Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation.

Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research. The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management. This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001). Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time. The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov( NCT02951416 ).

The acute respiratory distress syndrome (ARDS) is a frequent, life-threatening disease in which a marked increase in alveolar surface tension has been repeatedly observed. It is caused by factors including a lack of surface-active compounds, changes in the phospholipid, fatty acid, neutral lipid, and surfactant apoprotein composition, imbalance of the extracellular surfactant subtype distribution, inhibition of surfactant function by plasma protein leakage, incorporation of surfactant phospholipids and apoproteins into polymerizing fibrin, and damage/inhibition of surfactant compounds by inflammatory mediators. There is now good evidence that these surfactant abnormalities promote alveolar instability and collapse and, consequently, loss of compliance and the profound gas exchange abnormalities seen in ARDS. An acute improvement of gas exchange properties together with a far-reaching restoration of surfactant properties was encountered in recently performed pilot studies. Here we summarize what is known about the kind and severity of surfactant changes occurring in ARDS, the contribution of these changes to lung failure, and the role of surfactant administration for therapy of ARDS.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT–β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin–driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal–epithelial cross talk in COPD pathogenesis, which is amenable to therapy.

Bleomycin is a well known fibrogenic agent, provoking an initial adult respiratory distress syndrome–like injury with subsequent strong fibroproliferative response. Severe abnormalities of the alveolar surfactant system, which may be linked to the appearance of alveolar fibrin deposition, have been implicated in the pathogenetic sequence of events. Using a model of standardized aerosol delivery of 1.8 U bleomycin/kg body weight in rabbits, we investigated the influence of repetitive nebulization of heparin or urokinase-type plasminogen activator (u-PA) on the development of lung fibrosis. In an “early” (Days 2–12 postbleomycin) or “late” (Days 14–24 post-bleomycin) treatment protocol, approximately 3,500 U heparin or approximately 6,500 U u-PA was delivered to the bronchoalveolar space. Within four weeks, the bleomycin challenge provoked severe pulmonary fibrosis with reduction of lung compliance, marked increase in soluble collagen (bronchoalveolar lavage fluid) and hydroxyproline content (lung tissue), a typical reticular fibrosis pattern on high-resolution computed tomography, and typical histologic findings. Therapeutic intervention resulted in a far-reaching normalization of compliance, suppression of soluble collagen and hydroxyproline accumulation, and virtual abrogation of the computed tomography scan and histologic features of lung fibrosis, with most prominent effects seen in the early heparin and late u-PA administration. No bleeding complications occurred. These findings strongly support the concept that alveolar fibrin generation is an important event in the development of postbleomycin lung fibrosis. “Compartmentalized” anticoagulation and/or fibrinolysis via inhalational deposition of interventional agents in the alveolar compartment may thus offer a new therapeutic strategy for prevention of fibrosis.

Pirfenidone is currently approved in the EU for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) and offers a beneficial risk-benefit profile. However, there are several other, progressive fibrotic lung diseases, in which conventional anti-inflammatory therapy is not sufficiently effective and antifibrotic therapies may offer a novel treatment option. We designed a study protocol for inclusion of patients with progressive fibrotic lung disease despite conventional anti-inflammatory therapy (EudraCT 2014–000861-32). The study population comprises patients with collagen-vascular disease-associated lung fibrosis (CVD-LF), fibrotic non-specific interstitial pneumonia (fNSIP), chronic hypersensitivity pneumonitis (cHP), and asbestos-related lung fibrosis (ALF). Disease progression needs to be proven by slope calculation of at least three Forced Vital Capacity (FVC) values obtained within 6–24 months prior to inclusion, documenting an annualized decline in percent predicted FVC of 5% (absolute) or more despite appropriate conventional therapy. Absolute change in percent predicted FVC from baseline - analyzed using a rank analysis of covariance (ANCOVA) model - will serve as efficacy-related primary study endpoint. There is an urgent unmet clinical need for effective therapies for patients with a progressive fibrotic lung disease other than IPF. The current study protocol is unique with respect to selecting patients with different disease entities of lung fibrosis which have, however, essential pathophysiological characteristics in common. Moreover, by selecting patients with evidence of disease progression despite conventional therapy, the protocol ensures that a cohort of interstitial lung disease (ILD) patients with a high unmet medical need is targeted and it may allow a sufficiently high event rate for evaluation of treatment responses. DRKS00009822 (registration date: January 13th 2016).