Interleukin-1 beta Promotes Epithelial-Derived Alveolar Elastogenesis via alpha v beta 6 Integrin-Dependent TGF-beta Activation

Background/Aims:IL-1 beta creates persistent pulmonary inflammation accompanied by elevated transforming growth factor beta (TGF-beta) levels and is associated with abnormal elastogenesis, which is observed in bronchopulmonary dysplasia (BPD). Although progress has been made in this field, the mechanisms underlying this process remain only partially understood. Methods: We assessed aberrant elastin localization-associated signaling in mouse pups exposed to 85% O-2 treated with either IL-1Ra or 1D11, using morphometric analyses, quantitative RT-PCR, immunostaining, and ELISA. We also evaluated the derivation of elastin-producing cells using dual marker tracking. The regulatory mechanisms of IL-1 beta were investigated in vitro in lung epithelial and mesenchymal cells. Results: Elevated levels of IL-1 beta, alpha v beta 6 and TGF-beta 1 were each associated with aberrant elastin production in O-2-exposed lungs. IL-1Ra abolished TGF-beta 1 activation and alpha v beta 6 upregulation, which occurred as a result of exposure to hyperoxia, whereas 1D11 had no discernible effect on the expression of either alpha v beta 6 or IL-1 beta even following O-2-exposure, suggesting that IL-1 beta was initially induced. Additionally, double staining revealed the presence of epithelium-derived elastin-producing cells, which was confirmed via in vitro IL-1 beta stress-induced epithelial-mesenchymal transformation (EMT) morphological and molecular marker changes, which may explain the altered lung elastin deposition and defective septation observed in BPD. Conclusions: These data support the hypothesis that IL-1 beta was initially induced by hyperoxia; alpha v beta 6 subsequently interacted with and activated TGF-beta 1, acting as an epithelial/mesenchymal signaling molecule that contributed to excessive alveolar elastogenesis, the primary pathological feature of BPD. Copyright (C) 2015 S. Karger AG, Basel