Lung Injury & Repair Group

Injury, Repair & Therapy

William Martin II, M.D.
Principal Investigator

Tel (919) 541-4878
Fax (919) 541-4133
wjmartin@niehs.nih.gov

Curriculum Vitae (http://www.niehs.nih.gov/research/atniehs/labs/lrb/lung-inj/docs/martin-cv.pdf)   (36kb) P.O. Box 12233
Mail Drop B2-01
Research Triangle Park, North Carolina 27709
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Research Summary

The Lung Injury & Repair Group studies the mechanisms of injury and repair of the lung with special considerations for the development of novel cell-based therapies that can reverse life-threatening acute lung injury and progressive pulmonary fibrosis.

Pathologic hallmarks of acute lung injury are damage to the alveolar epithelial cells and capillary endothelial cells that maintain the alveolar capillary barrier. Alveolar epithelium is composed of two cells types: type I and type II cells. During normal cell turnover or lung damage, the type II cells differentiate into the predominant alveolar type I cells. A major function of type II cells is to produce pulmonary surfactant, which lowers surface tension in the distal gas exchange units of the lung. Widespread loss of the type I and type II cells appears to be the primary cause of diffuse alveolar damage, which can result in acute respiratory failure and death or, if partial recovery occurs, may result in irreversible pulmonary fibrosis.

The group intends to reverse the effects of lung injury and avoid fibrosis by restoring the critical cellular components of the alveolar capillary unit using the bleomycin model of acute lung injury. Restoring these components requires optimizing the conditions for airway delivery of type of II cells or other potential progenitor cells which will engraft onto the injured alveolar surface. This approach will restore the alveolar environment by covering the denuded alveolar epithelium. If successful, this approach may be used to treat lung injury in children and adults.

The Lung Injury & Repair Group also investigates the relationship between oxidant mediated damage to mitochondrial DNA and genomic DNA using a model of acute lung injury and fibrosis. Mitochondrial DNA is highly prone to oxidative damage and mutates much faster than nuclear DNA. In response to acute injury, pulmonary fibrosis typically begins with alveolitis, which progresses to excess collagen deposition and destruction of normal lung architecture. Bleomycin will be used to injure A549 cells and Q-PCR will measure DNA damage. In addition, changes in mitochondrial genome copy number during acute lung cell injury and repair are under investigation. This research is important because recent data have shown that mitochondria DNA copy number varies at different stages of pulmonary fibrosis and may have prognostic value.

Major areas of research:

• Repair mechanism associated with lung injury and repair
• Morphologic evidence of injury to type I and II alveolar epithelial cells associated with bleomycin treatment in mice
• Evidence for protective effect of airway delivered normal type II cells on bleomycin-induced lung injury
• Effect of hydration therapy on survival time of bleomycin-treated mice
• Mitochondrial DNA damage associated with bleomycin treatment
• Signaling pathway associated with bleomycin such as ROS, Ca²⁺ and inflammatory reactions
• Hyaluronan as a biomarker in bleomycin-induced lung injury and studying the role of type II cells, including their subpopulation, in lung injury and repair

Current projects:

• Identifying the repair mechanism, using in vivo models, associated with bleomycin-induced lung injury by studying different parameters of lung injury including survival, lung function and morphology
• Optimizing the conditions for isolation, purity, labeling and airway delivery of normal type II cells into bleomycin-injured recipient mice
• Monitoring the deposition of collagen and hydroxyproline in mice with bleomycin-induced pulmonary fibrosis
• Investigating the level of mitochondrial DNA and genomic DNA damage in bleomycin-treated lung cells by Q-PCR
• Assessing how bleomycin induces changes in the cell membrane potential and across the mitochondrial membrane using a variety of modulating factors
• Examining and quantifying cell injury/death and morphology changes in the lung after bleomycin treatment

William J. Martin II, M.D., is head of the Lung Injury & Repair Group and Associate Director for the Office of Translational Research at NIEHS. He received his M.D. from the University of Minnesota in 1974 and completed his pulmonary and critical care training at the Mayo Clinic in 1979. Following completion of his research training in the Pulmonary Branch at the National Heart, Lung and Blood Institute, he joined the staff of the Mayo Clinic as a clinician-investigator. Martin served as the Dean of the University of Cincinnati College of Medicine and is a past president of the American Thoracic Society. He also served as the Director of Pulmonary and Critical Care at Indiana University for twelve years before becoming the Executive Associate Dean for Clinical Affairs at the University's School of Medicine. He has authored more than 130 research and clinical papers and has been an NIH-funded scientist for the past 24 years.

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