Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis

Highlights

• Therapy with prednisone/azathioprine/N-acetylcysteine increases mortality in IPF.

• Several molecular pathways contribute to the pathogenesis of IPF.

• Heterogeneity in IPF emphasizes the need for patient specific treatments.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) of unknown origin characterized by epithelial cell dysfunctions, accumulation of fibroblasts and myofibroblasts and relentless deposition of extracellular matrix (ECM). Improved diagnostic accuracy and better trial design have provided important insights from recent clinical trials. Perhaps the most important insight was the realization that ‘standard therapy’ was actually harmful! This review summarizes the current understanding of the cell types that are altered in IPF and the pathogenic mechanisms that have been identified. It also reviews recent clinical trial results and interpretations. Finally, we highlight attractive biologic targets and therapies in development with recommendations for future therapeutic avenues.

Introduction

Fibrosis in ILD is caused by the accumulation of ECM proteins within the interstitium and alveolar space of the lung. Some forms of ILD can be caused by environmental exposures (e.g., asbestos, inorganic dusts, organic particulates, drug toxicity or radiation). ILD can also occur in the context of systemic disease (e.g., collagen vascular disease) or due to genetic mutations (e.g., mutations in surfactant proteins or telomerase components) [1]. However, the majority of severe cases comprise a classification known as IPF for which the origin is unknown. The classification of IPF is based on radiographic patterns and/or the identification of the usual interstitial pneumonia (UIP) pattern on histology [2^••]. The disease is progressive, and often results in respiratory insufficiency within 3–5 years post-diagnosis [3]. The pathogenesis of the disease is poorly understood and most insights are based on inferences made from histology or various animal models which result in lung fibrosis. The variable natural history of IPF is another confounding factor. Some patients experience a relatively gradual decline in lung function, some experience stable disease over extended periods of time, and others have acute deteriorations with rapid worsening and disease progression [4]. This heterogeneity has complicated the design of clinical trials and the identification of potential therapies.