ENHANCED EXPRESSION OF EOTAXIN AND CCR3 MESSENGER-RNA AND PROTEIN IN ATOPIC ASTHMA - ASSOCIATION WITH AIRWAY HYPERRESPONSIVENESS AND PREDOMINANT COLOCALIZATION OF EOTAXIN MESSENGER-RNA TO BRONCHIAL EPITHELIAL AND ENDOTHELIAL-CELLS

Eotaxin is a newly discovered C-C chemokine which preferentially attra cts and activates eosinophil leukocytes by acting specifically on its receptor CCR3. The airway inflammation characteristic of asthma is bel ieved to be, at least in part, the result of eosinophil-dependent tiss ue injury. This study was designed to determine whether there is incre ased expression of eotaxin and CCR3 in the bronchial mucosa of asthmat ics and whether this is associated with disease severity. The major so urces of eotaxin and CCR3 mRNA were determined by colocalization exper iments. Bronchial mucosal biopsy samples were obtained from atopic ast hmatics and normal non-atopic controls. Eotaxin and CCR3 mRNA were ide ntified in tissue sections by in situ hybridization (ISH) using radiol abeled riboprobes and their protein product visualized by immunohistoc hemistry (IHC). Co-localization experiments were performed by double I SH/IHC. Eotaxin and CCR3 (mRNA and protein) were significantly elevate d in atopic asthmatics compared with normal controls. In the asthmatic s there was a highly significant inverse correlation between eotaxin m RNA(+) cells and the histamine provocative concentration causing a 20% fall in FEV1 (PC20). Cytokeratin-positive epithelial cells and CD31() endothelial cells were the major source of eotaxin mRNA whereas CCR3 colocalized predominantly to eosinophils. These data are consistent w ith the hypothesis that damage to the bronchial mucosa in asthma invol ves secretion of eotaxin by epithelial and endothelial cells resulting in eosinophil infiltration mediated via CCR3. Since selective (eotaxi n) and non-selective C-C chemokines such as RANTES, MCP-3 and MCP-4 al l stimulate eosinophils via CCR3, this receptor is potentially a prime therapeutic target in the spectrum of diseases involving eosinophil-m ediated tissue damage.