Am. J. Respir. Crit. Care Med., Volume 159, Number 2, February 1999, 580-587

TRFK-5 Reverses Established Airway Eosinophilia But Not Established Hyperresponsiveness in a Murine Model of Chronic Asthma

MUDIT MATHUR, KARIN HERRMANN, XIANTANG LI, YIMIN QIN, JOEL WEINSTOCK, DAVID ELLIOTT, JOSEPH MONAHAN, and PHILIP PADRID

Section of Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, and the Committees on Immunology, and Comparative Medicine and Pathology, Division of the Biological Sciences, The University of Chicago, Chicago, Illinois; Department of Medicine, University of Iowa, Ames, Iowa; and the Monsanto Corp., St. Louis, Missouri

We studied the effects of an anti-interleukin (IL)-5 monoclonal antibody (TRFK-5) or dexamethasone (DEX) to reverse already established airway hyperresponsiveness (AHR) and tissue eosinophilia in a Schistosoma mansoni antigen-sensitized and airway-challenged mouse model of chronic asthma. In this model at 4 d after antigen challenge there is dramatic bronchoalveolar lavage fluid (BAL) eosinophilia, AHR to intravenous methacholine (MCh), and histologic evidence of peribronchial eosinophilic infiltration and mucoid cell hyperplasia. These changes persist for up to 2 wk after antigen challenge. Treatment with DEX from Days 4 through 10 significantly reduced established airway eosinophilia compared with animals sham-treated with saline from Days 4 -10 (120 ± 29 eosinophils/µl BAL for DEX-treated mice versus 382 ± 60 eosinophils/µl BAL for sham-treated animals, p < 0.01). DEX-treated mice also had dramatically reduced mucoid cell hyperplasia, and airway responsiveness returned to normal. In contrast, TRFK-5 given during the same time period reduced airway eosinophilia (86 ± 32 eosinophils/µl BAL versus 382 ± 60 eosinophils/µl BAL, p < 0.01) but did not reduce goblet cell hyperplasia or reverse already established AHR. Treatment with DEX but not TRFK-5 also inhibited interferon gamma (IFN-) content of BAL fluid (0.49 ± 0.09 ng/ml BAL fluid for DEX versus 1.50 ± 0.24 ng/ml BAL fluid and 1.36 ± 0.13 ng/ml BAL fluid for TRFK-5 and sham-treated mice, respectively, both p < 0.001 versus DEX). Thus, treatment with DEX reduces established eosinophilic airway inflammation and AHR in S. mansoni-sensitized and airway-challenged mice but treatment with TRFK-5 reversed established eosinophilia without ameliorating established AHR. Together, these data suggest that once airway inflammation develops, neutralizing the effects of IL-5 or reducing eosinophilia alone may not result in inhibiting established AHR in atopic asthma.

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