Abstract

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by extensive fibrosis of the lung tissue. Wnt5a expression was observed to be upregulated in IPF and suggested to be involved in the progression of the disease. Interestingly, smooth muscle cells (SMC) are a major source of Wnt5a in IPF patients. However, no study has been conducted until now to investigate the precise role of smooth muscle-derived Wnt5a in IPF. Here, we used the bleomycin-induced lung fibrosis model in a conditional gene-deficient mouse, where the Wnt5a gene was excised from SMC. We show here that the excision of the Wnt5a gene in SMC led to significantly improved health conditions with minimized weight loss and improved lung function. This improvement was based on a significantly lower deposition of collagen in the lung with a reduced number of fibrotic foci in lung parenchyma. Furthermore, the bleomycin-induced cellular infiltration into the airways was not altered in the gene-deficient mice compared with wild-type mice. Thus, we demonstrate that the Wnt5a expression of SMC of the airways leads to aggravated fibrosis of the lung with poor clinical conditions. This aggravation was not an influence in the bleomycin-induced inflammatory processes but on the development of fibrotic foci in lung parenchyma and the deposition of collagen.

Highlights

  • Interstitial lung diseases are characterized by widespread inflammation and/or extensive fibrosis that mainly affects the lung parenchyma

  • We demonstrated by knocking out Wnt5a in airway smooth muscle cells (SMC) that Wnt5a released from these cells contributes to the expression and deposition of collagen throughout the lung, leading to higher fibrosis

  • We demonstrated that airway SMC can suffer hypertrophy or hyperplasia upon bleomycin-induced lung fibrosis, which was abrogated upon the KO of the gene in these cells without affecting the TGF-β expression

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Summary

Introduction

Interstitial lung diseases are characterized by widespread inflammation and/or extensive fibrosis that mainly affects the lung parenchyma. Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive fibrogenesis of the lung and belongs to the family of interstitial lung diseases. Wnt5a (Wingless-Type MMTV integration site family, member 5A) was found to be highly expressed in humans who suffer from IPF [1]. It was shown here that smooth muscle cells (SMC), in addition to myofibroblasts, are a major source of Wnt5a in IPF patients. It is still undefined which role Wnt5a plays regarding the severity of the disease

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