Despite a substantial increase in our understanding of the mechanisms involved in the pathology of asthma, the mortality and morbidity rates continue to rise, especially in inner-city children. The identification of mechanisms that initiate or predispose individuals to severe childhood asthma is of utmost importance in order to begin treating the responses prior to development of chronic disease. The induction of airway hyperreactivity in young children is often first observed after an initial respiratory syncitial virus (RSV) infection. These infections can alter lung function and appear to promote severe long term asthmatic diseases later in childhood. In addition, the etiology of many inner city asthmatics appears to be related to cockroach derived allergens. In the present proposal, we have detailed studies to assess specific mechanisms of RSV exacerbations of cockroach allergen-induced airway hyperreactivity in mice which resembles human asthmatic responses. The specific focus of this grant will center around cytokines produced during the initial RSV infection that can exacerbate and/or predispose the airway to increased allergen-induced airway inflammation and hyperreactivity. We have devised an experimental protocol to specifically define how RSV can A) exacerbate allergen-induced hyperreactivity and B) whether RSV infection sets up an environment that predisposes the lung to a more severe allergen-induced hyperreactive response. We hypothesize that monocyte derived chemokine (MDC) and RANTES production, induced by IL-13 during RSV infections, will exacerbate Th2 type responses in the airway during subsequent allergen-induced responses. To test this hypothesis, we will use specific antibody reagents against IL-13, RANTES, and MDC. In addition, we will be examining the MDC and RANTES receptors using CCR -/- mice and receptor antagonist proteins. Our studies will address the following issues: 1) Do RANTES and/or MDC production regulated by IL-13 determine the severity of primary RSV infection and subsequent allergic responses? 2) Do IL-13 activational pathways through STAT6 lead to a predictable chemokine production profile in the lung that is associated with airway dysfunction? 3) Does blocking or inhibiting RANTES or MDC significantly alter the RSV-induced and/or subsequent allergen-induced airway responses? 4) Is the mechanism of MDC exacerbation of allergic airway disease mediated by recruitment of specific CCR4 + Th2 type lymphocyte populations? 5) Are particular RANTES receptors responsible for recruitment of specific leukocyte subsets that exacerbate the RSV and allergen responses? The development of these ideas will allow elucidation of mechanisms involved in RSV-induction of cockroach allergen exacerbations of airway inflammation, leading to increased airway hyperreactivity and help define potential initiating factors for severe airway hyperreactivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036302-07
Application #
6510544
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Adams, Ken
Project Start
1996-05-01
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
7
Fiscal Year
2002
Total Cost
$300,017
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Ptaschinski, Catherine; Mukherjee, Sumanta; Moore, Martin L et al. (2015) RSV-Induced H3K4 Demethylase KDM5B Leads to Regulation of Dendritic Cell-Derived Innate Cytokines and Exacerbates Pathogenesis In Vivo. PLoS Pathog 11:e1004978

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