Published ahead of print on April 12, 2007, doi:10.1164/rccm.200609-1279OC Am. J. Respir. Crit. Care Med., Volume 176, Number 1, July 2007, 78-89 A more recent version of this article appeared on July 1, 2007
Submitted on September 8, 2006 Important Roles for M-CSF, CCL2 and Mononuclear Phagocytes in the Pathogenesis of Pulmonary FibrosisChristopher P Baran1,1 Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA, 2 Division of Pulmonary, Critical Care, and Occupational Medicine, The University of Iowa College of Medicine, Iowa City, IA, USA, 3 Center for Cell and Vascular Biology, Children's Research Institute, Columbus, OH, USA, 4 Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA * To whom correspondence should be addressed. 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 CCL2, are elevated in bronchoalveolar lavage (BAL) fluid 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. Objective: To investigate the role of mononuclear phagocytes and M-CSF in pulmonary fibrosis. Methods: Wild-type, M-CSF (-/-), or CCL2 (-/-) mice received intra-peritoneal bleomycin. Lung inflammation and fibrosis were measured by immunohistochemistry, ELISA, collagen assay, BAL differentials, Real-Time PCR, and Western blot analysis. Human and mouse macrophages were stimulated with M-CSF for CCL2 expression. BAL fluid from IPF patients 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 following bleomycin administration than wild-type littermates. Human and mouse macrophages stimulated with M-CSF had increased CCL2 production, and intra-tracheal administration of M-CSF in mice induced CCL2 production in BAL fluid. Finally, BAL fluid from patients with IPF contained significantly more M-CSF and CCL2 than BAL fluid from normal volunteers. Elevated levels of M-CSF were associated with elevated CCL2 in BAL fluid 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: M-CSF, CCL2, mononuclear phagocytes, pulmonary fibrosis, bleomycin
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