The Pulmonary Fibrosis Research group at the University of Michigan utilizes bench-to-bedside approaches to better understand the diagnosis, pathogenesis and treatment of lung fibrosis. Although most of this work focuses on parenchymal fibrosis, exemplified by idiopathic pulmonary fibrosis (IPF) and collagen vascular disease-associated lung fibrosis, substantial overlap exists with airway fibrosis, as exemplified by lung transplant-associated bronchiolitis obliterans. Ours is a highly collaborative and interactive group. Abundant opportunities for training in both laboratory and patient-oriented research are available.
Clinical areas of expertise involve multi-disciplinary diagnosis of IPF using state of the art imaging, pathology and physiology measurements, classification and differentiation of IPF from other interstitial lung diseases, natural history of IPF progression and identification of biomarkers for disease progression. The University of Michigan Division of Pulmonary and Critical Care Medicine houses a Destination Program to evaluate such disorders. This includes a multidisciplinary group of clinicians to provide expedited, state of the art evaluations and provide therapeutic options for patients with fibrosing pulmonary disorders. The University of Michigan is a leader in clinical trials exploring new therapies for IPF patients and an integral part of the IPFnet clinical trial consortium which has actively recruited and participated in writing committees for multiple, sentinel studies, including Ace-IPF (warfarin as therapy), STEP-IPF (sildenafil as therapy) and PANTHER-IPF.
Basic Science Research Interests
Researchers at the University of Michigan are interested in numerous pathogenic processes pertinent to fibrosis.
We utilize animal models and isolated cells from normal or fibrotic lung to address issues such as the following:
- Epithelial cell-fibroblast interactions in the lung - Investigators are trying to understand how soluble factors and cell-cell contact mediate communication between epithelial cells and fibroblasts and to understand how epithelial cell damage modulates these intracellular cues.
- Mechanisms of fibroblast accumulation and activation - Investigators are studying soluble mediators and aberrant signaling pathways that influence fibroblast recruitment, proliferation, activation, and survival. Epigenetic determinants of fibroblast behavior are under investigation. The extracellular matrix itself is also being explored as a determinant of fibroblast activation.
- Regulation of extracellular matrix synthesis - There is a major effort to understand the composition of fibrotic matrix in IPF and how that differs from normal lung. Investigators are also trying to understand the pathways responsible for the overexuberant production of extracellular matrix proteins, how alterations in the components of the extracellular matrix can influence cell behavior, and how the stiffness of the extracellular matrix perpetuates fibrotic changes.
- Origin of fibroblasts within the lung - Lung fibroblasts might arise from resident mesenchymal cells, epithelial to mesenchymal transition, or circulating mesenchymal precursors. Unique genetically modified animals are being used to track the contribution of these cell types to the formation of the extracellular matrix in fibrotic lungs.
- 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.
- Anti-fibrotic roles of prostanoid and plasminogen activation pathways - Research at the University of Michigan over the past 15 years has pioneered the recognition that a) biosynthesis of prostaglandin E2 as well as activation of plasminogen to plasmin are both anti-fibrotic, and that b) both pathways are dysregulated in pulmonary fibrosis. Current work seeks to further elucidate their anti-fibrotic mechanisms and the cross-talk between them, and to develop potential therapies designed to restore their homeostatic functions as a means of ameliorating fibrosis.
Translational Research Interests
The University of Michigan is committed to correlating our basic science observations with clinical observations and outcomes to better understand the biological and clinical heterogeneity of this disease. 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. To this end, major efforts are ongoing to identify biomarkers which might inform our understanding of which patients manifest progressive disease, which molecular defects are present in particular patients, and which molecular alterations may be most amenable to therapeutic targeting.