Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways

Abstract

Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF.

Oxidative and endoplasmic reticulum stress in respiratory disease

“…Idiopathic pulmonary fibrosis is a progressive interstitial lung disease arising around the distal airway/alveoli that involves epithelial cell death, inflammation and fibrosis, with few treatment options and a high mortality rate 68. Although the aetiology is unclear, there are several strong genetic links to predisposition to IPF, including rare alleles in surfactant ( SFTPC , SFTPA2 ) and telomerase pathway ( TERT , TERC , PARN and RTEL ) genes, and more common alleles of MUC5B strongly associated with a less aggressive form of IPF (reviewed by Evans et al 68…”

“…The common variant rs35705950 in the promoter region of MUC5B is carried by 9% of the European population and is the strongest risk factor for developing IPF accounting for 30–35% of the risk and also predicting asymptomatic mild fibrosis 68, 77, 78, 79. There are multiple potential explanations for how this polymorphism could lead to fibrosis (for a discussion, Evans et al 68…”

“…Perhaps this level of stress can be managed in the absence of other stressors but with ageing and accumulated environmental insults, including from viral infection, ER stress and inflammation emerge and progress with consequent fibrosis. Whilst the mucin is normally expressed only in differentiated cells, the polymorphism may drive inappropriate MUC5B expression in stem cells, as suggested by Evans et al .,68 and could lead to altered survival or function of the stem cells that are needed to appropriately renew epithelium in the terminal airways.…”

Gel-forming mucins form distinct morphologic structures in airways

“…Chronic obstructive pulmonary disease manifests increased mucin production (9,13). Variations in the MUC5B gene promoter/enhancer region have been associated with interstitial pulmonary fibrosis (14). In advanced cystic fibrosis (CF), airways show goblet cell hyperplasia and submucosal gland hypertrophy, and imaging of radiolabeled particles deposited in the lung indicates that MCT is reduced (1,3).…”

A recurring theme in pulmonary fibrosis genetics

“…Similarly, mutations in the ABCA3, SFTPC and SFTPA genes were linked to cases of sporadic IPF [8]. Of these genes, MUC5B has the most robust linkage to IPF and has been confirmed in at least 10 independent studies [9]. Nevertheless, not all individuals with the common variants associated with IPF acquire the disease.…”