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Infection and Immunity, June 2002, p. 2989-2994, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.2989-2994.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Pirfenidone Blocks the In Vitro and In Vivo Effects of Staphylococcal Enterotoxin B

Martha L. Hale,1* Solomon B. Margolin,2 Teresa Krakauer,1 Chad J. Roy,1 and Bradley G. Stiles1

Toxinology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702-5011,1 Marnac, Inc., Dallas, Texas 752252

Received 16 October 2001/ Returned for modification 4 February 2002/ Accepted 4 March 2002

Pirfenidone [5-methyl-1-phenyl-2-(1H)-pyridone] down-regulates expression of cytokines and other mediators involved in the onset and development of pulmonary fibrosis. Pirfenidone also inhibits production of tumor necrosis factor alpha (TNF-{alpha}) from macrophages incubated with endotoxin and protects mice against endotoxin shock. Pirfenidone's ability to reduce cytokine expression in these disorders led us to investigate the drug's effect on another cytokine anomaly, superantigen-induced shock. BALB/c mice were exposed to staphylococcal enterotoxin B (SEB) either systemically or by aerosol and subsequently potentiated with a sublethal dose of lipopolysaccharide. In these experiments, pirfenidone given 2 to 4.25 h after SEB resulted in 80 to 100% survival versus only 0 to 10% survival among untreated control animals. Relative to serum cytokine levels from controls given toxin but no drug, there was a 35 to 80% decrease in TNF-{alpha}, interleukin 1, and other proinflammatory cytokines. In vitro experiments with human peripheral blood lymphocytes revealed that pirfenidone reduced SEB-induced cytokine levels 50 to 80% and inhibited 95% of SEB-induced T-cell proliferation. Overall, these studies demonstrated the potential utility of pirfenidone as a therapeutic against septic shock and the biological effects of SEB.

* Corresponding author. Mailing address: Toxinology Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Fort Detrick, MD 21702-5011. Phone: (301) 619-7454. Fax: (301) 619-2348. E-mail: martha.hale{at}amedd.army.mil.

Editor: J. T. Barbieri

Infection and Immunity, June 2002, p. 2989-2994, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.2989-2994.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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