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The Efficacy of TNF Blockade in Asthma Models Depends on Endotoxin Levels in the Allergic Challenge

¹ Department of Pharmacology, Abbott Bioresearch Center, Worcester, Massachusetts

Correspondence and requests for reprints should be addressed to Andrew J. Long, Ph.D., Abbott Bioresearch Center, 100 Research Dr., Worcester, MA 01605. E-mail: andrew.long{at}abbott.com

TNF is a proinflammatory cytokine whose expression is increased in lung tissue of patients with asthma. However, the contribution of TNF to the pathophysiology of asthma is controversial, as clinical trials with anti-TNF agents have generated both positive and negative results. To gain a better understanding of the potential role for TNF in the asthmatic phenotype, we tested the effects of an anti-mouse TNF antibody in ovalbumin (OVA)-induced mouse models with varying levels of endotoxin. Endotoxin-free OVA challenge induces airway hyperresponsiveness (AHR) to methacholine, and inflammation of the lung composed predominantly of eosinophil and T cell infiltrate and Th2 cytokines. Treatment of animals with anti-TNF antibody had no effect on AHR or cellular inflammation, whereas treatment with the steroid dexamethasone administered at 3 mg/kg/day during the OVA challenge period completely inhibited these responses. Addition of LPS (1, 10, and 100 ng) to the endotoxin-free OVA augmented airway hyperresponsiveness and resulted in an increased total cellularity within the airways in a dose-dependent manner that maintained the relative proportion of eosinophils, T cells, and neutrophils that is characteristic of allergic inflammation. Treatment of OVA + LPS (100 ng) groups with an anti-TNF antibody was able to partially inhibit AHR and cell infiltrate down to the level induced by OVA challenge alone. Steroid treatment inhibited AHR and cell infiltrate down to baseline. These data indicate that the pathogenic mechanisms in the OVA-induced animal models differ based on the level of endotoxin in the OVA preparation. Furthermore, the pathogenic role of TNF in patients with asthma may differ depending on the underlying etiology of the disease and may play a more prominent role in patients with an environmental exposure to endotoxin.

FOOTNOTES

All experiments were performed under the support of Abbott Laboratories.

Conflict of Interest Statement: A.J.L. is an employee of Abbott Laboratories. R.M. is an employee of Abbott Laboratories. L.R. is an employee of Abbott Laboratories. C.G. is employed by Abbott Laboratories October 2001 to the present. C.A.C. is employed by Abbott and receives direct compensation and stock options as a result.

(Received in original form June 2, 2008; accepted in final form November 4, 2008)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Long, A. J. Articles by Cuff, C. A. Search for Related Content PubMed Articles by Long, A. J. Articles by Cuff, C. A.