TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P

The pleiotropic growth factor TGF beta(1) promotes many of the pathogenic mechanisms observed in lung fibrosis and airway remodeling, such as aberrant extracellular matrix deposition due to both fibroblast activation and fibroblast to myofibroblast differentiation. Serum amyloid P (SAP), a member of the pentraxin family of proteins inhibits bleomycin-induced lung fibrosis through an inhibition of pulmonary fibrocyte and pro-fibrotic alternative (M2) macrophage accumulation. It is unknown if SAP has effects downstream of TGF beta(1), a major mediator of pulmonary fibrosis. Using the lung specific TGF beta(1) transgenic mouse model, we determined that SAP inhibits all of the pathologies driven by TGF beta(1) including apoptosis, airway inflammation, pulmonary fibrocyte accumulation and collagen deposition, without affecting levels of TGF beta(1). To explore the role of monocyte derived cells in this model we used liposomal clodronate to deplete pulmonary macrophages. This led to pronounced anti-fibrotic effects that were independent of fibrocyte accumulation. Administration of SAP mirrored these effects and reduced both pulmonary M2 macrophages and increased chemokine IP10/CXCL10 expression in a SMAD 3-independent manner. Interestingly. SAP concentrations were reduced in the circulation of IPF patients and correlated with disease severity. Last, SAP directly inhibited M2 macrophage differentiation of monocytes obtained from these patients. These data suggest that the beneficial anti-fibrotic effects of SAP in TGF beta(1)-induced lung disease are via modulating monocyte responses. (C) 2010 Elsevier Ltd. All rights reserved.