This indicates that GSK 3 contributes to this pathological feature and therefore possibly to the development of pulmonary hy pertension. Although citation investigations on the underlying mechanisms were not part Inhibitors,Modulators,Libraries of the design of the current study, it is well known that both vascular remodelling and functional changes in the vessel wall may lead to increased resistance Inhibitors,Modulators,Libraries in the pulmonary vasculature, causing pulmon ary hypertension. We have previously analysed vascu lar remodelling extensively in the LPS challenged guinea pig, but consistently found no effect on the thickness of the pulmonary artery medial area and pulmonary arteri ole wall area. This suggests that the ventricle remodeling is not due to pulmonary vascular remodelling, but due to functional changes in pulmonary vascular constriction, for example as a result of hypoxia.

Taken together, this study demonstrates that topical application of the selective GSK 3 inhibitor SB216763 is capable of preventing pulmonary Inhibitors,Modulators,Libraries remodelling effects in a guinea pig model of COPD. Although the exact mech anism underlying these effects remains to be estab lished, we propose that the anti remodelling properties of the Inhibitors,Modulators,Libraries drug may be related to CREB dependent attenu ation of smad activation. In conclusion, our findings sug gest that inhibition of GSK 3 may provide a novel means for the treatment of chronic airway diseases, such as COPD. Background Chronic obstructive pulmonary disease is a het erogeneous disorder characterized by small airway inflammation/fibrosis, mucus plugging and emphysema.

COPD is the fourth leading cause of death worldwide and the prevalence is predicted to rise in the next two decades. Inhibitors,Modulators,Libraries Although the cellular and molecular mechanisms of COPD pathogenesis are not well known, oxidative stress, chronic inflammation and an imbalance of pro teases and antiproteases are thought to play key roles in development and progression of the disease. There fore, a treatment with antioxidant and anti inflammatory properties could be beneficial in preventing or slowing the progression of lung disease in COPD. Inhalation of cigarette smoke and other environmental exposures can stimulate resident alveolar macrophages and lung epithelial cells to generate reactive oxygen spe cies and reactive nitric oxide species in excess, thereby disturbing the oxidant to antioxidant balance, resulting in oxidative stress. ROS and RNS stimulate the production of a number of host mediators, some of which can attract neutrophils, macrophages and other inflammatory cells to the lungs. Recruited inflammatory cells check this and epithelial cells produce matrix metalloproteinases, thereby increasing protease activity in the lungs. MMPs, in turn, degrade alveolar walls, leading to enlargement of airspace and development of emphysema.