The 5-lipoxygenase (5-LO) products, the leukotriene (LT)s, are clearly important participants in the pulmonary inflammatory process in patients with asthma. We have developed a protocol for administration of ovalbumin (OVA_ as allergen to induce late-phase allergen-specific pulmonary disease in normal BAL:B/c and C57BL/6 mice. OVA-treated mice display a disease strikingly similar to allergen-induced human asthma. In our mouse model of asthma, we have found that leukotrienes are key mediators of the mucus release and eosinophil infiltration of the airways. With the availability of mutant mice deficient in 5-LO and both isoforms of cyclooxygenase (COX) (together wit specific inhibitors/antagonists of the lipid mediators), we will determine the contribution of the 5-LO pathway to the induction and resolution of allergic airway inflammation and AHR. These studies will be performed in both our standard protocol and a long-term model of allergen-induced lung fibrosis in mice. Our goal will be to define immune mechanisms by which leukotrienes influences the activation and effector functions of T cells and dendritic cells, key cells in the mediation of allergic airway inflammation. Our specifi aims are as follows:
Specific Aim 1. To characterize further the role of the 5-LO pathway in allergic pulmonary inflammation and AHR. We will examine these questions: a) Will intrapulmonary 5-LO pathway blockade prevent AHR? b) Will 5-LO pathway blockade resolve ongoing allergic airway inflammation? and c) Wil 5-LO pathway blockade prevent allergen-induced lung fibrosis? Specific Aim 2. To determine the interrelationship of the 5-LO pathway with COX-2 pathway and platelet activating factor (PAF) in the mediation of allergic airway inflammation and AHR. The following questions will be studied: a) Is COX-2 pathway activation important in development of allergic inflammation and AHR? and b) Will blockade of secretory phospholipase A2 (sPLA2) and PAF inhibit allergic lung inflammation and AHR? and Specific Aim 3. To determine the mechanisms by which leukotriene inhibition blocks allergic pulmonary inflammation and AHR in the murine model of asthma. We will study these questions: a) Will 5-LO pathway blockade prevent allergen-induced T cell proliferation and/or cytokine generation necessary for airway inflammation and AHR? and b) Is 5-LO pathway activation required for adoptive transfer of AHR b T cells? The more specific our knowledge of the biochemical and immunological changes becomes, the more likely it is that specific interventions producing more benefit than harm in reducing leukotriene-reduced inflammation, will be found.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042989-03
Application #
6170884
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Adams, Ken
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$249,194
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Henderson Jr, William R; Ye, Xin; Lai, Ying et al. (2013) Key role of group v secreted phospholipase A2 in Th2 cytokine and dendritic cell-driven airway hyperresponsiveness and remodeling. PLoS One 8:e56172
Henderson Jr, William R; Oslund, Rob C; Bollinger, James G et al. (2011) Blockade of human group X secreted phospholipase A2 (GX-sPLA2)-induced airway inflammation and hyperresponsiveness in a mouse asthma model by a selective GX-sPLA2 inhibitor. J Biol Chem 286:28049-55
Hallstrand, Teal S; Henderson Jr, William R (2010) An update on the role of leukotrienes in asthma. Curr Opin Allergy Clin Immunol 10:60-6
Henderson Jr, William R; Chi, Emil Y; Ye, Xin et al. (2010) Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci U S A 107:14309-14
Hallstrand, Teal S; Henderson Jr, William R (2009) Role of leukotrienes in exercise-induced bronchoconstriction. Curr Allergy Asthma Rep 9:18-25
Mehrotra, Anjuli K; Henderson Jr, William R (2009) The role of leukotrienes in airway remodeling. Curr Mol Med 9:383-91
Hallstrand, Teal S; Chi, Emil Y; Singer, Alan G et al. (2007) Secreted phospholipase A2 group X overexpression in asthma and bronchial hyperresponsiveness. Am J Respir Crit Care Med 176:1072-8
Henderson Jr, William R; Chiang, Gertrude K S; Tien, Ying-Tzang et al. (2006) Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am J Respir Crit Care Med 173:718-28
Christie, P E; Jonas, M; Tsai, C H et al. (2004) Increase in laminin expression in allergic airway remodelling and decrease by dexamethasone. Eur Respir J 24:107-15
Iwata, Akiko; Nishio, Kazumi; Winn, Robert K et al. (2003) A broad-spectrum caspase inhibitor attenuates allergic airway inflammation in murine asthma model. J Immunol 170:3386-91

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