Wilms Tumor 1-Driven Fibroblast Activation and Subpleural Thickening in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is often fatal due to the formation of irreversible scar tissue in the distal areas of the lung. Although the pathological and radiological features of IPF lungs are well defined, the lack of insight into the fibrogenic role of fibroblasts that accumulate in distinct anatomical regions of the lungs is a critical knowledge gap. Fibrotic lesions have been shown to originate in the subpleural areas and extend into the lung parenchyma through processes of dysregulated fibroproliferation, migration, fibroblast-to-myofibroblast transformation, and extracellular matrix production. Identifying the molecular targets underlying subpleural thickening at the early and late stages of fibrosis could facilitate the development of new therapies to attenuate fibroblast activation and improve the survival of patients with IPF. Here, we discuss the key cellular and molecular events that contribute to (myo)fibroblast activation and subpleural thickening in IPF. In particular, we highlight the transcriptional programs involved in mesothelial to mesenchymal transformation and fibroblast dysfunction that can be targeted to alter the course of the progressive expansion of fibrotic lesions in the distal areas of IPF lungs.

Keywords: collagen; extracellular matrix; fibroblast; idiopathic pulmonary fibrosis; lung function.

Figure 1

Representative images of Movat Pentachrome-stained distal areas of normal and IPF lungs. Highlighted dashed region in low magnification (Scale bar, 1500 µm) images represents the high magnification (Scale bar, 200 µm) images that show the prominent subpleural thickening and fibrotic foci that accumulate in the distal areas of the alveolar parenchyma of IPF lungs compared to normal lungs. Pentachrome staining highlights collagen (yellow color), muscle (red color), and elastic fibers (black to blue color) in mature fibrotic lesions of IPF. Arrowhead is used to highlight the fibrotic foci.

Figure 2

Accumulation of WT1- and Sox9-positive or Sox9-positive fibroblasts in IPF. WT1-mediated Sox9 upregulation in mesothelium and fibroblasts induces accumulation of fibroblasts that are positive for both WT1 and Sox9 in subpleural fibrotic lesions. Additionally, we observed accumulation of Sox9 positive fibroblasts that are negative for WT1 in peribronchial fibrotic lung lesions. Both WT1 and Sox9 expressing fibroblasts can transform to myofibroblasts resulting in progressive accumulation in fibrotic lesions of IPF lungs (right) compared to normal lungs (left).