Recent advances in understanding idiopathic pulmonary fibrosis

Abstract

Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF.

Keywords: idiopathic pulmonary fibrosis; interstitial lung diseases.

Figure 1.. Typical high-resolution computed tomography (HRCT) pattern of usual interstitial pneumonia (UIP).

The image shows subpleural and basal predominance of reticular opacities associated with traction bronchiectasis and honeycomb change (clustered cystic airspaces with well-defined thick walls and diameter of 0.3–1.0 cm).

Figure 2.. Photomicrograph of biopsy from a 63-year-old man with a multi-disciplinary diagnosis of idiopathic pulmonary fibrosis.

The patient shows the typical histopathological features of usual interstitial pneumonia characterised by spatial heterogeneity with areas of subpleural and paraseptal fibrosis and honeycombing changes (cystic airspaces lined by bronchiolar epithelium) alternating with areas of relatively spared lung parenchyma, temporal heterogeneity with admixed areas of active fibrosis with fibroblast foci, extracellular matrix deposition (mainly collagen), and relative mild or absence of inflammatory cell infiltrate together with regions of histologically normal lung tissue.

Figure 3.. A schematic representing the current model for the pathogenesis of idiopathic pulmonary fibrosis.

In genetically susceptible individuals, injury activates multiple inflammatory, cell signalling, and repair pathways. Activation of these cascades causes an imbalance in profibrotic and antifibrotic mediators. In turn, these mediators activate multiple cell types, causing changes in cellular functioning and cell-cell interactions that ultimately result in progressive fibrosis. Abbreviations: CTGF, connective tissue growth factor; FXa, factor Xa; HGF, hepatocyte growth factor; IFNγ, interferon-γ; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; TGFβ, transforming growth factor β, Th, T-helper; VEGF, vascular endothelial growth factor.