Important roles for macrophage colony-stimulating factor, CC chemokine ligand 2, and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis.

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.