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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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Survival analysis of Staphylococcal enterotoxin B (SEB)-exposed mice treated with intranasal rapamycin. Number of animals and schedule of treatment are identical to those presented in Table 1.
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toxins-04-00718-f001: Survival analysis of Staphylococcal enterotoxin B (SEB)-exposed mice treated with intranasal rapamycin. Number of animals and schedule of treatment are identical to those presented in Table 1.

Mentions: We previously established that rapamycin was effective in attenuating the biological effects of SEB in vitro and that multiple dosing schedule of intraperitoneal rapamycin protected mice from SEB-induced shock [32]. Due to the potency of rapamycin by the i.p. route, we investigated if lower doses of rapamycin administered only by the intranasal route would be protective against SEB-induced toxic shock. We explored the therapeutic window of treatment by administrating rapamycin at increasing intervals after SEB exposure. Intranasal administration of rapamycin (0.16 mg/kg) at 5 h after SEB followed by the same dose i.n. at 24, 48, 72, 96 h (R5h5d) protected mice 100% (Table 1). Only 22% survival was recorded if intranasal rapamycin was delayed to 24 h after SEB (R245d). However, starting rapamycin at 5 h after SEB exposure but using one less dose was 100% effective (R5h4d). Importantly, low intranasal doses of rapamycin administered as late as 17 h after SEB exposure followed by doses at 23, 41 h was still 100% protective (R17h3d). The last dose at 41 h was necessary using this schedule of treatment, as eliminating this dose yielded only 70% survival. Kaplan Meier survival analysis (Figure 1) shows rapamycin extended survival times even in unprotected animals. Clinical signs of intoxication such as ruffled fur and lethargy observed with SEB-treated mice starting at 72 h were completely absent from the SEB plus rapamycin group.


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

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

Survival analysis of Staphylococcal enterotoxin B (SEB)-exposed mice treated with intranasal rapamycin. Number of animals and schedule of treatment are identical to those presented in Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

toxins-04-00718-f001: Survival analysis of Staphylococcal enterotoxin B (SEB)-exposed mice treated with intranasal rapamycin. Number of animals and schedule of treatment are identical to those presented in Table 1.
Mentions: We previously established that rapamycin was effective in attenuating the biological effects of SEB in vitro and that multiple dosing schedule of intraperitoneal rapamycin protected mice from SEB-induced shock [32]. Due to the potency of rapamycin by the i.p. route, we investigated if lower doses of rapamycin administered only by the intranasal route would be protective against SEB-induced toxic shock. We explored the therapeutic window of treatment by administrating rapamycin at increasing intervals after SEB exposure. Intranasal administration of rapamycin (0.16 mg/kg) at 5 h after SEB followed by the same dose i.n. at 24, 48, 72, 96 h (R5h5d) protected mice 100% (Table 1). Only 22% survival was recorded if intranasal rapamycin was delayed to 24 h after SEB (R245d). However, starting rapamycin at 5 h after SEB exposure but using one less dose was 100% effective (R5h4d). Importantly, low intranasal doses of rapamycin administered as late as 17 h after SEB exposure followed by doses at 23, 41 h was still 100% protective (R17h3d). The last dose at 41 h was necessary using this schedule of treatment, as eliminating this dose yielded only 70% survival. Kaplan Meier survival analysis (Figure 1) shows rapamycin extended survival times even in unprotected animals. Clinical signs of intoxication such as ruffled fur and lethargy observed with SEB-treated mice starting at 72 h were completely absent from the SEB plus rapamycin group.

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