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Monocytes May Regulate Tissue Fibrosis*: Role of Reactive Oxygen Species in Monocyte Survival and in the Activation of Latent Transforming Growth Factor-β

Clay B. Marsh, MD; Todd W. Kelley, MS; Mandy M. Graham; Chunming Dong, PhD; Pascal J. Goldschmidt-Clermont, MD
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*From the Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH.

Correspondence to: Clay B. Marsh, MD, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, The Ohio State University, N325 Means Hall, 1654 Upham Dr, Columbus, OH 43210



Chest. 2001;120(1_suppl):S15-S16. doi:10.1378/chest.120.1_suppl.S15
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Pathologic samples from patients with idiopathic pulmonary fibrosis (IPF) show accumulations of monocytes and macrophages in the lung. Monocytes and macrophages recovered from the lungs of patients with IPF show enhanced survival of recently recruited, young monocyte/macrophages that spontaneously produce oxidants.14 Moreover, antioxidant strategies have been used successfully to treat patients with IPF.57 We previously demonstrated that the macrophage colony-stimulating factor (M-CSF) promoted monocyte survival through the activation of phosphatidylinositol 3-kinase (PI 3-K) and the serine threonine kinase Akt.8 M-CSF also promoted the production of reactive oxygen species (ROS) in human monocytes. ROS produced in M-CSF–stimulated monocytes were inhibited by PI 3-K inhibitors, flavoprotein inhibitors (diphenyleneiodonium [DPI]), or the intracellular superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin. Inhibiting the effects of these ROS resulted in apoptosis of monocytes, even in the presence of M-CSF. Moreover, PI 3-K inhibitors, DPI, and superoxide dismutase mimetic suppressed Erk activation in M-CSF–treated cells. Erk is known to be important in the production of urokinase plasminogen activator (uPA) in M-CSF–stimulated monocytes, which catalyzes the production of plasmin from plasminogen. Since plasmin is an important activator of latent transforming growth factor (TGF)-β, we next hypothesized that M-CSF–stimulated monocytes may also activate latent TGF-β. To test this hypothesis, human monocytes (5 × 106/condition) were left not stimulated or stimulated with M-CSF for 18 h and cell lysates and supernatants recovered. The samples were incubated with latent TGF-β (1 nmol) with the mink lung epithelial cells transfected with the TGF-β–sensitive plasminogen activator inhibitor-1 promoter with a luciferase reporter. Cell-free supernatants from M-CSF–stimulated monocytes incubated with latent TGF-β induced fourfold increase in luciferase activity vs all other conditions. The luciferase activity induced by supernatants from M-CSF–stimulated monocytes was suppressed by latency-associated peptide, which inhibits binding of active TGF-β to its receptor, suggesting that the luciferase activity was from active TGF-β. We are currently attempting to define the identity of these soluble factor(s) released in the monocyte supernatant, specifically focusing on uPA and plasmin. Although we do not know that uPA and plasmin are important for this effect, the flavoprotein inhibitor DPI and the PI 3-kinase inhibitor LY294002 also suppressed Erk activation in M-CSF–stimulated monocytes. These data provide a potential mechanism by which monocyte survival factors may regulate tissue fibrosis through activation of latent TGF-β, and provide insight on the potential role of ROS in facilitating fibrosis through promoting monocyte survival and Erk activation.

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