This competitive renewal will address a novel area of asthmatic disease that builds upon our previously funded grant and new preliminary data pertaining to the maintenance of chronic airway disease. In this proposal we will examine the role of stem cell factor (SCF) in the development of chronic allergic airway disease leading to overproduction of mucus and peribronchial remodeling through the overproduction of IL-17E (IL-25)-induced Th2 disease. Peribronchial leukocyte accumulation and activation is a major disease factor during development of asthmatic airway responses that leads to chronic airway disease. In particular, T cells and eosinophils have been reported to be the primary cells associated with induction of bronchial injury, and are thought to participate in bronchial obstruction, airway remodeling, and airway hyperreactivity. Our data provided for this application indicate that SCF is an eosinophil-activating factor that induces IL-25 production leading to increases in Th2 cytokine production in the airway via the activation of an IL-17RB+ (IL-25R) myeloid cell population. This proposal will examine how SCF production participates directly and indirectly in chronic allergen-induced IL-25-mediated Th2 responses through the activation and development of the bone marrow- derived myeloid cell population. Our hypothesis is that SCF expressed during allergen-induced responses is a key mediator for local production of IL-25 as well as the induction and accumulation of IL-25 responsive cell populations that contribute to the severity of the pathogenic responses, including Th2 cytokine production, mucus overexpression and airway remodeling. To test this postulate we will focus on mechanisms involved in the ability of pulmonary-derived SCF to induce Th2 cytokines and eosinophil related functions. Our studies will 1) establish that SCF contributes to the development of chronic airway disease and define its relationship to inflammation and Th2 cytokine production, 2) establish a role for SCF in IL-25 production in the airway, 3) determine what role pulmonary SCF production has during allergen responses on the development of IL-25 responsive T cells and myeloid cells in the lung and/or bone marrow, 4) identify whether the Th2 cytokine environment along with SCF is required for the development of the IL-25 responsive myeloid cell population, 4) determine whether inhibition of IL-25 reduces the development of long term chronic disease independent of SCF, and 5) identify IL-25 induced myeloid cells in naove animals. To assess the mechanisms of SCF-induced activation we will especially concentrate on those pertaining to differential SCF activation of local pulmonary and bone marrow associated cell populations. In addition, we will assess changes in normal, c-kit mutant, IL-25R-/- and 4get GFP/IL-4 reporter mice to elucidate the mechanism of SCF-induced activation during chronic disease development. Thus, these studies will clarify a number of previously unexplored questions in this novel area of research.

Public Health Relevance

Asthma is one of the most common ailments that affects Americans of all ages. The treatment to asthma has not changed significantly and the prevalence of asthma continues to increase. While we are beginning to better understand the pathogenesis, we continue to struggle with identifying viable targets for therapeutic intervention. The primary aim of our proposal will be to both better define the role of novel targets (stem cell factor and interleukin-25) and the mechanism of how they influence the severity of disease progression. The continuation of this line of studies will allow us to begin to design modes of therapy that could have better efficacy for controling asthmatic responses. Our studies will utilize a well defined model of asthma that recapituates asthmatic disease in humans and will allow a systematic analysis of the mechanisms involved in the responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059178-12
Application #
8453419
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
1999-09-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
12
Fiscal Year
2013
Total Cost
$352,009
Indirect Cost
$118,744
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Jang, Sihyug; Morris, Susan; Lukacs, Nicholas W (2013) TSLP promotes induction of Th2 differentiation but is not necessary during established allergen-induced pulmonary disease. PLoS One 8:e56433
Ding, Lin; Dolgachev, Vladilsav; Wu, Zhuang et al. (2013) Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis. J Pathol 230:205-14
Petersen, Bryan C; Budelsky, Alison L; Baptist, Alan P et al. (2012) Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology. Nat Med 18:751-8
Dolgachev, Vladislav; Petersen, Bryan C; Budelsky, Alison L et al. (2009) Pulmonary IL-17E (IL-25) production and IL-17RB+ myeloid cell-derived Th2 cytokine production are dependent upon stem cell factor-induced responses during chronic allergic pulmonary disease. J Immunol 183:5705-15
Dolgachev, Vladislav A; Ullenbruch, Matthew R; Lukacs, Nicholas W et al. (2009) Role of stem cell factor and bone marrow-derived fibroblasts in airway remodeling. Am J Pathol 174:390-400
Lindell, Dennis M; Berlin, Aaron A; Schaller, Matthew A et al. (2008) B cell antigen presentation promotes Th2 responses and immunopathology during chronic allergic lung disease. PLoS One 3:e3129
Dolgachev, Vladislav; Thomas, Molly; Berlin, Aaron et al. (2007) Stem cell factor-mediated activation pathways promote murine eosinophil CCL6 production and survival. J Leukoc Biol 81:1111-9
Tekkanat, Kim K; Maassab, Hussein; Miller, Allison et al. (2002) RANTES (CCL5) production during primary respiratory syncytial virus infection exacerbates airway disease. Eur J Immunol 32:3276-84
Oliveira, Sandra H P; Taub, Dennis D; Nagel, James et al. (2002) Stem cell factor induces eosinophil activation and degranulation: mediator release and gene array analysis. Blood 100:4291-7
Oliveira, S H; Lukacs, N W (2001) Stem cell factor and igE-stimulated murine mast cells produce chemokines (CCL2, CCL17, CCL22) and express chemokine receptors. Inflamm Res 50:168-74

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