Idiopathic Pulmonary Fibrosis Is a Genetic Disease Involving Mucus and the Peripheral Airways

Abstract

Idiopathic pulmonary fibrosis (IPF) is localized to the lung, is characterized by a pattern of heterogeneous, subpleural patches of fibrotic, remodeled lung, and is associated with a median survival of 3-5 years after diagnosis. A common gain-of-function MUC5B promoter variant, rs35705950, is the strongest risk factor (genetic and otherwise), accounting for at least 30% of the total risk of developing IPF. The MUC5B promoter variant can be used to identify individuals in the preclinical phase of this progressive disease, and, in the IPF lung, we have found that MUC5B is specifically overexpressed in bronchoalveolar epithelium. Thus, MUC5B represents a key molecule to understand the mechanisms that appear to initiate the fibroproliferative process in the bronchoalveolar epithelium. Moreover, focusing on MUC5B may provide a unique opportunity to define the early molecular events that lead to, and potentially prevent, the development of IPF.

Keywords: IPF; MUC5B; idiopathic pulmonary fibrosis.

Figure 1.

Model of stem cells repopulating bronchioles and alveoli under normal physiologic conditions and when challenged with increased expression of MUC5B. We hypothesize that excessive production of MUC5B by stem cells that attempt to regenerate injured bronchiolar and alveolar epithelium disrupt normal developmental pathways and hijack the normal reparative mechanisms in the distal lung, resulting in chronic fibroproliferation and honeycomb cyst formation. Adapted by permission from Reference .

Figure 2.

Model of recurrent injury/repair at the bronchoalveolar junction that is initiated and exacerbated by overexpression of MUC5B, retention of inhaled particles, and enhanced lung injury. The upper panel is the normal bronchoalveolar region and the lower panel represents a bronchoalveolar region affected by idiopathic pulmonary fibrosis (IPF). We hypothesize that IPF is a mucociliary disease that is caused by recurrent injury/repair at the bronchoalveolar junction that is initiated and exacerbated by overexpression of MUC5B leading to reduced ciliary function, retention of particles, and enhanced injury. Reprinted by permission from Reference .

Figure 3.

Our overall concept is that family history of idiopathic pulmonary fibrosis (IPF), the MUC5B variant, and biomarkers can identify individuals at high risk for preclinical pulmonary fibrosis (PrePF), establishing the opportunity for primary and secondary prevention of IPF. The “at-risk” population (family history of IPF) and the population with PrePF is large, and the yield of PrePF will be enriched by family history of IPF, the MUC5B variant, other genetic variants, and biomarkers that we discover in this program. Recent findings (38) indicate that PrePF (detected via chest CT scan) is associated with a poor prognosis, suggesting that PrePF may be a harbinger of IPF. CT = computed tomography; FIP = familial interstitial pneumonia; HR = hazard ratio; ILA = interstitial lung abnormality; NHWs = non–Hispanic white individuals; OR = odds ratio. Adapted by permission from Reference .