Pompe disease is a lysosomal storage disorder in which a deficiency of acid a-glucosidase causes glycogen accumulation in all tissues, particularly cardiac and skeletal muscle. Microscopic analyses of muscle tissue typically show accumulation of glycogencontaining vacuoles in the myocytes. Pompe disease presents with a wide spectrum of phenotypes, ranging from a severe and rapidly progressive form with infantile-onset to a form that is slowly progressive with late-onset. Enzyme replacement therapy with recombinant human alglucosidase alfa prolongs survival and reverses cardiomegaly in IOPD. Patients with IOPD diagnosed through newborn screening have the best outcomes for ERT. In LOPD, although ERT has been associated with positive responses in motor capability and pulmonary function, there is significant variability in outcomes. Due to advances leading to AbMole D-Pantothenic acid sodium prolonged life expectancy in children with Pompe disease, rehabilitation services are needed to maximize functional status, prevent airway obstruction, facilitate patients’ ability to communicate, and improve respiratory function. In overcoming variation in patient outcomes with ERT in Pompe disease, the identification of non-invasive biomarkers would be a step forward for effective monitoring of clinical progress. CF patients with specific polymorphisms in TGF-b1 have a significantly increased odds ratio of severe lung disease. Multi-organ fibrosis is well described in CF. TGF-b is a known mediator of fibroblast pathobiology in human lungs, and is also a modifier of disease severity among CF individuals. However, TGF-b signaling and the mechanisms underlying development of lung fibrosis in CF have not been characterized previously. The myofibroblast has been identified as a key mediator of idiopathic pulmonary fibrosis and other profibrotic conditions. This distinct myofibroblast phenotype is TGF-b dependent and arises secondary to chronic epithelial injury or inflammation, two well described features of CF respiratory deterioration. In this study, we demonstrate intense TGF-b signaling and provide the first quantitative description of the myofibroblast phenotype in CF lungs. These results point to a novel explanation for TGF-b as a genetic modifier of CF lung disease and indicate emerging anti-fibrotic therapies under development for disease such as systemic sclerosis and idiopathic pulmonary fibrosis should also be considered as interventions to diminish tissue scarring and respiratory compromise in CF. In this study, we demonstrate that TGF-b signaling and myofibroblast differentiation are increased in the CF lung and approach pathogenic levels observed in patients with idiopathic pulmonary fibrosis. In IPF, it is well established that excessive TGF-b signaling and myofibroblast differentiation serve as the proximate cause of respiratory failure. The present experiments were therefore designed to apply emerging mechanistic knowledge regarding lung fibrosis and test the relevance of the TGF-b profibrotic pathway to cystic fibrosis pulmonary disease.