CAVEOLINS · Caveolae and Caveolins: Integrating signals for airway smooth muscle cell proliferation

Final Activity Report Summary - CAVEOLLINS (Caveolae and Caveolins: Integrating signals for airway smooth muscle cell proliferation)

In westernised countries worldwide more than 10 % of children and 6 % of adults are afflicted with asthma. Incidence and morbidity have risen steadily in the past 15 years despite a significant increase of pharmacological medication. From a biological perspective, asthma is presented as chronic inflammation of the bronchi that drives airway wall thickening and remodelling, leading to airway hyperresponsiveness, the hallmark clinical symptom of the disease. The key pathological feature contributing to excessive bronchial constriction is an increased mass of contractile airway smooth muscle that encircles the airways and regulates lumen diameter. Though numerous asthma-associated growth factors have been linked to this pathophysiological response, more recent studies, by us and others, revealed that, in combination with these growth factors, the neurotransmitter acetylcholine has a profound synergistic effect on the proliferative behaviour of the airway smooth muscle. Our project investigated the mechanisms that co-ordinated the effects of acetylcholine and growth factors leading to hyper-proliferative responses of airway smooth muscle cells. A number of significant novel findings were made in this project. It was discovered that receptors for growth factors and acetylcholine were not randomly distributed among the cell, but sequestered and organised in specific membrane compartments, called caveolae. These caveolae and their marker proteins caveolins appeared to play specific roles in several airway smooth muscle cell responses. Thus, contraction induced by acetylcholine was facilitated by these organisational structures, whereas cell proliferation induced by growth factors was strongly inhibited. The organisation of signalling molecules in caveolae was a strong mechanism for inhibition of proliferation, because caveolin proteins silenced the activity of the enzymes and proteins that coordinated a proliferative response. However, when muscle cells were induced to proliferate, these signalling molecules moved out of the caveolae. In addition, caveolae number was decreased. These findings indicated that caveolae and caveolins exerted an important suppressive control of airway smooth muscle proliferation, and that this inhibitory role was actively reversed by growth factors. The synergistic interaction of acetylcholine and growth factors appeared not to be mediated by caveolae or caveolin dependent mechanisms. We identified instead a new mechanism of signalling cross-talk between these receptors, which involved the enzyme glycogen synthase kinase 3. This enzyme was a strong inhibitor of cell proliferation and appeared cooperatively inhibited by acetylcholine and growth factors. Since acetylcholine was recently identified by us as an important regulator of airway smooth muscle thickening in a guinea pig model of asthma, these findings would indicate that this novel mechanism determined airway remodelling in this disease. Our future studies therefore aimed at determining the importance of this signalling pathway in several respiratory diseases, including asthma and Chronic obstructive pulmonary disease (COPD).

Data: CORDIS, © European Union