5 research outputs found
Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury
Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDAâapproved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0â21) and therapeutic (day 11â21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease.We demonstrate that prophylactic and therapeutic inhibition of phosphodiesterase 4 with several different antagonists reduces lung fibrosis induced by a targeted injury to the type II alveolar epithelium. In conjunction with the reduction in lung collagen content, phosphodiesterase inhibition also reduced serum surfactant protein C levels and the expression of profibrotic genes by lung fibroblasts.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144679/1/phy213753.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144679/2/phy213753_am.pd
Local GM-CSFâDependent Differentiation and Activation of Pulmonary Dendritic Cells and Macrophages Protect against Progressive Cryptococcal Lung Infection in Mice
Early or Late IL-10 Blockade Enhances Th1 and Th17 Effector Responses and Promotes Fungal Clearance in Mice with Cryptococcal Lung Infection
Dataset for: Phosphodiesterase 4 Inhibition Reduces Lung Fibrosis Following Targeted Type II Alveolar Epithelial Cell Injury
Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the anti-fibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous anti-fibrotic mediators that signal through cyclic AMP. In the present study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the anti-fibrotic activity of PDE4 inhibition to the two therapies that are FDA-approved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0-21) and therapeutic (day 11-21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast pro-fibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease
Adaptable and sustainable? Male farm service and the agricultural labour force in midland and southern England,c.1850-1925
This article argues that farm service was an adaptable and sustainable system of hiring labour in areas of midland and southern England after 1850, having much in common with the model recently identified for northern England and Scotland. Analysing the Census Enumerators Books from selected parishes in seven counties in 1851, 1871, and 1891, we reveal an intricate pattern of farm service âsurvivalâ both within and between counties. We then use a range of reports printed between the 1860s and 1920s to examine the national picture. The later regional persistence of farm service has implications for broader debates on the rural workforce and social relations