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Important Roles for Macrophage Colony-stimulating Factor, CC Chemokine Ligand 2, and Mononuclear Phagocytes in the Pathogenesis of Pulmonary Fibrosis

¹ Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the Dorothy M. Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio; ² Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa College of Medicine, Iowa City, Iowa; ³ Center for Cell and Vascular Biology, Children's Research Institute, Columbus, Ohio; and ⁴ Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio

Correspondence and requests for reprints should be addressed to Clay B. Marsh, M.D., 473 West 12th Avenue, Room 201, the Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH 43210. E-mail: clay.marsh{at}osumc.edu

Rationale: An increase in the number of mononuclear phagocytes in lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) worsens prognosis. Chemokines that recruit mononuclear phagocytes, such as CC chemokine ligand 2 (CCL2), are elevated in bronchoalveolar lavage (BAL) fluid (BALF) from patients with IPF. However, little attention is given to the role of the mononuclear phagocyte survival and recruitment factor, macrophage colony-stimulating factor (M-CSF), in pulmonary fibrosis.

Objectives: To investigate the role of mononuclear phagocytes and M-CSF in pulmonary fibrosis.

Methods: Wild-type, M-CSF^–/–, or CCL2^–/– mice received intraperitoneal bleomycin. Lung inflammation and fibrosis were measured by immunohistochemistry, ELISA, collagen assay, BAL differentials, real-time polymerase chain reaction, and Western blot analysis. Human and mouse macrophages were stimulated with M-CSF for CCL2 expression. BALF from patients with IPF was examined for M-CSF and CCL2.

Measurements and Main Results: M-CSF^–/– and CCL2^–/– mice had less lung fibrosis, mononuclear phagocyte recruitment, collagen deposition, and connective tissue growth factor (CTGF) expression after bleomycin administration than wild-type littermates. Human and mouse macrophages stimulated with M-CSF had increased CCL2 production, and intratracheal administration of M-CSF in mice induced CCL2 production in BALF. Finally, BALF from patients with IPF contained significantly more M-CSF and CCL2 than BALF from normal volunteers. Elevated levels of M-CSF were associated with elevated CCL2 in BALF and the diagnosis of IPF.

Conclusions: These data suggest that M-CSF contributes to the pathogenesis of pulmonary fibrosis in mice and in patients with IPF through the involvement of mononuclear phagocytes and CCL2 production.

Key Words: bleomycin • CC chemokine ligand 2 • macrophage colony-stimulating factor • mononuclear phagocytes • pulmonary fibrosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although mononuclear phagocytes have been shown to play an important role in pulmonary fibrosis, the mechanisms underlying their contributions have not been identified. What This Study Adds to the Field M-CSF contributes to the pathogenesis of pulmonary fibrosis in mice and in patients with IPF through the involvement of mononuclear phagocytes and CCL2 production.

 

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