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/ mice: implications for
fibroproliferation
1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109; and 2 Pulmonary Section of the Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48108
Prostaglandin
E2 (PGE2) is a potent suppressor of fibroblast
activity. We previously reported that bleomycin-induced pulmonary fibrosis was exaggerated in granulocyte-macrophage
colony-stimulating factor knockout (GM-CSF
/) mice
compared with wild-type (GM-CSF+/+) mice and that increased
fibrosis was associated with decreased PGE2 levels in lung
homogenates and alveolar macrophage cultures. Pulmonary fibroblasts and
alveolar epithelial cells (AECs) represent additional cellular sources
of PGE2 within the lung. Therefore, we examined fibroblasts
and AECs from GM-CSF/ mice, and we found that they
elaborated significantly less PGE2 than did cells from
GM-CSF+/+ mice. This defect was associated with reduced
expression of cyclooxygenase-1 and -2 (COX-1 and COX-2), key enzymes in
the biosynthesis of PGE2. Additionally, proliferation of
GM-CSF/ fibroblasts was greater than that of
GM-CSF+/+ fibroblasts, and GM-CSF/ AECs
were impaired in their ability to inhibit fibroblast proliferation in
coculture. The addition of GM-CSF to fibroblasts from
GM-CSF/ mice increased PGE2 production and
decreased proliferation. Similarly, AECs isolated from
GM-CSF/ mice with transgenic expression of GM-CSF under
the surfactant protein C promoter (SpC-GM mice) produced more
PGE2 than did AEC from control mice. Finally, SpC-GM mice
were protected from fluorescein isothiocyanate-induced pulmonary
fibrosis. In conclusion, these data demonstrate that GM-CSF regulates
PGE2 production in pulmonary fibroblasts and AECs and thus
plays an important role in limiting fibroproliferation.
granulocyte-macrophage colony-stimulating factor; idiopathic pulmonary fibrosis; cyclooxygenase-1; cyclooxygenase-2
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