Persistent damage to airway epithelium is a cardinal feature in chronic, severe asthma, and repair of this damaged epithelium frequently does not occur in asthmatic airways. We suggest a new paradigm that may explain why epithelial repair in asthmatic airways does not function properly. In normal airways, injury induces the production of """"""""pro-inflammatory"""""""" cytokines such as TNFa and IL-1?. Both cytokines activate specific signaling pathways that activate the mitogen-activated protein kinases (MAPKs), such as p38 MARK and JNK, that in turn initiate early steps in the migration of airway epithelial cells to cover damaged airways. However, the milieu of the asthmatic airway acts to slow this repair process, by repeated stretching and compressing airways via severe and continued bronchoconstriction that will impair MAPK-mediated migration. To address this paradigm we propose the following specific aims:
Aim #1. Determine whether or not p38 MARK and JNK regulate the migration of airway epithelial cells after injury. We hypothesize that signaling via MAPK pathways within minutes to hours of injury integrates a number of local and regional stimuli that are pro-reparative, by activating gene expression via transcription factors such as ATF-2 and AP-1, and by initiating actin remodeling via p38 MAPK mediated activation of heat shock protein-27.
Aim #2. Determine whether or not cyclic stretch and compression impairs airway epithelial cell migration by down-regulating activation of p38 MAPK and JNK, specifically by suppressing upstream pathways that ordinarily lead to their activation. We hypothesize that cyclic stretch and compression counter the proreparative signals and inhibit repair in part by down-regulating activation of p38 MAPK and/or JNK, and that this occurs in part by suppressing activation of upstream activating pathways.
Aim #3. Determine whether or not bronchoalveolar lavage fluid, IL-1? and TNFa accelerate airway epithelial cell migration via p38 MAPK and JNK, and whether IL-1? and TNFa fail to accelerate repair under conditions of cyclic stretch and compression. We hypothesize that TNFa and IL-13 accelerate the process of epithelial repair after injury via activation of MAPKs, but fail to do so when countered by cyclic stretch and compression. Other products found within asthmatic airways, as can be collected in bronchoalveolar lavage fluid, also stimulate repair but will not be able to overcome the inhibitory effects of cyclic deformation on airway epithelial cell migration. Understanding the steps in the signaling pathway in early cell migration, the role of cytokines in initiating migration, and the physical forces that impair early, required signaling and thereby slow migration will help us to understand how the airway epithelium may fail to repair adequately in chronic asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080417-04
Application #
7620384
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2006-08-17
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$365,094
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
White, Steven R; Loisel, Dagan A; Stern, Randi et al. (2013) Human leukocyte antigen-G expression in differentiated human airway epithelial cells: lack of modulation by Th2-associated cytokines. Respir Res 14:4
Floreth, Timothy; Stern, Eric; Tu, Yingli et al. (2011) Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine. Respir Res 12:44
White, Steven R; Martin, Linda D; Stern, Randi et al. (2010) Expression of IL-4/IL-13 receptors in differentiating human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 299:L681-93
Desai, Leena P; White, Steven R; Waters, Christopher M (2010) Cyclic mechanical stretch decreases cell migration by inhibiting phosphatidylinositol 3-kinase- and focal adhesion kinase-mediated JNK1 activation. J Biol Chem 285:4511-9
White, S R; Loisel, D A; McConville, J F et al. (2010) Levels of soluble human leukocyte antigen-G are increased in asthmatic airways. Eur Respir J 35:925-7
Crosby, Lynn M; Waters, Christopher M (2010) Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 298:L715-31
Desai, Leena P; White, Steven R; Waters, Christopher M (2009) Mechanical stretch decreases FAK phosphorylation and reduces cell migration through loss of JIP3-induced JNK phosphorylation in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 297:L520-9
White, Steven R; Martin, Linda D; Abe, Mark K et al. (2009) Insulin receptor substrate-1/2 mediates IL-4-induced migration of human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 297:L164-73
White, Steven R; Fischer, Bernard M; Marroquin, Bertha A et al. (2008) Interleukin-1beta mediates human airway epithelial cell migration via NF-kappaB. Am J Physiol Lung Cell Mol Physiol 295:L1018-27