THE COORDINATED ACTION OF CC CHEMOKINES IN THE LUNG ORCHESTRATES ALLERGIC INFLAMMATION AND AIRWAY HYPERRESPONSIVENESS

The complex pathophysiology of lung allergic inflammation and bronchia l hyperresponsiveness (BHR) chat characterize asthma is achieved by th e regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes corre late with the coordinated production of chemokines. Here, we have asse ssed the role that different chemokines play in lung allergic inflamma tion and BHR by blocking their activities in vivo. Our results show th at blockage of each one of these chemokines reduces both lung leukocyt e infiltration and BHR in a substantially different way. Thus, eotaxin neutralization reduces specifically BHR and lung eosinophilia transie ntly after each antigen exposure. Monocyte chemoattractant protein (MC P)-5 neutralization abolishes BHR not by affecting the accumulation of inflammatory leukocytes in the airways, but rather by altering the tr afficking of the eosinophils and other leukocytes through the lung int erstitium. Neutralization of RANTES (regulated upon activation, normal T cell expressed and secreted) receptor(s) with a receptor antagonist decreases significantly lymphocyte and eosinophil infiltration as wel l as mRNA expression of eotaxin and RANTES. In contrast, neutralizatio n of one of the ligands for RANTES receptors, macrophage-inflammatory protein 1 alpha, reduces only slightly lung eosinophilia and BHR. Fina lly, MCP-1 neutralization diminishes drastically BHR and inflammation, and this correlates with a pronounced decrease in monocyte- and lymph ocyte-derived inflammatory mediators. These results suggest that diffe rent chemokines activate different cellular and molecular pathways tha t in a coordinated fashion contribute to die complex pathophysiology o f asthma, and that their individual blockage results in intervention a t different levels of these processes.