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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 attenuated the hypothermic response of mice treated with SEB. Body temperatures 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 means ± 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-f002: Intranasal rapamycin attenuated the hypothermic response of mice treated with SEB. Body temperatures 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 means ± 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: Additional data were collected regarding temperature fluctuations in mice treated with SEB and those treated with SEB plus intranasal rapamycin given at various times after SEB (Figure 2). Mice given SEB experienced hypothermia starting at 48 h. This hypothermic response, indicating systemic shock that mimicked those found in other murine models [26,33,34], was completely absent in rapamycin-treated SEB-exposed mice. Reducing the duration of treatment with rapamycin to 72 h also protected mice from hyperthermia if treatment was started at 5 h (SEB + R5h4d). However, delaying treatment with rapamycin until 24 h resulted in shock like symptoms and hyperthermia (SEB + R24h5d). We progressively adjusted the time between the exposure of mice to SEB and rapamycin treatment to determine the maximum therapeutic window. A protective regimen of rapamycin starting at 17 h after SEB exposure followed by two other intranasal doses at 23 and 41 h also did not result in hypothermia. Clearly, rapamycin-treated and protected mice had minor temperature changes during the entire observation period.


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

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

Intranasal rapamycin attenuated the hypothermic response of mice treated with SEB. Body temperatures 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 means ± 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-f002: Intranasal rapamycin attenuated the hypothermic response of mice treated with SEB. Body temperatures 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 means ± 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: Additional data were collected regarding temperature fluctuations in mice treated with SEB and those treated with SEB plus intranasal rapamycin given at various times after SEB (Figure 2). Mice given SEB experienced hypothermia starting at 48 h. This hypothermic response, indicating systemic shock that mimicked those found in other murine models [26,33,34], was completely absent in rapamycin-treated SEB-exposed mice. Reducing the duration of treatment with rapamycin to 72 h also protected mice from hyperthermia if treatment was started at 5 h (SEB + R5h4d). However, delaying treatment with rapamycin until 24 h resulted in shock like symptoms and hyperthermia (SEB + R24h5d). We progressively adjusted the time between the exposure of mice to SEB and rapamycin treatment to determine the maximum therapeutic window. A protective regimen of rapamycin starting at 17 h after SEB exposure followed by two other intranasal doses at 23 and 41 h also did not result in hypothermia. Clearly, rapamycin-treated and protected mice had minor temperature changes during the entire observation period.

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