David K. Madtes
M.D., University Pittsburgh School of Medicine, 1979.
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.
Navigational Bronchoscopy With Biopsy Versus Computed Tomography-guided Biopsy for the Diagnosis of a Solitary Pulmonary Nodule: A Cost-Consequences Analysis.. Journal of bronchology & interventional pulmonology. 19(4):294-303.. 2012.
BCNU-associated pneumonitis: portrait of a toxicity.. Leukemia & lymphoma. 53(6):1019-1020.. 2012.
Expression of human alpha1-antitrypsin in mice and dogs following AAV6 vector-mediated gene transfer to the lungs.. Molecular therapy : the journal of the American Society of Gene Therapy. 18(6):1165-72.. 2010.
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.. 2009.
Tissue inhibitor of metalloproteinase-1 moderates airway re-epithelialization by regulating matrilysin activity.. The American journal of pathology. 172(5):1256-70.. 2008.
Comparison of statistical data models for identifying differentially expressed genes using a generalized likelihood ratio test.. Gene regulation and systems biology :. 2:125-139.. 2008.
Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice.. American journal of respiratory cell and molecular biology. 33(3):271-9.. 2005.