In various cells it has been demonstrated that smad selleck compound dependent signalling can be functionally antag onized by activation of CREB, which provides an explan ation for the inhibitory effects of SB216763 on airway fibrosis. Unfortunately, due to lack of availability of phospho serine133 specific antibodies against guinea Inhibitors,Modulators,Libraries pig CREB, it was not possible to determine the phosphor ylation status of CREB in our studies. Nonetheless, GSK 3 mediated regulation of CREB and smad dependent sig nalling appears a plausible explanation Inhibitors,Modulators,Libraries for the paradox ical inhibition of LPS induced B catenin expression and subsequent matrix protein production by SB216763 as we did not observe anti inflammatory effects of SB216763 in our experiments.

Growth factors, including TGF B, re gulate Inhibitors,Modulators,Libraries cellular B catenin expression by smad mediated gene transcription in addition to GSK 3 dependent post translational effects on Inhibitors,Modulators,Libraries B catenin protein stability. In support, TGF B induced B catenin expression in pul monary fibroblasts, and this was attenuated by either SB216763 or by smad3 inhibition using SIS3. In further support, a recent study indicated that hyperoxia induced B catenin expression by pulmonary vessels could be repressed by SB216763 treatment in rats. Collectively, these data indicate that in vivo activation of B catenin signalling is associated with an increase in the pulmonary extracellular matrix deposition, whereas selective inhibition of GSK 3 prevents this LPS induced process. In addition to fibrosis, increased smooth muscle content in the airways may be part of the airway remodelling, con tributing to COPD pathophysiology.

It is important to note, that alterations in airway smooth muscle content are observed in individuals with very Inhibitors,Modulators,Libraries severe COPD only. In our guinea pig model, we did not observe alterations in smooth muscle content, as determined by sm MHC po sitive area, in either the large or smaller airways, which is in agreement with previously published findings in this model. Of inter est is that smooth muscle mass did inhibitor bulk not change in response to GSK 3 inhibition either. Published findings indicate that growth factor induced inhibition of GSK 3 promotes airway smooth muscle cell proliferation and hypertrophy. Further, airway smooth muscle growth in re sponse to allergen exposure correlates with GSK 3 in activation in airway smooth muscle in mice. The observation that pharmacological inhibition of GSK 3 using SB216763 is not sufficient to promote airway smooth muscle growth is therefore reassuring and pro vides further support for the suitability of GSK 3 as a drug target. COPD is a disease with significant extrapulmonary ef fects that contribute to disease severity. Therefore, we investigated right ventricle size in response to repeated LPS instillation.