Host predisposition by endogenous Transforming Growth Factor-β1 overexpression promotes pulmonary fibrosis following bleomycin injury

Yussef Haider,Mark Wj Ferguson,Gail Martin,Andrea P Malizia,Dominic T Keating,Jim J Egan,Peter P Doran,Annette Tomlinson,Mary Birch

doi:10.1186/1476-9255-4-18

Abstract

BackgroundIdiopathic Pulmonary Fibrosis (IPF) is a progressive diffuse disease involving the lung parenchyma. Despite recent advances, the molecular mechanisms of the initiation and progression of this disease remain elusive. Previous studies have demonstrated TGFβ1 as a key effector cytokine in the development of lung fibrosis.MethodsIn this study we have used a transgenic mouse based strategy to identify the effect of overexpression of this key effector mediator on the development of pulmonary fibrosis in response to exogenous injury. We bred two lines (line 25 and 18) of transgenic mice (Tr+) that overexpressed active TGFβ1. Three-month old transgenic and wild type mice were subsequently wounded with intraperitoneal bleomycin. Mice were sacrificed at 6 weeks post-bleomycin and their lungs analysed histologically and biochemically.ResultsThe severity of lung fibrosis was significantly greater in the Tr+ mice compared to the wild type mice. Using an oligonucleotide microarray based strategy we identified discrete patterns of gene expression contributing to TGFβ1 associated pulmonary fibrosis.ConclusionThis data emphasises the importance of a host predisposition in the form of endogenous TGFβ1, in the development of pulmonary fibrosis in response to an exogenous injury.

Highlights

Idiopathic Pulmonary Fibrosis (IPF) is a progressive diffuse disease involving the lung parenchyma
TGFβ1 expression was confirmed by PCR amplification in Tr+ TGFβ1 transgenic mice (Figure 1a)
Tr+ transgenic mouse livers were histologically abnormal as early as 1 month, though the most marked changes were seen from 3 months onwards

Summary

Introduction

Idiopathic Pulmonary Fibrosis (IPF) is a progressive diffuse disease involving the lung parenchyma. Idiopathic pulmonary fibrosis (IPF) is a progressive diffuse fibrotic process involving the lung parenchyma. It is a chronic, progressively debilitating and fatal disorder [1]. In IPF, exogenous mediators are thought to precipitate the lung injury, and in synergy with genetic factors contribute to the disease. Evidence from studies of fibrotic disorders, including renal and liver fibrosis, supports that TGFβ1 may play a novel role in fibrogenesis by promoting epithelial-mesenchymal transition (EMT) and activating fibroblasts to myofibroblasts [7,8,9]. Several approaches to reduce TGFβ1 levels have been evaluated in human tissue in vivo, showing downregulation of the fibrotic process by IFN-1b, which may occur both directly and indirectly by modification of the fibroblast response to reduced TGFβ1. [16,17]

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Conclusion