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Essential Contribution of Monocyte Chemoattractant Protein-1/C-C Chemokine Ligand-2 to Resolution and Repair Processes in Acute Bacterial Pneumonia

Hideaki Amano^1,*, Kounosuke Morimoto^*, Masachika Senba, Hui Wang^¶, Yuko Ishida^¶, Atsushi Kumatori, Hiroyuki Yoshimine, Kazunori Oishi, Naofumi Mukaida^¶ and Tsuyoshi Nagatake

^* Department of Respiratory Medicine, Nijigaoka Hospital, Nagasaki, Japan; Departments of Internal Medicine, Pathology, and Biochemistry, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan; and ^¶ Division of Molecular Bioregulation, Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Isikawa, Japan

Neutrophil infiltration is the first step in eradication of bacterial infection, but neutrophils rapidly die after killing bacteria. Subsequent accumulation of macrophage lineage cells, such as alveolar macrophages (AMs), is essential to remove dying neutrophils, which are a source of injurious substances. Macrophage lineage cells can promote tissue repair, by producing potential growth factors including hepatocyte growth factor (HGF). However, it remains elusive which factor activates macrophage in these processes. Intratracheal instillation of Pseudomonas aeruginosa caused neutrophil infiltration in the airspace; subsequently, the numbers of total AMs and neutrophil ingested AMs were increased. Bronchoalveolar lavage (BAL) fluid levels of monocyte chemoattractant protein (MCP)-1/CC chemokine ligand-2 (CCL2), a potent macrophage-activating factor, were increased before the increases in the number of AM ingesting neutrophils and HGF levels in BAL fluid. Immunoreactive MCP-1 proteins were detected in alveolar type II epithelial cells and AMs only after P. aeruginosa infection. The administration of anti-MCP-1/CCL2 Abs reduced the increases in the number of AM-ingesting neutrophils and HGF levels in BAL fluid, and eventually aggravated lung tissue injury. In contrast, the administration of MCP-1/CCL2 enhanced the increases in the number of AM ingesting neutrophils and HGF levels in BAL fluid, and eventually attenuated lung tissue injury. Furthermore, MCP-1/CCL2 enhanced the ingestion of apoptotic neutrophils and HGF production by a mouse macrophage cell line, RAW 267.4, in a dose-dependent manner. Collectively, MCP-1/CCL2 has a crucial role in the resolution and repair processes of acute bacterial pneumonia by enhancing the removal of dying neutrophils and HGF production by AMs

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