change in weight with some groups of mice gaining weight at later times (Figure 3). Mice receiving only two doses of rapamycin starting at 17 h (SEB + R17hd2) had 8% weight loss and weight remained at this level after 53 h (70% survival). Protection against temperature and weight fluctuations essentially paralleled the lethality data.


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

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

Intranasal rapamycin prevented weight loss in mice treated with SEB. Weights of mice (n = 9 or n = 10) exposed to SEB and SEB plus rapamycin (0.16 mg/kg) at different time points after SEB exposure. Group identifiers are identical to those in Table 1. Points represent the average % weight change ± SD for each group. Grey arrow indicates time of SEB exposure and black arrows represent time of rapamycin administration for the SEB + R17h3d group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

toxins-04-00718-f003: Intranasal rapamycin prevented weight loss in mice treated with SEB. Weights of mice (n = 9 or n = 10) exposed to SEB and SEB plus rapamycin (0.16 mg/kg) at different time points after SEB exposure. Group identifiers are identical to those in Table 1. Points represent the average % weight change ± SD for each group. Grey arrow indicates time of SEB exposure and black arrows represent time of rapamycin administration for the SEB + R17h3d group.
Mentions: Weight loss is another prominent indicator of SEB-induced shock in other animal models of superantigen-induced disease [16]. We therefore examined the effect of rapamycin on the weight of animals after intranasal SEB. SEB-exposed mice experienced weight loss of 3%–7% at 53 h with drastic weight reduction over time. Most of the rapamycin-treated, SEB-exposed mice had 1% change in weight with some groups of mice gaining weight at later times (Figure 3). Mice receiving only two doses of rapamycin starting at 17 h (SEB + R17hd2) had 8% weight loss and weight remained at this level after 53 h (70% survival). Protection against temperature and weight fluctuations essentially paralleled the lethality data.

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