NHLBI Workshop
Cellular Plasticity in Lung Injury and Repair

Published in the Proceedings of the American Thoracic Society, Vol 8. pp 215-222, 2011, http://pats.atsjournals.org/

Executive Summary

Definition of Cell Plasticity:  The ability of some cells to switch from one specific program of gene expression (phenotype) to another in response to specific signals from the environment in a regulated manner. The changes may be reversible or irreversible and may or may not involve changes in cell shape, adhesion and proliferation.

Recent observations suggest that epithelial cells are inherently plastic.  The most extreme example of this plasticity, first recognized in the 1970’s, is the process of epithelial to mesenchymal transition (EMT).  More commonly, epithelial cells lose epithelial characteristics and become migratory, but do not acquire mesenchymal marker expression.  Alternatively, epithelial cells transiently convert to a mesenchymal shape without losing epithelial marker expression.  These observations suggest that a spectrum of epithelial plasticity changes can occur, resulting in downregulation of epithelial differentiation and integrity to different extents, and in changes that may or may not qualify as EMT.

The realization that epithelial cells are not only a target for injury leading to fibrosis but a critical driver of the pathobiology has stimulated interest to find therapeutic modalities that interfere with epithelial signaling driving mesenchymal expansion and EMT including strategies to promote epithelial survival. 

Recognizing the relationship of cell and molecular events on lung health and disease, the National Heart, Lung, and Blood Institute (NHLBI) convened extramural experts, from many disciplines (lung development, cell biology, stem/progenitor cell biology, lung injury, and lung cancer), at a Workshop “Cellular Plasticity in Lung Injury and Repair” on April 19-20, 2010.    

The objective of the workshop was: 1) To review the state of science in cellular plasticity in the lung; 2) To make recommendations to the Institute to fill gaps; 3) To prioritize new research directions; and, 4) To capitalize on scientific opportunities.  Experts from multiple fields participated, who made recommendations that could facilitate translation of basic research findings into practice to better diagnose, treat, and prevent irreversible lung remodeling in diseases such as idiopathic pulmonary fibrosis and bronchopulmonary dysplasia. The priority areas identified for research in cell plasticity in lung injury and repair included:  1) epithelial plasticity, 2) control of plasticity, 3) fibroblast plasticity and cross-talk, and 4) translation to human disease. 

Recommendations

1. Develop additional lineage specific markers/drivers (for both epithelial cells and fibroblasts) to enable generation of a cell type-specific gene expression database during the lifespan of a healthy mouse (a so-called LUNGMAP).
2. Generate an integrated gene expression database for tissue and primary cell isolates from healthy and diseased human lungs and provide the NIH-funded scientific community with highly curated, easily accessible tissue and disease-specific primary cell isolates.   
3. Develop better animal models for progressive fibrosis. Focus on potential therapeutic targets that have been implicated in human pulmonary fibrosis and validated in an animal fibrosis model(s) evaluated after the inflammatory phase of injury.
4. Support investigator-initiated attempts to discover and test new biochemical markers that reflect disease mechanisms prominent in the pathobiology both by elucidating underlying cell biology and molecular pathways important to fibrogenesis and mining information from studies of disease progression of fibrosis in other organs that likely share common pathogenic mechanisms.
5. Establish a collaborative infrastructure involving clinical and translational investigators to integrate large human tissue sample numbers with longitudinal collection to clinical annotation including linkage to histopathology, functional measurements, and clinical outcome in order to validate biomarkers.

Working Group Members

Co-Chairs

• Zea Borok, M.D.,  University of Southern California, Los Angeles
• Harold Chapman, M.D., University of California, San Francisco

Participants

• Diana W. Bianchi, M.D. (Boston, MA)
• Peter Bitterman, M.D.(Minneapolis, MN)
• Brigid Hogan, Ph.D. (Durham, NC)
• Mark Krasnow, M.D., Ph.D. (Stanford, CA)
• Jonathan Kurie, M.D. (Houston, TX)
• Edward Morrisey, Ph.D. (Philadelphia, PA)
• Stephen Nishimura, M.D. (San Francisco, CA)
• Paul Noble, M.D. (Durham, NC)
• Derek Radisky, Ph.D. (Jacksonville, FL)
• Susan Reynolds, Ph.D. (Denver, CO)
• Philip L. Sannes, Ph.D. (Raleigh, NC)
• Steven D. Shapiro, M.D. (Pittsburgh, PA)
• Victor Thannickal, M.D. (Birmingham, AL)
• Shelia Violette, Ph.D. (Cambridge, MA)
• David Walker, Ph.D. (Vancouver, BC)
• Jeffrey Whitsett, M.D. (Cincinnati, Ohio)

NHLBI, Division of Lung Division Staff

• Carol J. Blaisdell, M.D.
• James Kiley, Ph.D.
• Dorothy Gail, Ph.D.
• Weinu Gan, Ph.D.
• Andrea Harabin, Ph.D.
• Hannah Peavy, M.D.
• Sandra Colombini-Hatch, M.D.

National Institute of Diabetes, Digestion, and Kidney

• Deborah K. Hoshizaki, Ph.D.

Last Updated: June 2011