Soluble TNF Mediates the Transition from Pulmonary Inflammation to Fibrosis

Nikos Oikonomou,Jonathan Zalevsky,Vassilis Aidinis,George Kollias,Vaggelis Harokopos,Anastasia Kotanidou,Christos Valavanis,David E Szymkowski,Nina Papavasiliou

doi:10.1371/journal.pone.0000108

Abstract

BackgroundFibrosis, the replacement of functional tissue with excessive fibrous tissue, can occur in all the main tissues and organ systems, resulting in various pathological disorders. Idiopathic Pulmonary Fibrosis is a prototype fibrotic disease involving abnormal wound healing in response to multiple sites of ongoing alveolar epithelial injury.Methodology/Principal FindingsTo decipher the role of TNF and TNF-mediated inflammation in the development of fibrosis, we have utilized the bleomycin-induced animal model of Pulmonary Fibrosis and a series of genetically modified mice lacking components of TNF signaling. Transmembrane TNF expression is shown to be sufficient to elicit an inflammatory response, but inadequate for the transition to the fibrotic phase of the disease. Soluble TNF expression is shown to be crucial for lymphocyte recruitment, a prerequisite for TGF-b1 expression and the development of fibrotic lesions. Moreover, through a series of bone marrow transfers, the necessary TNF expression is shown to originate from the non-hematopoietic compartment further localized in apoptosing epithelial cells.ConclusionsThese results suggest a primary detrimental role of soluble TNF in the pathologic cascade, separating it from the beneficial role of transmembrane TNF, and indicate the importance of assessing the efficacy of soluble TNF antagonists in the treatment of Idiopathic Pulmonary Fibrosis.

Highlights

Fibroproliferative diseases are among the leading causes of morbidity and mortality worldwide
The replacement of functional tissue with excessive fibrous tissue, can occur in all the main tissues and organ systems resulting in various disorders including cardiac, cerebral and peripheral vascular disease, liver cirrhosis, progressive kidney disease and a number of interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF)
IPF is associated with the appearance of Usual Interstitial Pneumonitis (UIP), which is characterized by patchy subpleural and/or paraseptal interstitial fibrosis alternating with areas of mild inflammation and normal lung

Summary

Introduction

Fibroproliferative diseases are among the leading causes of morbidity and mortality worldwide. The replacement of functional tissue with excessive fibrous tissue, can occur in all the main tissues and organ systems resulting in various disorders including cardiac, cerebral and peripheral vascular disease, liver cirrhosis, progressive kidney disease and a number of interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF). Despite their obvious etiological and clinical distinctions, most of these fibrotic diseases have in common a persistent inflammatory stimulus that sustains and/or stimulates the production of growth factors and fibrogenic cytokines, which together stimulate the deposition of connective-tissue elements that progressively remodel and destroy normal tissue architecture. These results suggest a primary detrimental role of soluble TNF in the pathologic cascade, separating it from the beneficial role of transmembrane TNF, and indicate the importance of assessing the efficacy of soluble TNF antagonists in the treatment of Idiopathic Pulmonary Fibrosis

Methods

Results

Conclusion