Idiopathic Pulmonary Fibrosis, a Disease Initiated by Mucociliary Dysfunction
Abstract
Topic Area/Priority Research Area: Respiratory Health/Pulmonary Fibrosis. Idiopathic Pulmonary Fibrosis (IPF) affects five million worldwide, disproportionately affects men, is associated with cigarette smoking and combat-related particulate exposures, increases with age, is inexplicably increasing in prevalence, is a source of morbidity and mortality among military personnel, and is likely underdiagnosed. Patients with IPF are usually diagnosed when the disease has caused permanent and extensive lung parenchymal damage. Given the irreversible nature of this disease, even approved treatments for IPF only modestly slow progression and have not been shown to alter the poor 3- to 5-year survival after diagnosis. We have found that (1) a genetic variant in the MUC5B gene is the strongest risk factor (genetic and otherwise) for the development of IPF, accounting for at least 30% of the risk of disease; (2) the genetic variant in the MUC5B gene can be used to identify individuals in the preclinical phase of this life-threatening disease; (3) the product of the MUC5B gene appears to be involved in the pathogenesis of IPF; and (4) in IPF, the MUC5B gene is overexpressed in the distal lung or the bronchoalveolar epithelium. Thus, the MUC5B gene provides a unique opportunity to define the early molecular events that lead to the development of IPF, and can be used to identify patients in the early preclinical phases of IPF. Earlier diagnosis of IPF will detect subjects with a lower burden of lung disease, more salvageable lung, and may reveal novel molecular targets for intervention that are effective in the preclinical and/or early clinical stages of this progressive disease. We are addressing an unmet need in IPF by building on our knowledge of the genetic risk factors involved in IPF and mucin biology to develop the scientific basis to predict and prevent the progression of preclinical idiopathic pulmonary fibrosis before the lung has been irreversibly compromised by extensive scarring and fibrosis. Given our understanding of MUC5B, mucin biology/physiology, transcriptional regulation, biomarker sciences, and IPF, we have developed an integrated approach that assimilates early molecular stages of fibrosis with predictive biomarkers to detect preclinical stages of pulmonary fibrosis and develop strategies to prevent the progression of IPF. The scientific themes that unify the projects are: (1) mechanisms that regulate MUC5B transcription in airway epithelia; (2) biological consequences of MUC5B overproduction that result in mucociliary dysfunction, retention of particles, and disruption of normal reparative and regenerative mechanisms in the distal lung; and (3) the utility of MUC5B and other biomarkers to predict pulmonary fibrosis and identify those with preclinical pulmonary fibrosis who are at risk of disease progression. We believe that understanding the basic and translational aspects of our unifying scientific themes will provide the rationale to develop clinical interventions and establish primary, secondary, and tertiary approaches for disease prevention and intervention. At the completion of this highly integrated program, we will have identified the role of lung mucins in fibrosis, the unique contribution of the bronchoalveolar epithelia and cilia to disease, and the dynamic biology that can be captured in reliable biomarkers to better define those at risk of pulmonary fibrosis and disease progression. Impact: Patients with IPF are usually diagnosed when the fibroproliferative process has caused permanent and extensive lung parenchymal damage. Given the irreversible nature of this disease, even approved treatments for IPF only modestly slow progression and have not been shown to alter the 3- to 5-year survival. However, the MUC5B promoter variant, coupled with the development of preclinical interstitial lung abnormalities that appears to be a harbinger of IPF, creates a window of opportunity to identify
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710597
Entities
People
- David A Schwartz
Organizations
- United States Army
- University of Colorado Denver