'WNT-er is coming': WNT signalling in chronic lung diseases.

Chronic lung diseases represent a major public health problem with only limited therapeutic options. An important unmet need is to identify compounds and drugs that target key molecular pathways involved in the pathogenesis of chronic lung diseases. Over the last decade, there has been extensive interest in investigating Wingless/integrase-1 (WNT) signalling pathways; and WNT signal alterations have been linked to pulmonary disease pathogenesis and progression. Here, we comprehensively review the cumulative evidence for WNT pathway alterations in chronic lung pathologies, including idiopathic pulmonary fibrosis, pulmonary arterial hypertension, asthma and COPD. While many studies have focused on the canonical WNT/β-catenin signalling pathway, recent reports highlight that non-canonical WNT signalling may also significantly contribute to chronic lung pathologies; these studies will be particularly featured in this review. We further discuss recent advances uncovering the role of WNT signalling early in life, the potential of pharmaceutically modulating WNT signalling pathways and highlight (pre)clinical studies describing promising new therapies for chronic lung diseases

WNT receptor signalling in lung physiology and pathology.

The WNT signalling cascades have emerged as critical regulators of a wide variety of biological aspects involved in lung development as well as in physiological and pathophysiological processes in the adult lung. WNTs (secreted glycoproteins) interact with various transmembrane receptors and co-receptors to activate signalling pathways that regulate transcriptional as well as non-transcriptional responses within cells. In physiological conditions, the majority of WNT receptors and co-receptors can be detected in the adult lung. However, dysregulation of WNT signalling pathways contributes to the development and progression of chronic lung pathologies, including idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma and lung cancer. The interaction between a WNT and the (co-)receptor(s) present at the cell surface is the initial step in transducing an extracellular signal into an intracellular response. This proximal event in WNT signal transduction with (cell-specific) ligand-receptor interactions is of great interest as a potential target for pharmacological intervention. In this review we highlight the diverse expression of various WNT receptors and co-receptors in the aforementioned chronic lung diseases and discuss the currently available biologicals and pharmacological tools to modify proximal WNT signalling

WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. IPF is characterized by epithelial cell injury and reprogramming, increases in (myo)fibroblasts, and altered deposition of extracellular matrix. The Wnt1-inducible signaling protein 1 (WISP1) is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis. Here, we aimed to further investigate WISP1 regulation and function in primary human lung fibroblasts (phLFs). We demonstrate that WISP1 is directly upregulated by Transforming growth factor β1 (TGFβ1) and Tumor necrosis factor α (TNFα) in phLFs, using a luciferase-based reporter system. WISP1 mRNA and protein secretion increased in a time-and concentration-dependent manner by TGFβ1 and TNFα in phLFs, as analysed by qPCR and ELISA, respectively. Notably, WISP1 is required for TGFβ1-and TNFα-dependent induction of interleukin 6 (IL-6), a mechanism that is conserved in IPF phLFs. The siRNA-mediated WISP1 knockdown led to a significant IL-6 reduction after TGFβ1 or TNFα stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of WISP1 reduced phLFs proliferation, a process that was in part rescued by IL-6. Taken together, these results strongly indicate that WISP1-induced IL-6 expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFβ1 and TNFα

Linking bronchopulmonary dysplasia to adult chronic lung diseases: Role of WNT signaling.

Bronchopulmonary dysplasia (BPD) is one of the most common chronic lung diseases in infants caused by pre- and/or postnatal lung injury. BPD is characterized by arrested alveolarization and vascularization due to extracellular matrix remodeling, inflammation, and impaired growth factor signaling. WNT signaling is a critical pathway for normal lung development, and its altered signaling has been shown to be involved in the onset and progression of incurable chronic lung diseases in adulthood, such as chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). In this review, we summarize the impact of WNT signaling on different stages of lung development and its potential contribution to developmental lung diseases, especially BPD, and chronic lung diseases in adulthood

Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: I. Effects on lung remodeling and pathology

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that regulates multiple signalling proteins and transcription factors involved in a myriad of cellular processes. The kinase acts as a negative regulator in beta-catenin signalling and is critically involved in the smad pathway. Activation of both pathways may contribute to pulmonary features of chronic obstructive pulmonary disease (COPD). METHODS: In the present study, we investigated the effect of the selective GSK-3 inhibitor SB216763 on pulmonary pathology in a guinea pig model of lipopolysaccharide (LPS)-induced COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pre-treated with either intranasally instilled SB216763 or corresponding vehicle 30 min prior to each LPS/saline challenge. RESULTS: Repeated LPS exposures activated beta-catenin signalling, primarily in the airway epithelium and submucosa. LPS also induced pulmonary inflammation and tissue remodelling as indicated by inflammatory cell influx, increased pulmonary fibronectin expression and enhanced small airway collagen content. Inhibition of GSK-3 by SB216763 did not affect LPS-induced inflammatory cell influx, but prevented the small airway remodelling and, unexpectedly, inhibited the activation of beta-catenin in vivo. LPS or SB216763 treatment had no effect on the airway smooth muscle content and alveolar airspace size. However, GSK-3 inhibition prevented LPS-induced right ventricle hypertrophy. CONCLUSIONS: Our findings indicate that GSK-3 inhibition prevents LPS-induced pulmonary pathology in guinea pigs, and that locally reduced LPS-induced beta-catenin activation appears in part to underlie this effect