Newman Donna R, Sills W Shane, Hanrahan Katherine, Ziegler Amanda, Tidd Kathleen McGinnis, Cook Elizabeth, Sannes Philip L
Department of Molecular Biomedical Sciences, Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, and Center for Human Health and the Environment, College of Sciences, North Carolina State University, Raleigh, North Carolina (DRN, WSS, KH, AZ, KMT, EC, PLS).
J Histochem Cytochem. 2016 Feb;64(2):99-111. doi: 10.1369/0022155415617988. Epub 2015 Nov 4.
The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF.
无翅型（Wnt）信号配体家族对肺发育有重要作用，且在寻常型间质性肺炎（UIP）患者中高表达。我们试图确定Wnt5A在特发性肺纤维化（IPF）患者肺组织中的细胞分布，以及在人肺成纤维细胞和IPF肌成纤维细胞中控制其表达的信号配体。对40例诊断为IPF或UIP的患者的组织切片进行Wnt5A免疫定位检测。此外，对从正常或IPF人肺中分离出的肺成纤维细胞进行腺病毒转导，使其过表达或沉默Wnt7B，或用转化生长因子-β1（TGF-β1）或其抑制剂处理，然后分析Wnt5A蛋白表达情况。Wnt5A在IPF肺中由气道和肺泡上皮细胞、平滑肌细胞、内皮细胞以及纤维母细胞灶中的肌成纤维细胞表达，并遍布整个间质。在正常人类平滑肌细胞和成纤维细胞中，无论是否用TGF-β1处理，强制过表达Wnt7B均显著增加Wnt5A蛋白表达，但在Wnt5A已高表达的IPF肌成纤维细胞中则不然。结果表明Wnt5A在IPF肺细胞中广泛表达，且Wnt7B和TGF-β1可使其显著增加，二者联合可能代表调节IPF发病机制的关键信号通路。
