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(American Journal of Pathology. 2007;170:843-854.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.051213

Essential Roles of the CC Chemokine Ligand 3-CC Chemokine Receptor 5 Axis in Bleomycin-Induced Pulmonary Fibrosis through Regulation of Macrophage and Fibrocyte Infiltration

Yuko Ishida^*, Akihiko Kimura^*, Toshikazu Kondo^*, Takahito Hayashi^*, Masaya Ueno, Nobuyuki Takakura, Kouji Matsushima and Naofumi Mukaida

From the Department of Forensic Medicine,^* Wakayama Medical University, Wakayama; the Divisions of Molecular Bioregulation and Stem Cell Biology, Kanazawa University, Cancer Research Institute, Kanazawa; and the Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

We investigated the pathogenic roles of CC chemokine ligand (CCL)3 and its receptors, CC chemokine receptor (CCR)1 and CCR5, in bleomycin (BLM)-induced pulmonary fibrosis (PF). An intratracheal injection of BLM into wild-type (WT) mice caused a massive infiltration of granulocytes and macrophages, followed by the development of diffuse PF with fibrocyte accumulation. Intrapulmonary CCL3 expression was enhanced rapidly and remained at elevated levels until PF developed. Moreover, CCL3 protein was detected mainly in infiltrating granulocytes and macrophages, whereas transforming growth factor-ß1 protein was detected in macrophages and myofibroblasts. Compared with WT mice, collagen accumulation was reduced in CCL3^–/– and CCR5^–/– but not CCR1^–/– mice. Moreover, the BLM-induced increases in intrapulmonary macrophage and fibrocyte numbers were attenuated in CCL3^–/– and CCR5^–/– but not CCR1^–/– mice, although BLM increased bone marrow (BM) fibrocyte number to a similar extent in these strains. BM transplantation from CCR5^–/– to WT, but not that from WT to CCR5^–/– mice, recapitulated the phenotypes in CCR5^–/– mice. Furthermore, CCR5^+/– mice exhibited a significant reduction in BLM-induced fibrotic changes. These results demonstrated that locally produced CCL3 was involved in BLM-induced recruitment of BM-derived macrophages and fibrocytes, main producers of transforming growth factor-ß1, and subsequent development of PF by interacting mainly with CCR5.

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