Idiopathic Pulmonary Fibrosis: From Epithelial Injury to Biomarkers - Insights from the Bench Side

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most frequent fibrotic diffuse parenchymal lung disease. Its prognosis is devastating: >50% of the patients die within 3 years after diagnosis. Options for the treatment of IPF are limited and lung transplantation is the only ‘curative' therapy. Currently, in the absence of validated indicators of disease progression/activity and diagnostic tools, the clinical management of IPF remains a major challenge. A better understanding of the pathogenesis of IPF is critical for the identification of new therapeutic targets as well as molecules that may serve as surrogate markers for clinically significant endpoints. The current paradigm on the mechanisms leading from a normal to a fibrotic lung postulates that chronic epithelial lesion leads to aberrant wound healing activation, which is characterized by deregulated fibroblast proliferation and activation together with an uncontrolled extracellular matrix synthesis. In this review, we shed light on the role of epithelial cell damage in the pathogenesis of fibrosis. Finally, we examine the markers of epithelial damage and their potential use as biomarkers and the future of this continuously expanding field.

Pirfenidone in Idiopathic Pulmonary Fibrosis: Real-Life Experience from a German Tertiary Referral Center for Interstitial Lung Diseases

“…This was also demonstrated in a recent cost-effectiveness analysis which showed unfavorable cost ratios for any quality-adjusted life year gained by pirfenidone treatment [30]. Nonetheless, it has to be acknowledged that the advent of pirfenidone has brought about a series of clinical trials with novel drugs that specifically interfere with cellular and molecular pathways implicated in the fibrosing process in IPF [4]. This is an important step forward towards a targeted therapy in IPF, and hopefully in the future there will be a range of pharmacological interventions to choose from when having to decide on appropriate treatment strategies for patients with IPF.…”

“…Men in their 6th or 7th decade of life are predominantly affected. The etiology of the disease is largely unknown, but ample evidence suggests that an initial insult to the alveolar epithelium sets off a complex cascade of repair mechanisms which ultimately results in abundant deposition of extracellular matrix within the pulmonary interstitium [3,4]. …”

ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling

“…The insidious progression of clinical pulmonary fibrosis has seriously hampered the understanding of the pathological development and mechanisms, but it is now generally recognized that an aberrant epithelial wound healing in association with dysregulated fibroblast proliferation and matrix synthesis has a key role in the disease development. 1 To investigate the initiation and early development of pulmonary fibrosis animal models are commonly used, one of the most common being local bleomycin administration. Local (intratracheal) bleomycin administration causes epithelial necrosis and severe inflammation severely affecting all cells within the central part of the lung, which is followed by development of a heterogeneous fibrosis and later resolution.…”

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

“…Aging, smoking and infection have been reported as risk factors for pulmonary fibrosis (11). The pathological characteristics of pulmonary fibrosis are repetitive microscopic alveolar epithelial cell injury, dysregulated repair, fibroblast proliferation and accumulation of extracellular matrix, which ultimately result in respiratory failure (12). EMT is an important mechanism of lung fibrogenesis through the generation of mesenchymal-type myofibroblasts from lung epithelial cells (13).…”