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Glycogen synthase kinase-3 (GSK-3) and B-catenin: potential novel therapeutic targets for COPD

15 June 2012

PhD ceremony: Mr. H.A. Baarsma, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Glycogen synthase kinase-3 (GSK-3) and B-catenin: potential novel therapeutic targets for COPD

Promotor(s): prof. H. Meurs, prof. H.A.M. Kerstjens

Faculty: Mathematics and Natural Sciences

Hoeke Baarsma has demonstrated that both β-catenin and GSK-3 are important in specific cellular processes that contribute to the pathogenesis of COPD. Furthermore, he proposes that therapeutic intervention by GSK-3 inhibition may provide a novel therapeutic treatment for COPD.

Chronic obstructive pulmonary disease (COPD) is primarily caused by tobacco smoking and is characterized by a progressive decline of lung function. The persistent airflow limitation is the resultant of chronic inflammation and of structural alterations in the lungs, including airway remodeling and emphysema. Baarsma explored the functional roles of β-catenin and glycogen synthase kinase-3 (GSK-3), both critical effectors in the WNT-signaling pathway, in the pathological processes that underpin COPD.

Aberrant extracellular matrix (ECM) turnover is a pathological feature of COPD and contributes to the structural alterations in the lung. Baarsma demonstrated that activation of β-catenin contributes to ECM production by airway smooth muscle cells and pulmonary fibroblasts induced by the growth factor TGF-ß. Interestingly, this activation of the WNT pathway appeared enhanced in pulmonary fibroblasts of COPD patients. Moreover, the differentiation process of fibroblasts into more active myofibroblasts induced by TGF-β appeared dependent on both β-catenin and GSK-3. Further, the inflammatory response induced by exposure of airway smooth muscle cells to cigarette smoke appeared to be GSK-3 dependent.

Inhibition of GSK-3 protected against the ECM production and myofibroblast differentiation in lung fibroblasts. Moreover, in a guinea pig model of COPD GSK-3 inhibitors protected against airway fibrosis as well as extrapulmonary pathological features, such as right ventricle hypertrophy and skeletal muscle atrophy, which are similarly involved in COPD.

Last modified:15 September 2017 3.42 p.m.
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