The medium survival of idiopathic pulmonary fibrosis (IPF) patients is 2.5 to 3.5 years after diagnosis. In the U.S. alone, approximately 40,000 people die of IPF annually. The pathogenesis of IPF is only partially understood and the cause(s) of IPF are not yet known. Although a number of IPF clinical trials are currently ongoing, there are still no proven medical therapies for this lethal disease. In fact, the results from the latest phase III clinical trial sponsored by NHLBI (the PANTHER-IPF study) have shown that a commonly prescribed regimen consisting of prednisone, azathioprine and n-acetylcysteine is harmful in IPF patients. Thus, lung transplantation remains the only therapeutic option available for a small fraction of end-stage IPF patients.
To facilitate development of novel therapies for IPF based on a better understanding of its pathogenesis, NHLBI convened a workshop on November 27-28, 2012 to draft a strategic plan for future IPF research. The workshop brought together basic, translational and clinical pulmonary fibrosis investigators along with pharmaceutical, FDA and patient advocacy group representatives to discuss 1) knowledge gaps in IPF pathogenesis, 2) unmet needs in IPF research, 3) obstacles to translating basic discoveries into clinical tools/therapies, 4) potential collaborations and coordination of research efforts.
The following priority areas were highlighted by the workshop participants:
More emphasis on in situ investigations of human IPF and control lung tissues to define cellular derangements in individual lung cell types involved in the pathogenesis of IPF, as well as derangements in the interactions of these cells, that initiate/perpetuate pulmonary fibrosis.
- Support and refine the Lung Tissue Research Consortium (LTRC) and/or develop additional bio-repository resources that also contain complementary, annotated long-term clinical data of tissue donors to support bench/translational research and to improve our understanding of the heterogeneity of IPF.
- Develop and standardize scientific approaches to allow identification of factors that maintain homeostasis of alveolar epithelial cells and those that injure/re-program these cells.
- Characterize epigenetic and other cellular changes of the re-programmed alveolar epithelial cells and other cell types (including myofibroblasts and macrophages) involved in the pathogenesis of IPF.
- Develop novel approaches to investigate critical cell:cell interactions, including epithelial-mesenchymal cell interaction, in IPF lung tissues.
- Characterize progenitor/stem cells that replenish alveolar epithelial cells in response to injuries as well as those give rise to (myo)fibroblasts and define their roles in the pathogenesis of IPF.
More emphasis on studies to clarify how matrix components and/or physical properties that include stiffness can lead to persistence or resolution of fibrosis.
- Develop novel non(or minimally) invasive technology to measure matrix composition and stiffness in vivo, particularly in humans.
- Identify pathways involved in the mechanotransduction of pro-fibrotic signals in the lungs and clarify how these pathways may contribute to pulmonary fibrosis.
- Define how critical matrix components and their signaling pathways can resolve or perpetuate inflammation and pulmonary fibrosis.
More emphasis on studies to elucidate gene-to-function and gene-environment interactions contributing to the pathogenesis of IPF.
- Focus on multi-generational families to better understand heritability of disease and to study at-risk subjects during preclinical stages to better understand early pathogenesis.
- Re-examine and/or monitor environmental factors that may initiate/contribute to IPF using novel biosensors that can collect long-term, chronic exposure data rather than relying on cross-sectional data to define exposures.
- Investigate the biological consequences of gene variants/mutations associated with pulmonary fibrosis, including those that are associated with pediatric and adult interstitial lung diseases, and develop an integrated “omics” approach to incorporate other data to better understand IPF pathogenesis.
Develop animal models that are progressive and better recapitulate human lung pathology (UIP) for bench research and for drug discoveries.
- Develop and refine pulmonary fibrosis animal models that are induced by relevant genetic or environmental stimuli.
- Encourage studies with aged mice, and potentially develop resources to encourage this line of research.
Develop additional clinical tools and collaborations among different stakeholders to facilitate future clinical trials/studies of IPF.
- Develop biomarkers that correlate with disease progression, potentially using samples and clinical data collected during (and in future) NHLBI/pharmaceutical sponsored clinical trials.
- Develop a consensus for appropriate phase III end points balancing reliability versus feasibility issues. This may require development and validation of a simple staging system, possibly incorporating newer parameters such as imaging parameters and validated biomarkers.
- Identify new, creative means for conducting efficient and cost-effective clinical trials and for partnering with industry to sponsor phase II/III clinical trials.
Timothy S. Blackwell, M.D., Vanderbilt University Medical Center
Andrew M. Tager, M.D., Harvard Medical School
Kevin J. Anstrom, Ph.D., Duke Clinical Research Institute
Ziv Bar-Joseph, Ph.D., Carnegie Mellon University
Teresa Barnes, Coalition for Pulmonary Fibrosis
Michael R. Blackburn, Ph.D., The University of Texas Medical School at Houston
Peter Bitterman M.D., University of Minnesota Medical School
Bill Bradford, M.D., Ph.D., InterMune, Inc.
Zea Borok, M.D., University of Southern California
Harold A. Chapman, M.D., University of California, San Francisco
Harold R. Collard, M.D., University of California, San Francisco
Gregory P. Cosgrove, M.D., National Jewish Health & University of Colorado-Denver
Robin Deterding, M.D., University of Colorado
Kevin R. Flaherty M.D., University of Michigan
Christine Kim Garcia, M.D., Ph.D., UT Southwestern Medical Center
James S. Hagood, M.D., University of California, San Diego
Craig A. Henke, M.D., University of Minnesota
Erica Herzog M.D., Ph.D., Yale University School of Medicine
Cory M. Hogaboam, Ph.D., University of Michigan Medical School
Jeffrey C. Horowitz, M.D., University of Michigan Medical School
Naftali Kaminski, M.D., University Pittsburgh
Dolly Kervitsky, R.C.P., Pulmonary Fibrosis Foundation
Talmadge E. King, Jr., M.D., University of California, San Francisco
William E. Lawson, M.D., Vanderbilt University Medical Center
James E. Loyd, M.D., Vanderbilt University Medical Center
Fernando Jose Martinez, M.D., University of Michigan Health System
Clay B. Marsh, M.D., The Ohio State University
Bethany B. Moore, Ph.D., University of Michigan
Paul W. Noble, M.D., Duke University Medical Center
Imre Noth, M.D., University of Chicago
Thomas G. O’Riordan, M.D., Gilead Sciences, Inc
Julie Olsson, M.D., Genentech/Roche
Luis A. Ortiz, M.D., University Pittsburgh
Tim Oury, M.D., Ph.D., University Pittsburgh Medical Center
Ganesh Raghu, M.D., University of Washington Medical Center
Daniel M. Rose, M.D., Pulmonary Fibrosis Foundation
David A. Schwartz, M.D., National Jewish Health, University of Colorado School of Medicine
Dean Sheppard, M.D., University of California, San Francisco
Patricia J. Sime, M.D., University of Rochester School of Medicine
Thomas H. Sisson, M.D., University of Michigan
Victor J. Thannickal, M.D., University of Alabama at Birmingham
Daniel Tschumperlin, Ph.D., Harvard School of Public Health
Shelia M. Violette, Ph.D., Biogen Idec
Timothy E. Weaver Ph.D., University of Cincinnati College of Medicine
Rebecca G. Wells, M.D., University of Pennsylvania
Eric S. White, M.D., University of Michigan Medical School
Tom Wynn, Ph.D., NIAID/NIH
Food and Drug Administration/Center for Drugs Evaluation and Research
Lydia Gilbert McClain M.D.
Banu Karimi-Shah, M.D.
NHLBI/Division of Lung Diseases Staff
Jerry Eu, M.D.
James Kiley, Ph.D.
Dorothy Gail, Ph.D.
Andrea Harabin, Ph.D.
Hannah Peavy, M.D.
Lisa Postow, Ph.D.
Thomas Croxton, M.D., Ph.D.
Antonio Punturieri, M.D., Ph.D.
Michelle Freemer M.D.
Carol Blaisdell, M.D.
Center for Scientific Reviews
Ghenima Dirami, Ph.D.