Research

Research Activities
Fairview University Medical Center

Pulmonary and Critical Care
Fairview-University Medical Center's pulmonary and critical care research program is focused on understanding the basic mechanisms controlling the process of lung repair following injury in two clinical disorders: acute lung injury and post-transplantation obliterative bronchiolitis.

The University of Minnesota Acute Lung Injury Study has been ongoing for more than 10 years, with support from our Clinical Research Center. The Lung Transplant Program has maintained an extensive database on the more than 200 lung transplant patients and this has resulted in both retrospective, interventional clinical studies.

Much of the research activity at Fairview-University evolved from Dr. Peter Bitterman's long-standing interest in the fibroproliferative response in the airspace and vessel wall following acute lung injury. His research examines the important roles that growth regulatory peptides derived from inflammatory cells may play in intraalveolar fibrosis that occurs in acute lung injury and lung fibrosis.

Specifically, his group has found a novel form of platelet-derived growth factor in lavage fluid from Acute Respiratory Distress Syndrome (ARDS) patients. The role of this form of PDGF is being assessed since it probably promotes mesenchymal cell replication and migration into the alveolar airspace.

New research techniques used in these studies include the use of in situhybridization to localize mRNA for growth factors, transgenic mice, and transfection of airway and alveolar cells with genes coding for proteins of interest. Studies of fibroblast cell lines derived from patients with ARDS have revealed that these cells grow in the absence of the usually required growth factors.

Characterization of the growth control in these cells is ongoing. Another related ongoing project led by Dr. Craig Henke is based on his finding that there are at least two factors in ARDS patient lavage fluid that promote growth of new capillaries - basic fibroblast growth factor (bFGF) and a new larger protein that is being purified and identified. Dr. Henke is studying factors involved in endothelial cell migration and new vessel formation within protein-rich matrices similar to those found in the alveoli during ARDS. Angiogenesis is an important component of intra-alveolar granulation tissue and understanding its genesis should permit us to interrupt this process.

Dr. Bitterman's laboratory also is studying the way that excess granulation tissue in the alveolar space is removed by the process of programmed cell death (or apoptosis). His group has found that patients recovering from ARDS have a protein in their lavage fluid that induces non-necrotic death of fibroblasts and endothelial cells. This protein is being purified and its' biology is being defined. Dr. Vitaly Polunovsky is studying the regulation of programmed cell death in endothelial cells and fibroblasts.

The alveolar epithelial cells also play important roles in repair of the damaged lung. Dr. David Ingbar's laboratory is examining alveolar epithelial cell differentiation and function during lung development, lung injury, and repair including specialized functions of these cells during injury and repair, such as the regulation of ion transport proteins that clear sodium and fluid from the flooded alveolus.

There is a homeostatic early upregulation of the amounts of Na,K-ATPase and active sodium transport during hyperoxic injury with pulmonary edema in rat lungs. The molecular mechanism of this upregulation is being studied in cultured lung cells with Dr. Christine Wendt.

In collaboration with Drs. Bitterman and Polunovsky, they also are studying the role of the alveolar epithelium in apoptosis. Dr. Ingbar's group also is examining the regulation and function of other epithelial proteins that protect against oxidant injury, such as gamma-glutamyl transpepitdase.

Dr. Ingbar's group works closely with faculty in physiology (O. Douglas Wangensteen, PhD, and Scott O'Grady, PhD), the Institute of Human Genetics (Kathleen Conklin, PhD), and biochemistry and molecular biology (Howard Towle, PhD). In collaboration with Dr. Henke, the ways that type II cells adhere and migrate on matrix proteins is being examined.

Dr. Marshall Hertz is leading a group of investigators exploring the pathogenesis of obliterative bronchiolitis (OB) after lung transplantation. His efforts focus on two areas: the immunologic basis of OB and the role of growth factors in causing OB. In terms of the former, he has developed an animal model of OB that depends upon MHC incompatibilities of transplanted tracheas. This model is being used to test prophylactic and therapeutic strategies for OB. Drs. Melissa King-Biggs and Marshall Hertz also are using gene transfer studies to determine the role of growth factors in OB since they have identified increased levels of PDGF and basic fibroblast growth factor in the airways of patients with OB. In this work they collaborate with Scott McIvor, PhD, associate professor of laboratory medicine and pathology. Drs. Hertz and Wendt also have developed a number of clinical studies related to lung transplantation.

Each laboratory interacts extensively with other pulmonary research labs, as well as collaborating with a number of basic scientists and basic biologists.

Allergy and Asthma

The University of Minnesota Asthma and Allergy research program has been ongoing for more than 30 years. It has evolved from Dr. Malcolm Blumenthal's long time interest in the role genetic and environmental factors have in the development of atopy, asthma, and other related phenotypes. The primary research goals of the Asthma and Allergy Program are to determine the basic biology and genetics of so-called 'complex diseases' of atopic origin; disorders initiated and/or propagated by the humoral immune system due to the production of allergen-specific IgE.

Recent research has focused upon such things as what are the thermodynamic characteristics of allergen-specific antibodies (concentrations and binding affinities), how do these parameters relate to atopic responses, what distinguishes an atopic response from a non-atopic response, and what are the developmental changes in early life leading to these outcomes?

The goals of these efforts are to define atopic diseases such as asthma by objective, laboratory-based measures rather than clinical terms, and improve phenotypic characterizations to aid with genome-wide searches for the gene(s) involved with these diseases.

Using these phenotypes, Dr. Blumenthal has led a group of investigators in performing genetic studies of aggregation, hereditability, mode of inheritance as well as gene investigations. They have used candidate genes, genome screens, fine mapping as well as case control approaches. Many loci have been identified. Their work involves collaborations with Richard King, MD, PhD, professor of medicine and director of genetics, John Connett, PhD, professor of biostatistics, Michael Miller, PhD, assistant professor of epidemiology, and Cavan Reilly, PhD, assistant professor of biostatistics. These investigations have and will provide information that will enhance our understanding and management of asthma and atopic conditions.