My research focuses on the role of airway epithelium in the lung. Airway epithelium is the first line of defense against external stimuli. Airway epithelial cells lining on the airway epithelium contribute to homeostasis in the lung, but when they are exposed to excessive biochemical or physical stimuli, the normal defense mechanism turns into the progression of various pathophysiologic conditions. Airway epithelial cells also play important roles in innate and adaptive immunities and inflammation.
Much of the morbidity and mortality associated with persistent asthma is attributable to progressive and irreversible remodeling of the airway wall. Most theories concerning airway remodeling argue that the remodeling process is triggered in response to inflammatory mediators and cytokines.
I hypothesize that airway remodeling is triggered in response to the mechanical stress imposed on the airway epithelium during bronchoconstriction. If my hypothesis is correct, the same level importance should be ascribed to bronchoconstriction as to airway inflammation in asthma research. Over a decade ago, Drs. Jeffrey Drazen and Roger Kamm began to present data supporting the idea that the application of compressive stress — equivalent to the stress experienced during bronchoconstriction in asthma — on airway epithelial cells induces cell changes that recapitulate aspects of airway remodeling (On the mechanism of mucosal folding in normal and asthmatic airways. J Appl Physiol 1997;83:1814-21).
I use a compressive in vitro model system (Figure 1). In this system, primary human bronchial epithelial cells are grown in an air-liquid interface (ALI) culture and subjected to compressive stress, which is modeled through the application of a transepithelial pressure gradient at a magnitude of 20 to 30 cm H2O. This magnitude of stress is similar to the magnitude that bronchoconstriction imposes on the airway epithelium, and is significantly higher than the magnitude experienced during normal breathing. The compressive in vitro system recapitulates many aspects of airway remodeling in the absence of inflammatory cells(1-5).
The findings using the compressive in vitro system have already led to experiments in humans showing that methacholine-induced bronchoconstriction, in the absence of eosinophilic inflammation, can lead to collagen deposition under the epithelial monolayer, enhanced expression of TGF-β, and increased numbers of goblet cells (The influence of bronchoconstriction on airway remodeling in asthma. New England Journal of Medicine 2011;364:2006-15.)— key aspects of airway remodeling. These experiments provide in vivo validation of our experimental approach.
A full understanding of the asthmatic response requires many different models; in vitro compressive model system highlights and isolates the effects of mechanical stress on airway epithelial cells. I also use mouse asthma models to verify the physiological effects of target molecules and to identify further mechanisms.
- Swartz MA, Tschumperlin DJ, Kamm RD, Drazen JM: Mechanical stress is communicated between different cell types to elicit matrix remodeling, Proc Natl Acad Sci U S A 2001, 98:6180-6185
- Tschumperlin DJ, Dai G, Maly IV, Kikuchi T, Laiho LH, McVittie AK, Haley KJ, Lilly CM, So PT, Lauffenburger DA, Kamm RD, Drazen JM: Mechanotransduction through growth-factor shedding into the extracellular space, Nature 2004, 429:83-86
- Park JA, Tschumperlin DJ: Chronic intermittent mechanical stress increases MUC5AC protein expression, Am J Respir Cell Mol Biol 2009, 41:459-466
- Park JA, Drazen JM, Tschumperlin DJ: The chitinase-like protein YKL-40 is secreted by airway epithelial cells at base line and in response to compressive mechanical stress, J Biol Chem 2010, 285:29817-29825
- Park JA, Sharif AS, Tschumperlin DJ, Lau L, Limbrey R, Howarth P, Drazen JM: Tissue factor-bearing exosome secretion from human mechanically stimulated bronchial epithelial cells in vitro and in vivo, J Allergy Clin Immunol 2012, 130:1375-1383
Chair, 2015 Gordon Research Seminar; Lung Development, Injury & Repair.
Invited speaker, the AirwayVista 2014
Editorial board member of the American Journal of Respiratory Cell and Molecular Biology (AJRCMB)
American Heart Association/Scientist Development Grant
1/1/2013 – 12/31/2016
Parker B. Francis Fellowship: Class of 2013
7/1/2013 – 6/30/2016
2006 Ph.D. in Toxicology
North Carolina State University