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

  • A Corrigendum to this article was published on 30 October 2017

Key Points

  • Idiopathic pulmonary fibrosis (IPF) is a chronic lethal lung disease, the prevalence and incidence of which dramatically increase with age.

  • Novel therapeutic interventions for IPF are necessary as approved therapies are limited to slowing the progression of the disease.

  • Similar to other age-related diseases, cell perturbations present in ageing cells are found in epithelial and mesenchymal cells from IPF lungs, including telomere shortening, senescence, stem cell exhaustion and mitochondrial dysfunction.

  • The development of novel therapies for IPF has been hampered by inadequate animal models, the lack of interventions that promote epithelial repair, and the lack of understanding of the contribution of the ageing process to damage and fibrosis.

  • Further insights into the pathogenesis of IPF, the mechanisms involved in ageing as a risk factor and the genetic predisposition to this disease are crucial to overcome current therapeutic obstacles.

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.

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Figure 1: Model of idiopathic pulmonary fibrosis pathogenesis.
Figure 2: Overview of the main clinical trials focused on idiopathic pulmonary fibrosis.
Figure 3: Selected emerging therapeutic interventions that target age-related cell perturbations in lung fibrosis.

Change history

  • 30 October 2017

    In the original version, navitoclax was incorrectly referred to as an apoptosis inhibitor in Figure 3. The error has been corrected online.

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Acknowledgements

The authors thank E. Chiang for assistance and production of the figures. A.L.M. is funded by NIH R01 HL131789A; the Aging Institute, University of Pittsburgh; the Institute for Transfusion Medicine; and the Hemophilia Center for Western Pennsylvania. M.R. is funded by NIH R01 HL123766-01A1.

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Correspondence to Ana L. Mora.

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Competing interests

M.S. contributes to the Adjudication Committee in a clinical trial on idiopathic pulmonary fibrosis conducted by Celgene. M.R., A.P. and A.L.M. declare no competing interests.

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Glossary

Alveolar epithelial cells

The alveolar epithelium consists of alveolar epithelial type 1 cells (AEC1s) and type 2 cells (AEC2s). Squamous AEC1s are flat and constitute ~95% of the surface area of the lung but account for a minor proportion of the total cell population. AEC1s closely interact with the alveolar capillary system and are the primary site for gas exchange and the regulation of fluid homoeostasis.

Fibroblasts

Connective tissue cells of mesenchymal origin located in the lungs beneath epithelial cells or scattered throughout the interstitium between the epithelial and endothelial layers. They secrete extracellular matrix (ECM) proteins, especially fibrillar collagens. Fibroblasts and the ECM form the structural framework of tissues in animals and have a crucial role in tissue physiology and repair.

Epithelial–mesenchymal transition

(EMT). The biological process that allows differentiated epithelial cells to assume a mesenchymal phenotype, which includes enhanced migratory capacity and increased production of extracellular matrix components. This process has been associated with tissue repair, fibrosis and metastasis.

Alveolar epithelial type 2 cells

(AEC2s). Cuboidal cells scattered within the alveolar walls that synthesize and secrete the surfactant that regulates alveolar surface tension. AEC2s also regulate fluid balance, coagulation and fibrinolysis, and the immune response and host defence. AEC2s proliferate and differentiate into AEC1s, functioning as self-renewing cells and precursors of AEC1s, thus contributing to epithelial repair.

Mucin

Member of a family of gel- forming glycoproteins characterized by the presence of tandem repeat domains. Mucins are produced by epithelial cells and classified as membrane- bound or secreted. Mucins are the main component of mucus.

Conducting airways

The airways of the lung provide a pathway for bringing air to the gas exchange surfaces of the lung, but do not exchange gas. Mucins and host-defence molecules are secreted by submucosal glands into the periciliary fluids of the conducting airways, so they are important for defence against pathogens.

Alveoli

These structures are the ultimate unit of respiratory gas exchange and consist of a specialized epithelium surrounded by a rich network of pulmonary capillaries, embedded in a delicate meshwork of connective tissue.

Desmosomes

Intercellular tight junctions that provide a connection between intermediate filaments of the cytoskeletons of adjacent cells. These structures give strength to epithelial cells and contribute to resistance against shearing forces.

Myofibroblast

A cell type resulting from the differentiation of fibroblasts (and other mesenchymal cells) following injury, cellular distress or inflammation. Myofibroblasts are crucial for normal tissue wound repair but, under persistent or repeated insult, drive the accumulation of extracellular matrix and the disruption of the basement membrane, thus contributing to aberrant remodelling. In this context, myofibroblasts are key effector cells in fibrotic diseases.

Fibrocytes

Bone marrow-derived circulating cells that express both fibroblasts and leukocyte markers and produce components of the extracellular matrix.

Bleomycin-induced lung injury

Bleomycin is an anti-cancer therapy, the main complication of which is pulmonary fibrosis, and so bleomycin is widely used in experimental animal models of lung fibrosis as an intratracheal instillation or systemic injection. In mice, severe inflammation in days 0–7 is followed by a progressive accumulation of collagen between days 14 and 21 after treatment.

Dyskeratosis congenita

(DKC). A disorder caused by mutations in the TERT, TERC, DKC1 or TINF2 genes, which are crucial for maintaining the structure and function of telomerase. The main clinical features vary widely, but include nail dystrophy, skin hyperpigmentation and oral leukoplakia. Patients with DKC have an increased risk of developing aplastic anaemia, cancer such as leukaemia and pulmonary fibrosis.

Ink-Attac mouse

Transgenic mouse model that removes p16Ink4a-positive senescent cells upon the administration of the synthetic drug AP20187. Mice express a FK506–caspase 8 membrane-bound fusion protein, which is dimerized and activated by AP20187 binding, and is expressed under the control of the p16INK4a promoter.

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Mora, A., Rojas, M., Pardo, A. et al. Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease. Nat Rev Drug Discov 16, 755–772 (2017). https://doi.org/10.1038/nrd.2017.170

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