The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/7/157/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 1, July 1, 1998 157-167

Articles

The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness

Jose-Angel Gonzalo*, Clare M. Lloyd*, Danyi Wen*, Juan P. Albar{ddagger}, Timothy N.C. Wells§, Amanda Proudfoot§, C. Martinez-A{ddagger}, Martin Dorf||, Torbjörn Bjerke, Anthony J. Coyle*, and Jose-Carlos Gutierrez-Ramos*

From * Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the {ddagger} Centro Nacional Biotecnologia Consejo Superior Investigaciones Cientificas, Madrid, 28049 Spain; the § Glaxo Institute for Molecular Biology, Geneva, CH1228 Switzerland; the || Harvard Medical School, Boston, Massachusetts 02115; and Astra Draco AB, S-22100 Lund, Sweden

The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of chemokines. Here, we have assessed the role that different chemokines play in lung allergic inflammation and BHR by blocking their activities in vivo. Our results show that blockage of each one of these chemokines reduces both lung leukocyte infiltration and BHR in a substantially different way. Thus, eotaxin neutralization reduces specifically BHR and lung eosinophilia transiently after each antigen exposure. Monocyte chemoattractant protein (MCP)-5 neutralization abolishes BHR not by affecting the accumulation of inflammatory leukocytes in the airways, but rather by altering the trafficking of the eosinophils and other leukocytes through the lung interstitium. 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 well as mRNA expression of eotaxin and RANTES. In contrast, neutralization of one of the ligands for RANTES receptors, macrophage-inflammatory protein 1{alpha}, reduces only slightly lung eosinophilia and BHR. Finally, MCP-1 neutralization diminishes drastically BHR and inflammation, and this correlates with a pronounced decrease in monocyte- and lymphocyte-derived inflammatory mediators. These results suggest that different chemokines activate different cellular and molecular pathways that in a coordinated fashion contribute to the complex pathophysiology of asthma, and that their individual blockage results in intervention at different levels of these processes.

Key Words: chemokines • allergic inflammation • bronchial hyperresponsiveness • eosinophilia • leukocytes

Address correspondence to J.-C. Gutierrez-Ramos, Millennium Pharmaceuticals, Inc., 640 Memorial Dr., Cambridge, MA 02139. Phone: 617-679-7262; Fax: 617-374-9379; E-mail: gutierrez{at}mpi.com

This work was partially funded by Astra Draco AB.

Abbreviations used: BAL, bronchoalveolar lavage; BHR, bronchial hyperresponsiveness; Eot, eotaxin; LT, leukotriene; MCP, monocyte chemoattractant protein; Met-RANTES, methionylated RANTES; MIP, macrophage-inflammatory protein; OVA, ovalbumin; RANTES, regulated upon activation, normal T cell expressed and secreted; RPA, RNase protection assay; TX, thromboxane.


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