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

Abstract

BackgroundEarlier studies have reported that transforming growth factor beta 1(TGFβ1) 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 TGFβ1-induced inflammatory signals that lead to cell death and abnormal alveolarization are poorly understood. We hypothesized that TGFβ1 signaling via TGFβR2 is necessary for the pathogenesis of the BPD pulmonary phenotype resulting from HALI.MethodsWe utilized lung epithelial cell-specific TGFβ1 overexpressing transgenic and TGFβR2 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 TGFβ1 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 TGFβ1 signaling via TGFβR2 for improved survival, reduced inflammation and apoptosis that may provide insights for the development of potential therapeutic strategies targeted against HALI and BPD.

Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer

“…This binding complexes activates TGFβ signaling via smad phosphorylation and nuclear translocation [5]. The TGFβ pathway is always aberrant in many diseases including cancers [6–8]. In diverse malignancies, TGFβ signaling has either tumor suppressive or pro-oncogenic functions in accordance with tumor stage [9, 10].…”

Hyperoxia in the Pathogenesis of Bronchopulmonary Dysplasia

“…Increased expression of TGF-β1 by epithelial cells on exposure to hyperoxia was noted and inhibition of JNK signaling signifi cantly improved the spontaneously impaired alveolarization in room air and decreased mortality on exposure to hyperoxia in lung epithelial cell targeted TGF-β1-overexpressing mice [ 118 ]. This was confi rmed in another study where it was shown that increased TGFβ1 expression in newborn mice lungs led to increased mortality, macrophage and immature monocyte infi ltration, apoptotic cell death specifi cally in type II alveolar epithelial cells (AECs) accompanied by impaired alveolarization, and dysregulated angiogenic molecular markers [ 119 ].…”

TLRs in pulmonary diseases

“…Development and progression of lung cancer involves anti-inflammatory cytokines such as TGF-β [212], IL-10 and growth factors such as VEGF and Fibroblast growth factor 2 (FGF2), which are induced by activation of TLR2, TLR4 and TLR9. In lung epithelial cells, TGF-β1 has been recognized to facilitate apoptosis and inflammation [212].…”

“…Development and progression of lung cancer involves anti-inflammatory cytokines such as TGF-β [212], IL-10 and growth factors such as VEGF and Fibroblast growth factor 2 (FGF2), which are induced by activation of TLR2, TLR4 and TLR9. In lung epithelial cells, TGF-β1 has been recognized to facilitate apoptosis and inflammation [212]. However, TLR2 and TLR4 activation induces extracellular matrix remodelling and EGFR-mediated signalling, respectively, stimulating progression of lung carcinoma [213,214].…”