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Over onsWaar vindt u onsprof. dr. R. (Reinoud) Gosens

prof. dr. R. Gosens

Adjunct Hoogleraar

Tissue repair in COPD: towards regenerative pharmacology for the lung

Investigators involved: Reinoud Gosens, John-Poul Ng-Blichfeldt, Chiara Ciminieri, Eline van Dijk, Xinhui Wu, Loes Kistemaker

Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases in the world, characterized by a progressive loss of lung function with airflow obstruction that is not fully reversible. The key problem underlying COPD is defective tissue repair, causing bronchitis, small airways remodelling and emphysema. As current therapies do not modify the course of the disease in COPD, new therapies need to be developed. The main goal of this project is to find a therapeutic pharmacological principle to restore tissue repair in early COPD. The pharmacological approach makes sense as it can be applied on a relatively large scale and used to halt the disease process resulting in real disease-modifying treatment. The major hurdle that obstructs the possibility to do so, however, is the immense lack of knowledge on the regulatory mechanisms that impair tissue repair in COPD. We believe that it should be feasible to reactivate endogenous repair mechanisms using pharmacological means.

Our research focuses on the WNT signalling pathway as a therapeutic strategy to achieve tissue repair in COPD. The WNT pathway is key to stem and progenitor cell renewal and clear indications of its dysregulation in COPD exist. We propose that the pathological mechanisms that impair adequate WNT-mediated repair in COPD provide rational molecular targets for drug design. Our research is aimed at identifying how WNT signalling mediates repair and investigate why WNT mediated repair is not adequate in COPD. With these data, we will establish molecular targets for drug design and develop small molecule antagonists of these targets. The integrative, transdisciplinary approach adopted in this project, using molecular genomics, functional studies of tissue repair, and drug discovery platforms, will characterize the spatiotemporal regulation of specific WNT ligands and their role in tissue repair in response to COPD-relevant pathophysiological stimuli.

Relevant literature:

A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis.

Spanjer AI, Menzen MH, Dijkstra AE, van den Berge M, Boezen HM, Nickle DC, Sin DD, Bossé Y, Brandsma CA, Timens W, Postma DS, Meurs H, Heijink IH, Gosens R.

Thorax. 2016 71(4):312-322.

Regulation of actin dynamics by WNT-5A: implications for human airway smooth muscle contraction.

Koopmans T, Kumawat K, Halayko AJ, Gosens R.

Sci Rep. 2016 Jul 29;6:30676.

Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β₁ is increased in chronic obstructive pulmonary disease.

Baarsma HA, Spanjer AI, Haitsma G, Engelbertink LH, Meurs H, Jonker MR, Timens W, Postma DS, Kerstjens HA, Gosens R.

PLoS One. 2011;6(9):e25450.

Cholinergic regulation of inflammation and remodelling in asthma and COPD: from molecular mechanism to clinical application

Investigators involved: Reinoud Gosens, Loes Kistemaker, Siti Farah Rahmawati, Pien Goldsteen, Amalia Dolga, Mariska van den Berg

Acetylcholine is the primary parasympathetic neurotransmitter in the airways, which induces bronchoconstriction and mucus secretion. The activity of the neuronal system is increased in COPD and asthma. Therefore, anticholinergics are effective bronchodilators in COPD and in asthma.

Recent data are changing this traditional view: resident and inflammatory cells that control inflammation and remodelling produce acetylcholine and express muscarinic receptors. Moreover, anticholinergics reduce neutrophilia and small airway remodelling in animal models of COPD, and eosinophilia and airway remodelling in animal models of allergic asthma. Although the clinical significance of these findings is not yet fully determined, a pro-inflammatory role for acetylcholine could explain the aforementioned effects of anticholinergics on exacerbations and fits with our recent clinical data suggesting anti-inflammatory effects of targeted lung denervation in patients with COPD. Whether anticholinergics can be anti-inflammatory in patients with COPD as well is currently under investigation.

The mechanisms involved are not completely understood yet; however, we recently demonstrated that the muscarinic M3 receptor plays a dominant role in the inflammatory response induced by cigarette smoke in mice and studies with bone-marrow chimeric mice clearly indicate a role for the M3 receptor on structural cells in this response. The same holds true for the role of muscarinic receptors in allergen-induced inflammation and remodelling, where anticholinergics or M3 knock-out have particularly profound effects on airway smooth muscle thickening, on mucus hypersecretion and on eosinophilic inflammation. These effects may in part be regulated by mechanical effects resultant from bronchoconstriction. This suggests that patients with COPD or asthma might benefit from anticholinergic therapy to a much larger extent than previously appreciated. We are presently investigating these molecular mechanisms and the clinical implications and applications.

Relevant literature:

Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling.

Kistemaker LE, Gosens R.

Trends Pharmacol Sci. 2015 36(3):164-171.

Bronchoconstriction and airway biology: potential impact and therapeutic opportunities.

Gosens R, Grainge C.

Chest. 2015 147:798-803.

Anti-inflammatory effects of targeted lung denervation in patients with COPD.

Kistemaker LE, Slebos DJ, Meurs H, Kerstjens HA, Gosens R.

Eur Respir J. 2015 46:1489-1492.

Laatst gewijzigd:01 maart 2018 13:29


Basiseenheid Moleculaire Farmacologie