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 1α, 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.
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1 July 1998
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July 01 1998
The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness
Jose-Angel Gonzalo,
Jose-Angel Gonzalo
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Clare M. Lloyd,
Clare M. Lloyd
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Danyi Wen,
Danyi Wen
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Juan P. Albar,
Juan P. Albar
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Timothy N.C. Wells,
Timothy N.C. Wells
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Amanda Proudfoot,
Amanda Proudfoot
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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C. Martinez-A,
C. Martinez-A
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Martin Dorf,
Martin Dorf
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Torbjörn Bjerke,
Torbjörn Bjerke
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Anthony J. Coyle,
Anthony J. Coyle
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Jose-Carlos Gutierrez-Ramos
Jose-Carlos Gutierrez-Ramos
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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Jose-Angel Gonzalo
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Clare M. Lloyd
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Danyi Wen
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Juan P. Albar
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Timothy N.C. Wells
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Amanda Proudfoot
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
C. Martinez-A
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Martin Dorf
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Torbjörn Bjerke
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Anthony J. Coyle
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
Jose-Carlos Gutierrez-Ramos
From *Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; the ‡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
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: [email protected]
This work was partially funded by Astra Draco AB.
Received:
December 11 1997
Revision Received:
April 06 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (1): 157–167.
Article history
Received:
December 11 1997
Revision Received:
April 06 1998
Citation
Jose-Angel Gonzalo, Clare M. Lloyd, Danyi Wen, Juan P. Albar, Timothy N.C. Wells, Amanda Proudfoot, C. Martinez-A, Martin Dorf, Torbjörn Bjerke, Anthony J. Coyle, Jose-Carlos Gutierrez-Ramos; The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness . J Exp Med 1 July 1998; 188 (1): 157–167. doi: https://doi.org/10.1084/jem.188.1.157
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