Role of Eotaxin-1 (CCL11) and CC chemokine receptor 3 (CCR3) in bleomycin-induced lung injury and fibrosis.
Eotaxin-1/CCL11 and its receptor CCR3 are involved in recruitment of eosinophils to diverse tissues, but their role in eosinophil recruitment in pulmonary fibrosis is unclear. The present study examined the pulmonary expression of CCL11 and CCR3 during bleomycin (blm)-induced lung injury and determined their importance in the recruitment of inflammatory cells and the development of lung fibrosis. In mice, blm induced a marked pulmonary expression of CCL11 and CCR3. Immunostaining for CCR3 revealed that this receptor was not only expressed by eosinophils but also by neutrophils. CCL11-deficient (CCL11(-/-)) mice developed significantly reduced pulmonary fibrosis. Expression of profibrotic cytokines such as transforming growth factor-beta1 was diminished in the absence of CCL11. Furthermore, increased lung expression of CCL11 significantly enhanced blm-induced lung fibrosis and production of profibrotic cytokines. These effects were also associated with an increase of eosinophil and neutrophil pulmonary infiltration. In contrast, mice treated with neutralizing CCR3 antibodies developed significantly reduced pulmonary fibrosis, eosinophilia, neutrophilia, and expression of profibrotic cytokines. Together, these data suggest that CCL11 and CCR3 are important in the pulmonary recruitment of granulocytes and play significant pathogenic roles in blm-induced lung fibrosis.
Huaux
Francois
F
Unit of Industrial Toxicology and Occupational Medicine, Université Catholique de Louvain, Brussels, Belgium.
Gharaee-Kermani
M
M
Liu
Tianju
T
Morel
Valérie
V
McGarry
Bridget
B
Ullenbruch
Matt
M
Kunkel
Steven L
SL
Wang
Jun
J
Xing
Zhou
Z
Phan
Sem H
SH
D000818:Animals; D001483:Base Sequence; D001761:Bleomycin / Q000633:toxicity*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015342:DNA Probes; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism
C515456:CCL11 protein, human; C515350:CCR3 protein, human; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D015342:DNA Probes; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D001761:Bleomycin