Statistical analysis revealed a trend towards a negative interaction between the effect of U0126 ERK SB216763 and of LPS. Next, we determined the expression of collagen in non cartilaginous airways by quantitative analysis of Sirius Red staining in these airways. Similar to the increase in pul monary fibronectin expression, repeated LPS instillation increased small airway collagen content by 1. 88 0. 18 fold compared to the average Inhibitors,Modulators,Libraries of the saline treated ani mals. Topical treatment of the airways with intranasally instilled SB216763 fully inhibited the LPS induced increase in collagen deposition in the walls of the small airways, whereas the selective GSK 3 inhibitor did not affect the collagen content in saline treated ani mals.

Emphysema, a pathological feature defined by the loss of the alveolar structure and increased parenchymal airspaces may be caused by tissue destruction in Inhibitors,Modulators,Libraries combination with an impaired repair process within the parenchyma. To evaluate the effect of GSK 3 inhibition on the size of the alveolar airspaces, LMI was determined in paraffin embedded lung sections. Repeated LPS instillation for 12 weeks did not significantly affect the LMI and, more importantly, inhibition of GSK 3 by SB216763 did not affect the size of the alveolar airspaces in either saline or LPS instilled animals. Collectively, this indi cates that repeated instillation of LPS induces alterations in pulmonary extracellular matrix expression and that in hibition of GSK 3 is beneficial in attenuating small airway fibrosis without affecting alveolar airspace size.

Effects of repeated LPS instillation and GSK 3 inhibition on airway smooth muscle content Published findings indicate that growth factor induced inhibition of GSK 3 promotes airway smooth muscle cell proliferation Inhibitors,Modulators,Libraries and hypertrophy. Therefore, the airway smooth muscle content in cartilaginous and non cartilaginous airways was determined by staining transverse frozen lung sections for the specific marker smooth muscle myosin heavy chain. Represen tative photomicrographs of serial lung sections containing the larger and small airways are shown in Figure 2. Morphometric analysis revealed that neither repeated LPS instillation nor SB2 Inhibitors,Modulators,Libraries 16763 treatment affected the smooth muscle content in either the cartilaginous or the non cartilaginous airways.

Effects of repeated LPS instillation and GSK 3 inhibition on right ventricle hypertrophy A well known co morbidity in COPD is the occurrence of pulmonary hypertension resulting in alterations in structure and function of the right ventricle of the heart. Repeated LPS challenge induced right ventricle hypertrophy in Inhibitors,Modulators,Libraries the guinea pigs as indicated by a signifi cant 1. 48 0. 13 directly fold increase in the ratio of right ven tricle weight over total heart weight compared to saline treated animals. SB216763 fully prevented the LPS induced right ventricle hypertrophy.