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While the transcription factor forkhead box M1 (FOXM1) is well known as a proto-oncogene, its potential role in lung fibroblast activation has never been explored. Here, we show that FOXM1 is more highly expressed in fibrotic than in normal lung fibroblasts in humans and mice. FOXM1 was required not only for cell proliferation in response to mitogens, but also for myofibroblast differentiation and apoptosis resistance elicited by TGF-[beta]. The lipid mediator [PGE.sub.2], acting via cAMP signaling, was identified as an endogenous negative regulator of FOXM1. Finally, genetic deletion of FOXM1 in fibroblasts or administration of the FOXM1 inhibitor Siomycin A in a therapeutic protocol attenuated bleomycin-induced pulmonary fibrosis. Our results identify FOXM1 as a driver of lung fibroblast activation and underscore the therapeutic potential of targeting FOXM1 for pulmonary fibrosis., Introduction Substantial morbidity and mortality are attributable to fibro-proliferative disorders that impair function of vital organs (1). Fibrotic remodeling of the lung parenchyma is observed in a variety of interstitial [...]

Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment., Introduction Organ function depends upon a connective tissue stromal network that imparts topographic integrity by precisely ordering cellular and tissue compartments. The stroma consists of cells and their extracellular matrix [...]

The use of induced pluripotent stem cells (iPSCs) has been postulated to be the most effective strategy for developing patient-specific respiratory epithelial cells, which may be valuable for lung-related cell [...]

Plasminogen activation to plasmin protects from lung fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. We found that mice lacking plasminogen activation inhibitor-1 (PAI-1), which are protected from bleomycin-induced pulmonary fibrosis, exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin [E.sub.2] ([PGE.sub.2]). Plasminogen activation upregulated [PGE.sub.2] synthesis in alveolar epithelial cells, lung fibroblasts, and lung fibrocytes from saline- and bleomycin-treated mice, as well as in normal fetal and adult primary human lung fibroblasts. This response was exaggerated in cells from [Pai1.sup.[-/-]] mice. Although enhanced [PGE.sub.2] formation required the generation of plasmin, it was independent of proteinase-activated receptor 1 (PAR-1) and instead reflected proteolytic activation and release of HGF with subsequent induction of COX-2. That the HGF/COX-2/[PGE.sub.2] axis mediates in vivo protection from fibrosis in Pai1 / mice was demonstrated by experiments showing that a selective inhibitor of the HGF receptor c-Met increased lung collagen to WT levels while reducing COX-2 protein and [PGE.sub.2] levels. Of clinical interest, fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce COX-2 and, therefore, unable to upregulate [PGE.sub.2] synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and [PGE.sub.2] generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway., Introduction In patients with acute and chronic fibrotic lung diseases, fibrin forms within the lung due to a leakage of plasma from damaged vasculature and activation of the coagulation cascade. [...]