Published ahead of print on August 17, 2006, doi:10.1165/rcmb.2006-0188OC
© 2007 American Thoracic Society DOI: 10.1165/rcmb.2006-0188OC Effects of a Low-Molecular-Weight CCR-3 Antagonist on Chronic Experimental AsthmaDepartment of Clinical Chemistry and Molecular Diagnostics, Hospital of the Philipps-University, Marburg; and Department of Pulmonary Research, Boehringer Ingelheim Pharma GmbH, Biberach, Germany Correspondence and requests for reprints should be addressed to Michael Wegmann, Ph.D., Department of Clinical Chemistry and Molecular Diagnostics, Biomedical Research Center (BMFZ), Hospital of the Philipps-University Marburg, Baldingerstrasse, 35033 Marburg, Germany. E-mail: wegmann{at}med.uni-marburg.de Eosinophils represent one of the main effector cell populations of allergic airway inflammation and allergic bronchial asthma. Their infiltration correlates with many characteristics of the disease, including airway hyperresponsiveness (AHR) and increased mucus production. CCR-3 is the principle chemokine receptor involved in eosinophil attraction into inflamed tissue. Therefore, antagonizing CCR-3 could be a novel promising approach toward asthma therapy. We investigated the effect of a low-molecular-weight CCR-3 antagonist on established airway inflammation in a chronic model of experimental bronchial asthma. For this purpose, BALB/c mice intraperitoneally sensitized with ovalbumin (OVA) were chronically challenged with OVA aerosol to induce chronic airway inflammation and airway remodeling. The effect of antagonizing CCR-3 on asthma pathology was examined in BAL and lung histology. Airway reactivity was assessed by head-out body plethysmography. Treatment with the CCR-3 antagonist resulted in a marked reduction of eosinophils in the bronchoalveolar lumen and in airway wall tissue, whereas infiltration of lymphocytes or macrophages remained unchanged. The reduction in eosinophil infiltration was accompanied by normalization of AHR and prevention of goblet cell hyperplasia, indicating reduced mucus production. Furthermore, antagonizing CCR-3 prevented airway remodeling as defined by subepithelial fibrosis and increased accumulation of myofibrocytes in the airway wall of chronically challenged mice. These data demonstrate that antagonism of CCR3 reduces eosinophil numbers, which is accompanied by diminution of asthma pathology in a mouse model of established chronic experimental asthma. Therefore, antagonizing CCR-3 represents a new approach toward a promising asthma therapy.
Key Words: CCR-3 • chronic asthma • eosinophils • remodeling
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