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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. [...]

Myofibroblasts are pathogenic in pulmonary fibrotic disease due to their exuberant production of matrix rich in collagen that interferes with gas exchange and the ability of these cells to contract and distort the alveolar space. Transforming growth factor-[beta]1 (TGF-[beta]1) is a well-known inducer of myofibroblast differentiation. TGF-[beta]-induced transformation of fibroblasts to apoptosis-resistant myofibroblasts is adhesion-dependent and focal adhesion kinase (FAK)-mediated. Prostaglandin [E.sub.2] (PG[E.sub.2]) inhibits this differentiation via E prostanoid receptor 2 (EP2) signaling and cAMP elevation, but whether PG[E.sub.2] does so by interfering with TGF-[beta]1 signaling is unknown. Thus we examined the effects of PG[E.sub.2] in the presence and absence of TGF-[beta]1 stimulation on candidate signaling pathways in human lung fibroblasts. We now demonstrate that PGE2 does not interfere with TGF-[beta]1-induced Smad phosphorylation or its translocation to the nucleus. Rather, PG[E.sub.2] has dramatic effects on cell shape and cytoskeletal architecture and disrupts the formation of appropriate focal adhesions. PG[E.sub.2] treatment diminishes TGF-[beta]1-induced phosphorylation of paxillin, STAT-3, and FAK and, in turn, limits activation of the protein kinase B (PKB/Akt) pathway. These alterations do not, however, result in increased apoptosis within the first 24 h of treatment. Interestingly, the effects of PG[E.sub.2] stimulation alone do not always mirror the effects of PG[E.sub.2] in the presence of TGF-[beta]1, indicating that the context for EP2 signaling is different in the presence of TGF-[beta]1. Taken together, our results demonstrate that PG[E.sub.2] has the potential to limit TGF-[beta]1-induced myofibroblast differentiation via adhesion-dependent, but Smad-independent, pathways. fibrosis; eicosanoid; lung; signal transduction

Background: Hospitalizations are common among patients with idiopathic pulmonary fibrosis (IPF). We investigated the impact of hospitalizations on outcomes in patients with IPF.Methods: The IPF-PRO Registry is an observational US registry that enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Associations between patient characteristics and hospitalization, and between hospitalization and mortality, were analyzed using Cox regression models.Results: A total of 1002 patients with IPF were enrolled into the IPF-PRO Registry. Over a median follow-up time of 23.7 months (maximum: 67.0 months), 568 patients (56.7%) had at least one hospitalization. Of these patients, 319 (56.2%) had at least one respiratory-related hospitalization and 120 (21.1%) had at least one hospitalization with ventilatory support. Younger age (HR 0.68 [95% CI 0.55, 0.84] per 5-year increase for patients < 62 years), lower BMI (0.96 [0.93, 0.98] per 1-point increase), lower FVC % predicted (0.90 [0.83, 0.97] per 10% increase), oxygen use at rest (2.85 [2.18, 3.72]) and history of pulmonary hypertension (2.02 [1.37, 2.96]) at enrollment were associated with an increased risk of respiratory-related hospitalization during follow-up. In a multivariable model, there was an eightfold increase in the risk of mortality during hospitalization or within 90 days of discharge compared with outside of this period. The risk of mortality associated with a respiratory hospitalization or a hospitalization with ventilatory support was even greater.Conclusions: Data from the IPF-PRO Registry demonstrate that hospitalizations are common among patients with IPF. The risk of mortality during hospitalization or within 90 days of discharge was high, particularly among patients who were hospitalized for a respiratory cause or received ventilatory support. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511. [ABSTRACT FROM AUTHOR]