Inflammation Is a complex process involving the interplay between leukocytes that infiltrate the tissue, cells that are resident in that tissue, and factors produced by both populations of cells. An additional layer of regulation and complexity are the changes in the composition ofthe extra cellular matrix that is associated with sites of inflammation. The nature ofthe factors that control these interactions is not at all clear. There is considerable evidence that the cytokine thymic stromal lymphopoietin (TSLP) is critical for the development and progression of Th2-type allergic inflammation in humans and rodents. While the importance of TSLP to allergic inflammation is becoming clear, its role in other inflammatory responses, especially to pathogens, is less clear. This is especially important for pulmonary infection with respiratory syncytial virus (RSV), which can induce both protective Thi responses and non-productive Th2 responses in humans and susceptible mouse strains. It has been postulated that the Th2 response induced by RSV is also responsible forthe RSV-induced exacerbations seen in asthmatics. Several studies have shown both epidemiologically in humans and in mouse models that there is a clear association between severe RSV infection and long-term functional impairment of the lungs, including the development of asthma. The data described above suggest that both TSLP and RSV are capable of driving potent Th2-type responses in the lung. In addition, as will be shown below, both elevated TSLP and RSV infection result in a marked increase in the deposition ofthe proteoglycan versican in the lung. Taken together, these data strongly suggests a functional link between RSV infection and TSLP in driving pathological responses in the lung. Consistent with this model, RSV infection of airway epithelial cells induces robust TSLP gene expression. The experiments in this proposal are designed to test the hypothesis that it is RSV-induced TSLP that is responsible for the Th2 response to infection and for the virus-induced asthmatic exacerbations, and that it is the interplay between infiltrating cells and versican that drives this inflammatory response.

Public Health Relevance

A link between early and serious respiratory virus infection and asthma has been established, as well as with exacerbations of established disease. The experiments in this study will test the role of the cytokine thymic stromal lymphopoietin (TSLP), which has been shown to be involved in the development and progression of asthma, in respiratory virus infection. These studies will provide important mechanistic insights into the development of asthma, as well as for the value of TSLP as a therapeutic target

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL098067-05
Application #
8701347
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$348,056
Indirect Cost
$96,944
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Wilson, S S; Tocchi, A; Holly, M K et al. (2015) A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol 8:352-61
Giannandrea, Matthew; Parks, William C (2014) Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech 7:193-203
Chang, Mary Y; Tanino, Yoshinori; Vidova, Veronika et al. (2014) A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease. Matrix Biol 34:1-12
Smigiel, Kate S; Richards, Elizabeth; Srivastava, Shivani et al. (2014) CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med 211:121-36
Srivastava, Shivani; Koch, Meghan A; Pepper, Marion et al. (2014) Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med 211:961-74
Srivastava, Shivani; Koch, Lisa K; Campbell, Daniel J (2014) IFN?R signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease. J Immunol 193:2733-42
Gharib, Sina A; Johnston, Laura K; Huizar, Isham et al. (2014) MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis. J Leukoc Biol 95:9-18
Smigiel, Kate S; Srivastava, Shivani; Stolley, J Michael et al. (2014) Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation. Immunol Rev 259:40-59
Chang, Mary Y; Tanino, Yoshinori; Vidova, Veronika et al. (2014) Reprint of: A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease. Matrix Biol 35:162-73
Kang, Inkyung; Yoon, Dong Won; Braun, Kathleen R et al. (2014) Expression of versican V3 by arterial smooth muscle cells alters tumor growth factor ? (TGF?)-, epidermal growth factor (EGF)-, and nuclear factor ?B (NF?B)-dependent signaling pathways, creating a microenvironment that resists monocyte adhesion. J Biol Chem 289:15393-404

Showing the most recent 10 out of 30 publications