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


OBJECTIVE
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.


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.
Baran
Christopher P
CP
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 43210, USA.
Opalek
Judy M
JM
McMaken
Sara
S
Newland
Christie A
CA
O'Brien
James M
JM
Hunter
Melissa G
MG
Bringardner
Benjamin D
BD
Monick
Martha M
MM
Brigstock
David R
DR
Stromberg
Paul C
PC
Hunninghake
Gary W
GW
Marsh
Clay B
CB
D000328:Adult; D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016022:Case-Control Studies; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010586:Phagocytes / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000503:physiopathology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D001761:Bleomycin; D016173:Macrophage Colony-Stimulating Factor