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Abstract
The invasion of activated fibroblasts is a key mechanism of tissue fibrosis pathology. The recognition and uptake of apoptotic cells can induce the anti-fibrogenic programming of macrophages. We demonstrate that after interacting with apoptotic cells, macrophages secrete bioactive molecules that antagonize TGF-β1-induced increases in myofibroblast (fibroproliferative) phenotypic markers and reduce the enhanced invasive capacity of TGF-β1- or EGF-treated mouse lung fibroblasts (MLg). Furthermore, numerous treatment strategies prevented the anti-fibrotic effects of conditioned media, including transfection of macrophages with COX-2 or RhoA siRNAs or treatment of MLg cells with receptor antagonists for prostaglandin E2 (PGE2), PGD2, or hepatocyte growth factor (HGF). Additionally, administration of apoptotic cells in vivo inhibited the bleomycin-mediated invasive capacity of primary fibroblasts, as well as adhesion and extracellular matrix protein mRNA expression. These data suggest that the anti-fibrogenic programming of macrophages by apoptotic cells can be used as a novel tool to control the progressive fibrotic reaction.
Highlights
Pulmonary fibrosis is a progressive and lethal disease characterized by the excessive deposition of extracellular matrix (ECM) components, such as collagens I and III, fibronectin, and lamin, in the lung parenchyma and distal airspace
We examined whether the interaction of macrophages and apoptotic cells can counteract the Transforming growth factor-β (TGF-β)-induced fibroblast activation leading to ECM deposition in organ fibrosis
We first demonstrated that the TGF-β1-induced increases in the expression of myofibroblast phenotypic markers, including α-SMA, type 1 collagen α2, and fibronectin, in mouse lung fibroblasts (MLg) lung fibroblasts and primary isolated lung fibroblasts was inhibited by the addition of conditioned medium (CM) from macrophages exposed to apoptotic cells
Summary
Pulmonary fibrosis is a progressive and lethal disease characterized by the excessive deposition of extracellular matrix (ECM) components, such as collagens I and III, fibronectin, and lamin, in the lung parenchyma and distal airspace. The pathogenic mechanisms leading to IPF have not been fully elucidated, dysregulation of apoptosis and ageing appears to be the major driving forces [2, 3]. Both the incidence and prevalence of IPF markedly increase with advancing age [3, 4]. Associated interstitial pneumonia in both mice and humans may represent a prominent reason for development of lung fibrosis [5] This excessive fibroblast accumulation depends on fibroblast migration to the site of tissue injury and invasion of the ECM [6]. Fibroblast invasion from the lung interstitium into the airspaces is a general feature of fibrosis progression [4, 7]
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