David K. Madtes

Appointments and Affiliations

 
 
Fred Hutchinson Cancer Research Center
Clinical Research Division
Associate Member
 
University of Washington
School of Medicine
Medicine
Pulmonary and Critical Care Medicine
Associate Professor, Appointed: 1994
Professional Headshot of David K. Madtes

Mailing Address

Fred Hutchinson Cancer Research Center
1100 Fairview Avenue N., D3-190
P.O. Box 19024
Seattle, Washington 98109-1024
United States

Contact

Phone: (206) 667-4589
Fax: (206) 667-5765
dmadtes@fhcrc.org

Degrees

M.D., University Pittsburgh School of Medicine, 1979.

Research Interests

Lung repair after injury is characterized by an orderly progression of events to re-establish an intact alveolar-capillary interface. The initial lung insult triggers a series of responses including inflammation, epithelial and mesenchymal cell proliferation and migration, angiogenesis, extracellular matrix remodeling, apoptotsis and eventually restoration of the normal alveolar architecture. These responses are modulated in part through regulatory signals transmitted through the interaction of cytokines and growth factors with their cognate receptors on the surface of cells as well as by direct cell-cell and cell-extracellular matrix interactions.

One of the goals of our laboratory is to identify growth factors secreted at sites of lung injury that regulate lung parenchymal cell proliferation and activity during the repair process. By a number of molecular and histochemical techniques, we have shown that Transforming Growth Factor-alpha (TGF-alpha), a potent stimulator of cell proliferation, is expressed in a temporally and spatially restricted pattern in response to lung injury. Through the use of TGF-alpha null mutation mice, we have demonstrated that TGF-alpha plays an important role in regulating the fibrotic response following bleomycin-induced lung damage. In conjunction with these studies, we have shown that TGF-alpha levels are increased in the alveolar lining fluid of 90% of patients with acute respiratory distress syndrome and that prolonged elevation of lung TGF-alpha concentrations is associated with an increased fatality rate in patients with delayed resolution of this syndrome. Ongoing studies are aimed at understanding the mechanisms responsible for TGF-alpha mediated fibrosis with an emphasis on the contribution of matrix metalloproteinases and their inhibitors in extracellular matrix remodeling.

A second goal of our laboratory is to identify the contribution of proteases and their inhibitors in the inflammatory response and extracellular matrix remodeling that occurs after lung injury. We have demonstrated that the expression of certain matrix metalloproteinases and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), is selectively induced in the alveolar and interstitial compartments of the acutely injured lung. Our work in progress indicates that TIMP-1 functions to regulate the acute inflammatory response to injury by restricting neutrophil accumulation in the lung. Expression of these extracellular matrix modifying proteins by inflammatory cells and lung structural cells is regulated, in part, through signaling proteins, such as CD40, present on the cell surface. Activation of CD40 induces metalloproteinase and TIMP expression by lung fibroblasts and macrophages. Work in progress is directed toward characterizing the molecular mechanisms responsible for CD40 induced metalloproteinase and TIMP expression. A better understanding of the mechanisms responsible for lung inflammation and remodeling in response to injury could identify new therapeutic interventions to facilitate lung repair.

A third goal of our research program is to identify and characterize non-infectious pulmonary complications of hematopoeitic stem cell transplantation. In a case-control study we have demonstrated a strong association of bronchiolitis obliterans organizing pneumonia (BOOP) with acute and chronic graft versus host disease. Ongoing studies are investigating the impact of pediatric HSCT preparative regimens on late pulmonary function.

 

Recent Publications

2014
2013
2012
2010
2009
Nash, RA, Yunosov M, Abrams K, Hwang B, Castilla-Llorente C, Chen P, Farivar AS, Georges GE, Hackman RC, Lamm WJE et al..  2009.  Immunomodulatory effects of mixed hematopoietic chimerism: immune tolerance in canine model of lung transplantation.. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 9(5):1037-47. Abstract
2008
2005