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  • Review Article
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Strategies for treating idiopathic pulmonary fibrosis

Key Points

  • Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia (IIP), a group of diseases of unknown cause that scar predominantly the gas-exchanging regions of the lungs — the alveoli. IPF is also the most lethal IIP, with a mortality rate which exceeds that of many cancers.

  • The current paradigm of pathogenesis is an aberrant healing response to epithelial cell injury, which probably occurs in response to a combination of environmental insults and/or genetic predispositions.

  • Prior to 2000, no studies of therapy had been undertaken that had provided clear evidence of efficacy.

  • More recent, better designed studies have generally been disappointing, although there is some evidence for benefit either with a combination of prednisone, azathioprine and N-acetylcysteine or with pirfenidone.

  • Novel initiatives that hold promise include the National Heart, Lung and Blood Institute's IPFnet, which aims to find effective therapy for early and late IPF; the use of expression arrays to identify pivotal targets; and the blockade of signalling pathways.

  • Future strategies need to focus on the cause and the consequences of the epithelial cell injury, without which the fibrogenic response would not occur. Further studies of the consequences of aberrant protein production by alveolar type II cells owing to genetic variants and other causes may prove fruitful.

  • Trial design, especially the issue of which end points are most meaningful, remains a challenge in IPF. However, the experiences of the past decade have resulted in considerable progress, particularly regarding the use of change in the lung volume measure, forced vital capacity, as a surrogate for the risk of mortality.

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common and most lethal diffuse fibrosing lung disease, with a mortality rate that exceeds that of many cancers. Recently, there have been many clinical trials of novel therapies for IPF. The results have mostly been disappointing, although two treatment approaches have shown some efficacy. This Review describes the difficulties of treating IPF and the approaches that have been tried or are in development, and concludes with suggestions of future therapeutic targets and strategies.

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Figure 1: Classification of interstitial lung diseases including the idiopathic interstitial pneumonias.
Figure 2: Key events in the pathogenesis of IPF.

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R.M.d.B. has been a paid consultant, steering-committee member and/or co-chair of a steering committee for InterMune, Actelion, Centocor, Boehringer Ingelheim, Novartis, Genzyme and Mondobiotech.

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Glossary

Ground glass pattern

A radiological term for a hazy pattern of increased attenuation that is seen on computed tomography scans of the lung. It is caused by any infiltrate that partially excludes air from the alveoli.

Usual interstitial pneumonia pattern

A histopathological term that denotes a patchy, temporally and anatomically heterogeneous pattern of disease that includes established fibrosis and less established disease with evidence of epithelial cell injury.

Metalloproteinase

An enzyme that catalyses peptide hydrolysis and requires a metal for the enzymatic reaction.

Apoptosis

Programmed cell death.

Endoplasmic reticulum stress

A coordinated cellular response to aberrant protein folding and transport through the endoplasmic reticulum. It can occur following oxidant injury or abnormal protein synthesis and prevents intracellular protein accumulation. If unsuccessful, cell apoptosis is triggered.

Telomere

Either end of a chromosome in a eukaryotic cell.

Cochrane review

A review of medical publications on a particular therapy or group of therapies using defined selection and adjudication criteria, undertaken by volunteers for the Cochrane collaboration, to produce systematic reviews of the effects of health-care interventions.

Alkylating nitrogen mustard

An agent that can donate an alkyl group to another molecule — such as DNA, which would inhibit cell division.

Pulmonary arterial hypertension

A condition in which patients have a mean pulmonary artery pressure of greater than 25 mm Hg at rest or 30 mm Hg during exercise.

6-minute walk test

A test that measures the distance that a patient can walk quickly on a flat, hard surface in a period of 6 minutes. It provides a global index of the integrated response required for exercise but no organ-specific information.

Honeycomb CT change

A computed tomographic pattern in which clusters of cysts are present at the lung periphery and extend contiguously into the adjacent, more central regions. They usually represent areas in which lung destruction is surrounded by established fibrosis.

Vital capacity

A measure of lung volume that is the difference in lung size between a maximal inspiration and a maximal expiration.

Gas exchange for carbon monoxide

An index of the lungs ability to move gas from the alveolar space into the vascular compartment. Abnormalities in this measure indicate a problem in the most peripheral regions of the lungs.

Tyrosine kinase

An enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein, often as part of an intracellular signalling process.

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du Bois, R. Strategies for treating idiopathic pulmonary fibrosis. Nat Rev Drug Discov 9, 129–140 (2010). https://doi.org/10.1038/nrd2958

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