Unraveling idiopathic pulmonary fibrosis endophenotypes; a lung-centric approach to prognostic and therapeutic biomarker validation

/ABSTRACT Idiopathic pulmonary fibrosis (IPF) presents a formidable challenge due to its complex pathology and the limited efficacy of current therapeutic strategies. Traditionally treated as a homogenous entity based on subjective clinical and radiological assessments, IPF's heterogeneity has been significantly underexplored, resulting in a one-size-fits-all treatment approach that fails to improve long-term survival. Our preliminary data has discovered unique inflammatory and hypoinflammatory endotypes within the IPF lung and lung microenvironment, each associated with unique survival trajectories, underscoring the need for a molecularly informed approach to IPF management. We aim to validate and expand on these findings by leveraging a global biorepository of IPF bronchoalveolar lavage fluid (BALF) and lung tissue samples. Our objective is to conduct an in-depth proteomic analysis to confirm the prognostic relevance of these endotypes, particularly focusing on protein profiles linked to autoinflammatory processes and immune cell signaling. These profiles, identified in our preliminary studies, show a strong correlation with patient outcomes and provide a promising foundation for precision medicine in IPF. Specific Aim 1 will validate the prognostic significance of these proteomic clusters in a large cohort of IPF patients and assess treatment response for each of the phenotypes to historic and current IPF treatment strategies. Specific Aim 2 will validate these inflammatory and hypoinflammatory endotypes in IPF lung tissue and explore pathways that define them with a particular focus on repurposing existing treatments such as complement pathway inhibitors based on exciting preliminary data. Our work is expected to lead to the establishment of a molecular classification system for IPF that informs therapeutic decisions and guides patient stratification for personalized treatments. Additionally, we anticipate discovering biomarkers that predict treatment responses, reducing exposure to ineffective therapies and thereby enhancing quality of life and survival rates for IPF patients. By combining cutting-edge systems biology with patient-centered research, this project is poised to transform IPF management, offering an evidence-based framework for precision treatment strategies that align with each patient’s unique molecular profile. Our findings have the potential for rapid translation into clinical practice, providing a new paradigm in the diagnosis and treatment of IPF and offering hope for improved outcomes in this devastating disease. Project Number: 1R01HL176772-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Scott Matson | Institution: UNIVERSITY OF KANSAS MEDICAL CENTER, KANSAS CITY, KS | Award Amount: $718,002 | Activity Code: R01 | Study Section: Cardiovascular and Respiratory Diseases Study Section[CRD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17677201A1