Pulmonary & Critical Care Medicine: Fibrotic Lung Disease Research
The Pulmonary Fibrosis Research group at the U-M Medical School Division of Pulmonary & Critical Care Medicine utilizes bench-to-bedside approaches to better understand the diagnosis, pathogenesis and treatment of lung fibrosis.
Research Overview
The Pulmonary Fibrosis Research group employs cutting-edge, bench-to-bedside approaches to understand the origins of pulmonary fibrosis, characterize its molecular drivers, and identify the endogenous molecular brakes that differentiate normal wound healing from persistent and progressive scarring. Through these approaches, our aim is to discover novel targets to more effectively treat this devastating condition. Our group is highly collaborative, providing ample opportunities for training across the spectrum of basic, translational and clinical research.
Basic scientists at U-M Medical School investigate numerous pathogenic processes pertinent to pulmonary fibrosis. We utilize animal models and human tissue from patients with pulmonary fibrosis as well as a variety of tools including primary cell isolation, precision-cut lung slices, single-cell sequencing, and spatial transcriptomics, to address key knowledge gaps, including:
Epithelial cell-fibroblast interaction in the lung – Investigators seek to understand how soluble factors and cell-cell contact mediate communication between epithelial cells and fibroblasts. They also strive to understand how epithelial cell damage modulates these intercellular cues.
Key investigators: Timothy Blackwell, MD; Kevin Kim, MD; Bethany Moore, PhD; Thomas Sisson, MD; Rachel Zemans, MD
Enhancing epithelial repair in pulmonary fibrosis – While the lung is usually adept at repairing after injury, factors that impair restoration after repetitive injury support persistent fibrotic remodeling. Although the factors that inhibit normal repair remain poorly understood, emerging evidence suggests that accumulation of an aberrant epithelial state and the persistent activation of stress-response pathways, including the Hypoxia Inducible Factor and Transforming Growth Factor-β pathways, contribute to aberrant epithelial repair in pulmonary fibrosis. Investigators use in vivo lineage tracing, cell culture, human tissue, and human genetics to identify key epithelial pathways and cellular interactions that are dysregulated during fibrosis with the goal of enhancing epithelial repair as an approach to treating progressive pulmonary fibrosis.
Key investigators: Timothy Blackwell, MD; Christopher Ting, MD; Rachel Zemans, MD
Mechanisms of fibroblast activation and molecular determinants of their accumulation versus clearance following lung injury – Fibroblasts are the end-effector cells of fibrosis and are prime targets for future therapeutic development. Researchers seek to discover novel treatments by studying how various soluble mediators and surrounding extracellular matrix influence fibroblast recruitment, proliferation, activation, and persistence in fibrotic lungs. We study how cAMP-generating mediators such as prostaglandin E2 and prostacyclin de-differentiates myofibroblasts, inhibits extracellular matrix production, and promotes resolution of fibrosis. We are currently interrogating how these mediators also promote epigenetic remodeling and post-transcriptional regulation of RNA-binding proteins, identifying new avenues for future drug development.
Key investigators: Sean Fortier, MD; Steven Huang, MD
Targeting epigenetic pathways for future treatment – Epigenetic mechanisms including DNA methylation and histone modifications play a key role in fibroblast activation and fibrogenesis. Through genome-wide epigenomics studies, researchers are investigating how these epigenetic changes arise and lead to fibroblast activation. Ongoing work utilizes epigenetic drugs as a strategy to reprogram cells and eventually treat fibrosis.
Key investigators: Steven Huang, MD
Infections as initiators or co-factors to augment disease progression – Investigators are working to understand how common viral infections may predispose the lung to the initiation of fibrosis and also to understand how viral infections may cause disease exacerbation. There are also ongoing studies looking at common bacterial infections as co-factors in the disease progression. These investigators are also examining how innate immune cells influence fibrotic outcomes.
Key investigators: Bethany Moore, PhD
Role of plasminogen activator inhibitor-1 in pulmonary fibrosis – our research has established PAI-1 as a profibrotic mediator of pulmonary fibrosis in multiple complementary models. These findings have motived the development of a small molecule PAI-1 inhibitor as a potential therapeutic for ILD, and this drug is currently in Phase I clinical trials. Current work in our laboratory seeks to further delineate how PAI-1 promotes pulmonary fibrosis with the goal of designing more targeted medications with fewer off target effects.
Key investigators: Thomas Sisson, MD
Microbiome host immune fibrotic pathway interactions – Recent pioneering work at UM ILD program identified that in gnotobiotic or germ-free models, the absence of a microbiome has a role in the development of lung fibrosis promoting less lung fibrosis and improved survival. Current work is building on these results to identify key molecular and cellular host microbiome interactions that drive lung fibrosis.
Key investigators: Bethany Moore, PhD; David O'Dwyer, MD, PhD
Clinician scientists at U-M Medical School leverage data collected from patients evaluated through the U-M interstitial lung disease (ILD) program to answer pressing clinical questions, test novel new technologies and advance promising new therapeutics to treat pulmonary fibrosis. This multidisciplinary group of clinicians provides expedited, state-of-the-art evaluations, providing exert diagnosis and therapeutic options for patients with diverse forms of ILD, including pulmonary fibrosing.
Pulmonary fibrosis clinical trials – U-M researchers help conduct multi-center clinical trials aimed at developing new therapies for idiopathic pulmonary fibrosis and other forms of progressive pulmonary fibrosis. Through these trials, new effective therapies are identified, providing additional treatment options for patients.
Key investigators: Elizabeth Belloli, MD; Kevin Flaherty, MD; Jamie Sheth, MD, MS
ILD epidemiology and clinical endpoints – investigators use data collected through the U-M ILD registry, one of the largest in the world, to answer current clinical questions, test existing constructs and identify new knowledge gaps. This deeply phenotyped registry has been developed through systematic interrogation of the electronic medical record and hand curation of dozens of key data elements, allowing investigators to seamlessly analyze this dataset as new research questions emerge.
Key investigators: Justin Oldham, MD, PhD; Janelle Pugashetti, MD
Early identification of interstitial lung abnormalities – researchers use cutting edge technology to identify interstitial lung abnormalities (ILAs), the earliest form of pulmonary fibrosis using AI-based screening techniques, quantitative imaging technology and testing of first-degree relatives of patients with pulmonary fibrosis.
Key investigators: Timothy Blackwell, MD; Justin Oldham, MD, PhD; Jennifer Wang, MD
Emerging evidence suggests that there are multiple molecular causes of disease and its progression, and thus a personalized approach to treatment is needed for each patient. Translational scientists focus on utilizing human biospecimens to better understand the molecular drivers of pulmonary fibrosis and develop biomarkers to predict clinically relevant endpoints. Researchers work closely with clinicians in the University of Michigan Medical School, Division of Pulmonary and Critical Care Medicine, who care for patients with pulmonary fibrosis evaluated through the U-M interstitial lung disease (ILD) program.
Proteomic biomarkers of pulmonary fibrosis outcomes – the recent emergence of high-throughput proteomic technology has allowed U-M researchers to identify novel biomarkers of near-term progression and long-term survival, which are shared across diverse forms of pulmonary fibrosis. These findings are now being used to develop clinical biomarkers to facilitate earlier detection and predict which patients are most likely to develop progressive disease and respond to existing therapies.
Key investigators: Justin Oldham, MD, PhD; Janelle Pugashetti, MD
Microbiome linked biomarkers of IPF disease progression and treatment response – the “microbiome” or resident bacteria, fungi, viruses and archaea in the human body may have significant impact on human metabolism, physiology, immunity and response to therapy. Recent breakthroughs have associated disease progression with key bacteria in the human gut, mouth and lung of patients with IPF. Current studies are ongoing to determine how the microbiome may change immune responses in lung fibrosis and how these relationships could be leveraged to slow disease progression, guide therapeutic selection and improve survival in IPF and other forms of ILD.
Key investigators: Bethany Moore, PhD; David O'Dwyer, MD, PhD
