MIPS Faculty

In the lung's airways molecular and cellular networks normally function in harmony; in airway diseases like asthma perturbations such as environmental and allergen exposure result in remodeling of the airway wall, contributing to the altered airway mechanics and excessive airway narrowing that is a hallmark of the disease. A particular focus of the lab is the epithelial lining of the airway wall, which provides a barrier against harmful environmental, viral, and bacterial agents, and thus serves as a focal point for system perturbations. The airway epithelium is highly interconnected through various soluble mediators with the cells of the immune system (eosinophils, T-lymphocytes) and the other structural cells of the airway wall (fibroblasts, smooth muscle); thus changes in epithelial behavior can have wide ranging consequences. We have designed a novel approach to study the response of cultured airway epithelial cells to mechanical forces which mimic those encountered in vivo when allergen or environmental exposures result in airway constriction. We have demonstrated that these mechanical forces can trigger signaling and downstream production of cytokines with fibrotic (TGF-beta, endothelin), mitotic (HB-EGF), and inflammatory (GM-CSF) functions. Current efforts in the lab are focused on:

1. Understanding the molecular mechanisms by which mechanical forces are transduced into biochemical signals in the airway epithelium, both in vitro and in the native setting of the airway wall. We use novel imaging techniques to visualize epithelial deformations under loading, biochemical assays and inhibitors to measure and interrogate signaling responses, and computational modeling of ligand-receptor interactions at the surface of the airway epithelium to integrate imaging and biochemical results;

2. Identifying the network of genes regulated by mechanical stress in airway epithelium using high throughput gene arrays and bioinformatic analyses. Gene networks are being investigated both in relation to the upstream signaling cascades studied above, and downstream integrative functions that contribute to airway disease, such as fibrosis, proliferation and differentiation, and inflammatory cell recruitment; and

3. Investigating the molecular mechanisms and functional consequences of epithelial remodeling. In asthma the epithelium is abnormally thickened and has a high proportion of mucous secreting goblet cells. We are probing the molecular pathways by which mechanical and cytokine stimuli alter the structure and phenotype of airway epithelial cells. Epithelial remodeling is measured using micromechanical testing and confocal imaging; computational modeling is then employed to link epithelial remodeling to airway mechanics.

The ultimate goal of these studies is to better understand the pathophysiology of asthma and airway narrowing within an integrative framework spanning the molecular to the tissue level, leading to novel preventive and therapeutic approaches to airway disease.

Tschumperlin, D.J., J.D. Shively, T. Kikuchi, J.M. Drazen. Mechanical stress triggers selective release of fibrotic mediators from bronchial epithelium. Am. J. Resp. Cell Mol. Biol. 28:142-9, 2003.

Tschumperlin, D.J., G. Dai, I.V. Maly, T. Kikuchi, L.H. Laiho, A.K. McVittie, K.J. Haley, C.M. Lilly, P.T.C. So, D.A. Lauffenburger, R.D. Kamm, J.M. Drazen. Mechanotransduction through growth-factor shedding into the extracellular space. Nature 429:83-6, 2004.

Tschumperlin, D.J., J.M. Drazen. Chronic effects of mechanical force on airways. Ann. Rev. Physiol. 68:563-83, 2006.

Kojic, N., M. Kojic, D.J. Tschumperlin. Computational modeling of extracellular mechanotransduction. Biophys. J. 90:4261-70, 2006.