title: The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness.
abstract: 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 1alpha, 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.
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Gonzalo
authors.forename: C M
authors.initials: CM
authors.lastname: Lloyd
authors.forename: D
authors.initials: D
authors.lastname: Wen
authors.forename: J P
authors.initials: JP
authors.lastname: Albar
authors.forename: T N
authors.initials: TN
authors.lastname: Wells
authors.forename: A
authors.initials: A
authors.lastname: Proudfoot
authors.forename: C
authors.initials: C
authors.lastname: Martinez-A
authors.forename: M
authors.initials: M
authors.lastname: Dorf
authors.forename: T
authors.initials: T
authors.lastname: Bjerke
authors.forename: A J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: J C
authors.initials: JC
authors.lastname: Gutierrez-Ramos
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001249:Asthma / Q000503:physiopathology; D054413:Chemokine CCL11; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000502:physiology*; D002631:Chemotactic Factors, Eosinophil / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D006967:Hypersensitivity / Q000276:immunology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018945:Monocyte Chemoattractant Proteins / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000906:Antibodies; C515457:Ccl11 protein, mouse; C491224:Ccl12 protein, mouse; D054413:Chemokine CCL11; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger; D010047:Ovalbumin