Characterization of Apolipoprotein A-I Pathways in Idiopathic Pulmonary Fibrosis

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive disease that occurs primarily in older individuals, 55 to 75 years of age, with a median survival of approximately 3 years from time of diagnosis. At present, there are no effective treatments for patients with IPF. Levels of apolipoprotein A-I (apoA-I) have been found to be reduced in the lungs of patients with IPF, while administration of human apoA-I has been shown to reduce bleomycin-induced collagen deposition in a murine model. Here, we would like to assess whether apoA-I pathways modify lung cell biology in patients with IPF. This is a specimen procurement, clinical phenotyping and genotyping protocol that will assess whether holo-apoA-I and apolipoprotein A-I mimetic peptides, can attenuate key pathogenic manifestations of IPF, such as proliferation and extracellular matrix generation by pulmonary fibroblasts, which may serve as evidence to support future human clinical trials of apoA-I for the treatment of IPF. Furthermore, the identification of new apoA-I responsive genes and pathways that mediate fibroblast proliferation in IPF may provide insights into disease pathogenesis and identify new therapeutic targets. Lastly, if induced pluripotent stem (iPS) cells can be successfully shown to model responsiveness of lung cells to apoA-I therapy, then this approach may be expanded with the goal of providing a personalized medicine analysis that could in the future guide selection of the most effective therapy for individual patients. Research from this project has shown that small HDL particles, as quantified by NMR spectroscopy, were negatively correlated with GAP index, which is a predictor of mortality in IPF. Furthermore, higher levels of small HDL particles were associated with lower odds of death or lung transplantation at 1, 2 and 3 years from study entry in IPF subjects. Thus, this study supports the hypothesis that small HDL particles may modify mortality risk in patients with IPF. These finding have been published in the European Respiratory Journal (PMID: 34289973 DOI: 10.1183/13993003.04053-2020).