Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.

Figure 1. Model of idiopathic pulmonary fibrosis pathogenesis

Genetic predisposition, age-related cell perturbations and environmental exposures increase susceptibility to epithelial lung injury as they reduce the capacity of the lung to regenerate and to respond to stress. Epithelial cells show several markers of stress, activation and senescence, including the reactivation of embryonic pathways. In lungs with idiopathic pulmonary fibrosis (IPF), progenitor KRT5⁺ Δp63⁺ lung epithelial cells fail to regenerate alveolar epithelial type 2 cells (AEC2s) and this event promotes the formation of the characteristic pathology of IPF known as ‘honeycomb lung’. Persistent aberrant activation and senescence of the epithelium leads to the hyperactive secretion of a set of pro-fibrotic growth factors, chemokines and angiostatic, procoagulant mediators collectively known as senescence-associated secretory phenotype (SASP) factors. SASP factors result in abnormal wound healing that is characterized by dysregulated crosstalk between the epithelium and the mesenchymal cells and by the accumulation of myofibroblasts. Fibroblasts and myofibroblasts in the IPF lung present a stressed and senescent phenotype, including resistance to apoptosis and exaggerated production of extracellular matrix components. Increased matrix stiffness generates changes in the niche that affect the behaviour of the fibroblasts and epithelial cells, thus causing irreversible damage and fibrosis.

Figure 2. Overview of the main clinical trials focused on idiopathic pulmonary fibrosis

Pharmacological compounds in clinical studies are shown according to the highest phase of clinical trial. Approved drugs are shown in blue. Studies with published negative results are shown in red. Ongoing studies with partial results are shown in green and those with pending data are shown in yellow. The triple therapy consists of prednisone, azathioprine and NAC. MSCs, mesenchymal stem cells; IFNγ, interferon-γ; NAC, N-acetyl-l-cysteine.

Figure 3. Selected emerging therapeutic interventions that target age-related cell perturbations in lung fibrosis

Novel therapies for age-related diseases target key cellular processes in ageing cells. Senolytic drugs include dasatinib, quercetin and navitoclax. Dasatinib and quercetin inhibit tyrosine kinases, and navitoclax inhibits anti-apoptotic family members of the B cell lymphoma 2 (BCL-2) protein family. The secretory associated senescence phenotype (SASP) is regulated by mechanistic target of rapamycin (mTOR), and mTOR inhibitors such as rapamycin can reduce the presence of SASP factors in senescent fibroblasts. mTOR inhibitors also promote autophagy and the apoptosis of fibroblasts in lungs with idiopathic pulmonary fibrosis (IPF). Rupatadine has also been shown to reduce cellular senescence and, potentially, SASP by preventing the activation of the p53–p21 pathway and by attenuating the expression of CCAAT/enhancer-binding protein-β (C/EBPβ), a positive modulator of SASP. Inhibitors of the nuclear factor (NF)-κB signalling pathway inhibit SASP. Pharmacological chaperones, inhibitors of Ca²⁺ mobilization and the osmolytic compound 4-phenyl butyric acid (4-PBA) can rebalance proteostasis. Several therapeutic strategies are under development to improve mitochondrial function, including MitoQ and small molecules such as XBJ-5-131 that act as antioxidants and radical scavengers. Specific alterations found in the cells of IPF lungs suggest that activators of sirtuin 3 (SIRT3), inducers of mitophagy and methods to increase levels of mitochondrial DNA (mtDNA) repair enzymes might have beneficial therapeutic effects. Oestrogen receptor modulators such as raloxifene, as well as androgens, have been used to induce telomerase activity and to increase telomere length, although further studies are needed. HDAC, histone deacetylase; JAK, Janus kinase; miR-21, microRNA-21; NOX4, NADPH oxidase 4; PI3K, phosphoinositide 3-kinase; STAT, signal transducer and activator of transcription.