Idiopathic pulmonary fibrosis (IPF), the most common and severe interstitial lung disease (ILD), is minimally responsive to current medical therapies, and has a mortality rate comparable to that of many end-stage malignancies. There is increasing awareness that IPF may transition through an asymptomatic stage where the primary detectable abnormalities are radiologic. It is our belief that risk factor modification and medical therapies, when instituted at an early stage, will lead to improved care for patients at risk to develop IPF. However, for this field to progress it will be imperative to develop comprehensive clinical, radiologic, physiologic, and molecular profiles to determine which subjects are at greatest risk to develop pulmonary fibrosis. Recently we demonstrated that smokers with interstitial lung abnormalities (ILA) on chest computed tomography (CT), who had not been previously diagnosed with ILD, had reduced total lung capacity, exercise capacity, and emphysema compared to smokers without ILA. We hypothesize that some of these subjects with ILA are at increased risk to develop IPF. To pursue our hypothesis we will capitalize on existing chest CTs, histopathologic, and genotypic data from large well-phenotyped cohorts. This proposal has the following Specific Aims:
Aim 1) We will identify the clinical predictors of ILA and ILA progression utilizing both the COPDGene and Framingham Heart Study cohorts;
Aim 2) Using a Brigham and Women's Hospital cohort of subjects with both preoperative chest CTs and lung tissue specimens we will determine the correlation between ILA and histopathologic evidence of interstitial pneumonitis/pulmonary fibrosis and;
Aim 3) we will evaluate the genetics and epigenetic correlations between ILA and IPF utilizing the above cohorts.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF), a disorder characterized by lung scarring, is not responsive to current medical therapies, and has a prognosis comparable to that of many end-stage malignancies. Identifying an early/asymptomatic stage of IPF may lead to improved care for these patients. This proposal will characterize large groups of subjects who may be at risk to develop IPF, identify the environmental, genetic, and epigenetic factors that may increase this risk, and evaluate if these factors are linked to those of patients with IPF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Gan, Weiniu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Ash, Samuel Y; Harmouche, Rola; Ross, James C et al. (2018) Interstitial Features at Chest CT Enhance the Deleterious Effects of Emphysema in the COPDGene Cohort. Radiology 288:600-609
Diaz, Alejandro A; Strand, Matthew; Coxson, Harvey O et al. (2018) Disease Severity Dependence of the Longitudinal Association Between CT Lung Density and Lung Function in Smokers. Chest 153:638-645
Miller, Ezra R; Putman, Rachel K; Vivero, Marina et al. (2018) Histopathology of Interstitial Lung Abnormalities in the Context of Lung Nodule Resections. Am J Respir Crit Care Med 197:955-958
Rosas, Ivan O; Goldberg, Hilary J; Collard, Harold R et al. (2018) A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. Chest 153:94-104
Ash, Samuel Y; Harmouche, Rola; Putman, Rachel K et al. (2018) Association between acute respiratory disease events and the MUC5B promoter polymorphism in smokers. Thorax 73:1071-1074
Axelsson, Gisli Thor; Putman, Rachel K; Araki, Tetsuro et al. (2018) Interstitial lung abnormalities and self-reported health and functional status. Thorax 73:884-886
Putman, Rachel K; Gudmundsson, Gunnar; Araki, Tetsuro et al. (2017) The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes. Eur Respir J 50:
Ash, Samuel Y; Harmouche, Rola; Putman, Rachel K et al. (2017) Clinical and Genetic Associations of Objectively Identified Interstitial Changes in Smokers. Chest 152:780-791
Ash, Samuel Y; Harmouche, Rola; Ross, James C et al. (2017) The Objective Identification and Quantification of Interstitial Lung Abnormalities in Smokers. Acad Radiol 24:941-946
Miller, Ezra R; Hunninghake, Gary M (2017) Malaria and the development of pulmonary fibrosis. Eur Respir J 50:

Showing the most recent 10 out of 40 publications