ERS 2016: WNT-4 regulates pro-inflammatory responses driven by epithelial- mesenchymal cross-talk (PA5067)

    Spanjer, A | Dept. of Molecular Pharmacology and Groningen Research Institute for Asthma and COPD (GRIAC) - University of Groningen | 14 november 2016 | 7.1.16.141CO (3.2.10.042)

Epithelial-fibroblast communication is an important aspect in the pathophysiology of chronic obstructive pulmonary disease (COPD). COPD is an obstructive lung disease, that is characterized by chronic inflammation, emphysema, mucus hypersecretion, fibrosis and remodeling in the small airways and lung tissue [1]. During the European Respiratory Society (ERS) annual conference 2016, Professor Andrew Bush stressed during his presentation [2] that the only possible response of the airways to injury is obstruction. We have to keep this in mind when we diagnose patients. As a measure of airway obstruction, the forced expiratory volume in 1 second (FEV1) is used. Another important aspect of airway obstruction that we have to keep in mind is that for a child, a FEV1 of less than 70 percent is very extraordinary (and alarming) while for a senior, a FEV1 under 70 percent is quite normal [2]. As with personalized medicine, the strict cut off should be individualized per person, there should be a personalized diagnose so to say. The take home message was that airflow obstruction itself is a description, not a disease.

Airflow obstruction is a characteristic of COPD. Currently available pharmacotherapy for COPD consists mostly of inhaled bronchodilators and corticosteroids. Although these drugs improve airflow limitation, exacerbation risk and decline in lung function to some extent; their beneficial effects on the chronic progression of the disease are very limited. As these drugs only treat the symptoms and do not stop the underlying mechanisms of disease, new therapies are urgently awaited. In session 719 ‘Airway pharmacology: drug targets and mode of action’ possible new therapies were discussed. Our research was also presented in this session. For the development of new therapies, we have to keep in mind that COPD is not only an inflammatory disease, but early development determines a lot and dysregulated repair also plays a crucial role [2]. WNT signalling is been found to play an important role in (embryonic) lung development [3-5] as well as inflammatory processes [6] and tissue repair and remodelling in the adult lung [7-10]. The role of WNT signaling in obstructive airways diseases including COPD is at present largely unknown. We previously showed that epithelial cells drive pro-inflammatory responses in fibroblasts. Here, we investigated if and which WNT ligands are involved in the inflammatory reaction that is induced upon co-culturing fibroblasts with epithelial cells. Our main conclusion is that WNT-4 negatively regulates interleukin (IL)-6 secretion that is induced in a co-culture of epithelial cells and fibroblasts [11]. Previous research showed that WNT-4 is pro-inflammatory and this is the main point that came out of the discussion that we further need to investigate.

Professor Königshoff also presented that WNT/β-catenin is signaling is essential for lung development [12] and that activation of WNT/β-catenin signaling attenuates emphysema. On the other hand, a reduction in WNT/β-catenin signaling drives emphysema. She presented her view on how to cure emphysema: we can either prevent WNT/β-catenin suppression or very specifically activate the pathway. When we would want to activate the pathway, we do need to pay extreme attention to which cells are activated as the effects of WNT pathway activation are cell type specific [12,13]. Visiting ERS 2016 was inspiring and the data presented at the conference clearly show the need for future research.

References

1. Barnes, NEJM, 2000, 343.
2. Session 619 - Lunchtime session: Early life origins of asthma and COPD. Andrew Bush. Links between childhood and adult airway obstruction.
3. Filali M, Liu X, Cheng N, et al. Mechanisms of submucosal gland morphogenesis in the airway. Novartis Found Symp 2002;248:38-45; discussion 45-50, 277-82.
4. Shannon JM, Hyatt BA. Epithelial-mesenchymal interactions in the developing lung. Annu Rev Physiol 2004;66:625-645.
5. Li C, Bellusci S, Borok Z, et al. Non-canonical WNT signalling in the lung. J Biochem 2015;158(5):355-365.
6. Baarsma HA, Meurs H, Halayko AJ, et al. Glycogen synthase kinase-3 regulates cigarette smoke extract- and IL-1beta-induced cytokine secretion by airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2011;300(6):L910-9.
7. Königshoff M, Balsara N, Pfaff E-, et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS ONE 2008;3(5):e2142.
8. Königshoff M, Eickelberg O. WNT signaling in lung disease: A failure or a regeneration signal? Am J Respir Cell Mol Biol 2010;42(1):21-31.
9. Baarsma HA, Menzen MH, Halayko AJ, et al. β-catenin signaling is required for TGF-β1-induced extracellular matrix production by airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2011;301(6):L956-L965.
10. Baarsma HA, Spanjer AI, Haitsma G, et al. Activation of WNT/beta-catenin signaling in pulmonary fibroblasts by TGF-beta(1) is increased in chronic obstructive pulmonary disease. PLoS One 2011;6(9):e25450.
11. Session 719 - Airway pharmacology: drug targets and mode of action. PA5067: Spanjer, A.I.R. et al.. WNT-4 regulates pro-inflammatory responses driven by epithelial-mesenchymal cross-talk.
12. Session 687 – Closing the gap: novel translational research strategies. Melanie Königshoff. Modelling tissue repair in COPD.
13. Session 596 TP – New signalling pathways in COPD. PA4014: Baarsma, H.A. et al.. Non-canonical WNT-5A signaling attenuates endogenous lung repair in COPD.

Keyword: ERS 2016 COPD WNT-4 emphysema

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