Monocyte chemoattractant protein-1 mediates cockroach allergen-induced bronchial hyperreactivity in normal but not CCR2-/- mice: the role of mast cells.
Bronchial eosinophil and mononuclear cell infiltrates are a hallmark of the asthmatic lung and are associated with the induction of reversible airway hyperreactivity. In these studies, we have found that monocyte chemotactic protein-1 (MCP-1), a CC (beta) chemokine, mediates airway hyperreactivity in normal and allergic mice. Using a murine model of cockroach Ag-induced allergic airway inflammation, we have demonstrated that anti-MCP-1 Abs inhibit changes in airway resistance and attenuate histamine release into the bronchoalveolar lavage, suggesting a role for MCP-1 in mast cell degranulation. In normal mice, instillation of MCP-1 induced prolonged airway hyperreactivity and histamine release. In addition, MCP-1 directly induced pulmonary mast cell degranulation in vitro. These latter effects would appear to be selective because no changes were observed when macrophage-inflammatory protein-1alpha, eotaxin, or MCP-3 were instilled into the airways of normal mice or when mast cells were treated in vitro. Airway hyperreactivity was mediated by MCP-1 through CCR2 because allergen-induced as well as direct MCP-1 instilled-induced changes in airway hyperreactivity were significantly attenuated in CCR2 -/- mice. The neutralization of MCP-1 in allergic animals and instillation of MCP-1 in normal animals was related to leukotriene C4 levels in the bronchoalveolar lavage and was directly induced in pulmonary mast cells by MCP-1. Thus, these data identify MCP-1 and CCR2 as potentially important therapeutic targets for the treatment of hyperreactive airway disease.
Campbell
E M
EM
Department of Pathology, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor 48109, USA.
Charo
I F
IF
Kunkel
S L
SL
Strieter
R M
RM
Boring
L
L
Gosling
J
J
Lukacs
N W
NW
D000281:Administration, Intranasal; D000403:Airway Resistance / Q000187:drug effects / Q000276:immunology; D000485:Allergens / Q000276:immunology*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000008:administration & dosage / Q000494:pharmacology*; D003058:Cockroaches / Q000276:immunology*; D005260:Female; D006636:Histamine Release / Q000276:immunology; D007117:Immunization, Secondary; D007274:Injections, Intraperitoneal; D007442:Intubation, Intratracheal; D017997:Leukotriene C4 / Q000096:biosynthesis; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics*; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics*
D000485:Allergens; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D017997:Leukotriene C4