Conditional overexpression of TGFβ1 promotes pulmonary inflammation, apoptosis and mortality via TGFβR2 in the developing mouse lung

Angara Sureshbabu, Mansoor A Syed, Chandra Sekhar Boddupalli, Madhav V Dhodapkar, Robert J Homer, Parviz Minoo, Vineet Bhandari

BackgroundEarlier studies have reported that transforming growth factor beta 1(TGFß1) is a critical mediator of hyperoxia-induced acute lung injury (HALI) in developing lungs, leading to impaired alveolarization and a pulmonary phenotype of bronchopulmonary dysplasia (BPD). However, the mechanisms responsible for the TGFß1-induced inflammatory signals that lead to cell death and abnormal alveolarization are poorly understood. We hypothesized that TGFß1 signaling via TGFßR2 is necessary for the pathogenesis of the BPD pulmonary phenotype resulting from HALI.MethodsWe utilized lung epithelial cell-specific TGFß1 overexpressing transgenic and TGFßR2 null mutant mice to evaluate the effects on neonatal mortality as well as pulmonary inflammation and apoptosis in developing lungs. Lung morphometry was performed to determine the impaired alveolarization and multicolor flow cytometry studies were performed to detect inflammatory macrophages and monocytes in lungs. Apoptotic cell death was measured with TUNEL assay, immunohistochemistry and western blotting and protein expression of angiogenic mediators were also analyzed.ResultsOur data reveals that increased TGFß1 expression in newborn mice lungs leads to increased mortality, macrophage and immature monocyte infiltration, apoptotic cell death specifically in Type II alveolar epithelial cells (AECs), impaired alveolarization, and dysregulated angiogenic molecular markers.ConclusionsOur study has demonstrated the potential role of inhibition of TGFß1 signaling via TGFßR2 for improved survival, reduced inflammation and apoptosis that may provide insights for the development of potential therapeutic strategies targeted against HALI and BPD.