Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic disease of the lung that is marked by progressive decline in pulmonary function and ultimately respiratory failure. Genetic and environmental risk factors have been identified that indicate injury to, and dysfunction of the lung epithelium is central to initiating the pathogenic process. Following injury to the lung epithelium, growth factors, matrikines and extracellular matrix driven signaling together activate a variety of repair pathways that lead to inflammatory cell recruitment, fibroblast proliferation and expansion of the extracellular matrix, culminating in tissue fibrosis. This tissue fibrosis then leads to changes in the biochemical and biomechanical properties of the extracellular matrix, which potentiate profibrotic mechanisms through a "feed-forward cycle." This review provides an overview of the interactions of the pathogenic mechanisms of IPF with a focus on epithelial-mesenchymal crosstalk and the extracellular matrix as a therapeutic target for idiopathic pulmonary fibrosis.

Keywords: Genetics; IPF; Interstitial lung disease; Matrix; Treatment.

Figure 1

Summary of the pathologic features of IPF disease initiation. A variety of genetic and environmental factors have been implicated as sources of injury to the lung and/or alveolar epithelium. Following epithelial injury, activation of canonical injury-repair programs leads to inflammatory cell and fibroblast recruitment, production of collagen and ECM which undergoes pathologic remodeling. This in turn leads to abnormal repair of the alveolar epithelium and failure to coordinate regeneration of functional alveoli.

Figure 2

Feed-forward profibrotic epithelial-mesenchymal interactions. After activation from injured AECs, there is elaboration and activation of profibrotic mediators including TGF-B, CTGF, and others that lead to recruitment and activation of fibroblasts, increased deposition of ECM and reduced breakdown of the ECM, ultimately leading to a stiffened and poorly organized ECM. The increased matrix stiffness creates a feedback loop along with autocrine signaling from activated fibroblasts to further activate fibrotic signaling.