Novel therapeutic approaches for pulmonary fibrosis

Abstract

Pulmonary fibrosis represents the end stage of a number of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small number of interstitial lung diseases have known aetiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis - median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial-mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biological pathways affecting inflammation and wound repair - including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways - modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clinical trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition.

Figure 1

Fibrotic foci – a histological hallmark of idiopathic pulmonary fibrosis. (A) Histological analysis of human IPF tissue reveals the presence of dense collagen deposition within the interstitium (Martius Scarlet Blue staining; original magnification ×10). Fibroblastic foci are revealed as accumulations of fibroblasts and alpha-SMA⁺ myofibroblasts, which are highly synthetic for collagen and have a contractile phenotype (B: Martius Scarlet Blue staining; C: immunohistochemistry for alpha-SMA. Original magnification ×20). The overlying epithelium is often hyperplastic, with frequent apoptosis and areas of denudation. The presence and distribution of fibrotic foci, together with the spatial and temporal heterogeneity of the pathology is crucial to defining a UIP pattern.

Figure 2

Key mediators in the pathogenesis of IPF. The pathobiological mechanisms underlying the development of IPF are highly complex. Recurring damage to the epithelium (possibly due to reactive oxygen species, endoplasmic reticulum stress or viral infection) results in an abnormal wound healing response characterized by dysregulated epithelial–mesenchymal crosstalk and the accumulation of myofibroblasts (the key effector cells in IPF fibrogenesis). The proposed cellular origin of these cells includes resident fibroblasts, epithelial/endothelial–mesenchymal transition or the recruitment of circulating fibrocytes. The fibrotic micro-environment may be skewed towards a pro-angiogenic and Th2-oriented profile, where multiple cytokines, growth factors and signalling pathways mediate the pro-fibrotic responses. Some of the potential anti-fibrotic strategies (shown in red) are highlighted and these are described further in the text.