Roles for TGF-β in Pulmonary Disease

Abstract

Fibrosis is a disease where the normally transitory wound healing response enters a chronic state. Bleomycin and Adenovector models of pulmonary fibrosis have implicated TGF-β1 in this disease. Concern regarding a synergistic combination of TGF-β1 with an adaptive immune response within the Adenovector model prompted its use within mice devoid of T Lymphocytes, Balb/c SCIDs. The lack of an adaptive immune response within these mice did not affect the severity of fibrogenesis, as compared to Balb/c data in a hydroxyproline assay. TGF-β1 is a pluripotent cytokine with key roles in wound healing, immune regulation, and development, making it a dangerous molecule to therapeutically modulate directly. Future strategies will likely focus on downstream fibrotic molecules uninvolved in immune regulation, such as CTGF. While CTGF has been associated with fibrosis and is likely activated by TGF-β1, no conclusive evidence is available within an animal model. TGF-β1 stimulates cells by binding its receptor and signaling through the Smad signal transduction pathway. Smad3 knockout mice were used to examine the regulation of CTGF by TGF-β1, and study its role in pulmonary fibrosis. We show that these mice produce dramatically less CTGF in response to TGF-β1 than littermates expressing Smad3, and they show protection against TGF-β1 induced pulmonary fibrosis, using the Adenovector system. TGF-β1 can alter lung development, and is thought to be a causative agent in Bronchopulmonary Dysplasia, a disease affecting immature lungs. Utilizing the Adenovector system, we developed a neonatal rat model of BPD that closely resembles the human disease, providing researchers with a system to study the disease course. TGF-β1 is part of a family of growth factors, of which TGF-β3 is also a member. What role TGF-β3 plays in pulmonary fibrosis has not been evaluated. To allow future in vivo studies on the effect of TGF-β3 on lung morphology, we constructed a replication deficient Adenovector expressing constitutively active TGF-β3.