Complement Pathway Activation in Idiopathic Pulmonary Fibrosis and other Progressive Fibrosing Interstitial Lung Diseases

Project Summary/Abstract Idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases (PF-ILDs) lead to inexorable lung function decline and death despite available treatments. Patients with PF-ILD can also experience acute respiratory deteriorations known as acute exacerbations (AE), which carry a high short-term mortality, lack approved treatments, and are poorly understood. Dr. Swaminathan’s long-term goal is to develop novel treatments for PF-ILD that improve outcomes and to use biomarkers to personalize therapies in PF-ILD. The overall objective of this application is to investigate the role of the complement pathway as a biomarker in PF-ILD disease progression, AE, and as a genetic risk factor for PF-ILD development and progression. The central hypothesis is that complement activation, as reflected either by C3b, C4b, or C5a protein generation or genetic variation, associates with PF-ILD progression, AE events, and AE outcomes. The rationale for this project is that identification of complement activation as a biomarker in PF-ILD progression or AE will identify patients for whom further intervention with complement-related therapies is warranted, expanding treatment options for patients with PF-ILD. The central hypothesis will be tested by pursuing three specific aims. In Aim 1, plasma C3b, C4b, and C5a will be quantified in 1,273 PF-ILD patients at baseline and 6 months of follow up to determine the association with a composite measure of disease progression. Aim 2 will recruit a prospective cohort of PF- ILD patients with AE (n=50) to determine the association of plasma C3b, C4b, and C5a with 90-day death or lung transplant and to compare C3b, C4b, and C5a in the plasma and lung tissue of patients with versus without AE. Aim 3 will leverage existing whole genome sequencing in patients with IPF (n=912) and newly generated whole exome sequencing in patients with non-IPF PF-ILD (n=400) to identify protein-coding variants in complement-related genes that confer risk for PF-ILD and associate with PF-ILD progression or AE. By completing the scientific aims and the career development activities of this proposal, Dr. Swaminathan will acquire rigorous clinical and translational research training, including in-depth knowledge of complement biology. Her career development activities will also build new expertise in these areas through graduate-level didactics in immunology and biostatistics, complement-focused conferences, laboratory externships, experiential training in clinical trials at the Duke Clinical Research Institute, and carefully mentored hands-on research experiences. Dr. Swaminathan’s research and career development will be guided by a multidisciplinary mentorship team with expertise in IPF, complement biology, translational pulmonary research, and biostatistics. Her scientific advisors will add further depth in complement activation, genetics, and pulmonary fibrosis mechanisms. The research training, along with strong institutional support, will accelerate Dr. Swaminathan’s transition to an independently- funded investigator to conduct trials evaluating complement-related therapies in patients with PF-ILD targeted in a personalized manner.