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.
Showing the most recent 10 out of 19 publications
