Asthma affects between 7.5% and 10% of the US population. Despite its high prevalence, the pathogenesis remains poorly understood. Although it is understood to be an inflammatory disease, the details in human asthma are still being determined. Additionally, it is becoming clear that asthma is not one disease, but several with overlapping phenotypes. Research in the Pulmonary, Allergy and Critical Care Medicine Division integrates state-of-the-art clinical, translational, and basic research to better understand asthma and its treatment.
Translational research, at the cross-roads of clinical and basic research, is essential to the asthma and allergic disease programs. This research evolves from questions arising at the bedside and from the translation of cutting-edge basic research to the human condition. Many of these programs are pursued in the laboratory of the Director of The Asthma Institute, Dr. Sally Wenzel, and her colleagues Dr. Silvana Balzar, and Dr. Xiuxia Zhou. Their research compares inflammatory responses in asthmatic and normal subjects using bronchoscopically obtained human airway cells. These studies have focused on: 1) differences in proximal and distal lung inflammation, evaluating the role of the fibroblast in eosinophilic/mast cell related processes in severe asthma and 2) interactions between Th2 cytokines and other stimuli, such as transforming growth factor-ß and interleukin-1ß, and viruses relevant to asthma exacerbations. These studies determine in vivo abnormalities in airway tissue or cells and then pursue the mechanisms for these processes in vitro using epithelial cells, fibroblasts and macrophage/lymphocyte models. Additional comparative studies of insulin-like growth factor-binding proteins are being pursued by Dr. Carol Feghali-Bostwick in human epithelial cells and fibroblasts.
The pillar of the asthma research programs is the basic science component. Drs. Anuradha Ray and Prabir Ray head independent programs (http://immunology.medicine.pitt.edu) to investigate dynamic interactions between the key antigen-presenting cells, dendritic cells (DCs), and T cells that determine allergen-induced lung inflammation that is characteristic of asthma or those that cause immune suppression or tolerance. These studies involve animal models of disease and tolerance using allergens or infectious agents that cause allergic airways disease. The in vivo studies involve genetic approaches using cell-specific inducible transgenic mice or knockout mice. Mechanisms underlying the immunological processes are being addressed using microarray and proteomic techniques, and a variety of biochemical, immunological and cell imaging methods. Examples of findings using these approaches include description of GATA-3 as the master regulator of Th2 differentiation (true in both mice and humans), induction of the chitinase family member Ym1 by the cholesterol-lowering drug simvastatin in dendritic cells promoting Th2 differentiation and interactions between the TGF-b and Notch pathways in induction of airway tolerance to antigens.
Closer to the bedside, the clinical research involves studies in the epidemiology of asthma, its phenotypes and relation to genotypes. All asthma patients seen in the pulmonary/allergy clinics are asked to participate in an asthma registry to database their clinical information. In addition, asthma exacerbations and factors, which may differentiate viral exacerbations from other types, are being studied. As part of the Pitt participation in the NHLBI Severe Asthma Research Program network (one of only 4 centers in the US), severe asthmatics (and controls) are extremely well characterized, including information from physiologic, immunologic, pathologic and radiologic/CT studies. Finally, the clinical programs at Pitt involve industry sponsored early phase and pivotal trials of new targeted therapies for asthma, including some of the early trials of Th2 modulation in asthma.