Role of the Leukotriene B4 Receptors in Asthma

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by the applicant): Asthma is now recognized as an inflammatory disease of the airways. Eosinophils, neutrophils, macrophages and lymphocytes, are also recruited into the airways. The arachidonic acid derivative leukotriene B4 (LTB4) and its receptors are important mediators of leukocyte chemotaxis. LTB4 signaling has been implicated in the pathogenesis of asthma and in a murine model of this disorder. However, the precise role of the LTB4 receptors, BLTR1 and BLTR2, in the pathobiology of asthma is incompletely known. Our laboratory has recently generated a mouse strain with a targeted deletion in the gene that codes for BLTR1 (BLTR1-/-). Preliminary experiments using this mouse strain in a murine model of asthma have shown a reduction in eosinophils recruited into the airways. Our hypothesis is that LTB4 is an important chemoattractant for leukocytes in this model of asthma and that its actions are mediated primarily through the BLTR1 receptor. We also propose that LTB4 signaling is important in the development of airway remodeling. Specifically we seek to determine the following: 1) if BLTR1 signaling is important for the recruitment of eosinophils, neutrophils, and macrophages in this model of asthma; 2) if BLTR1 effects the recruitment and profile of T lymphocytes in the airways and lymph nodes in this model; 3) if BLTR1 signaling is important in airways hyperreactivity and mucous production; 4) if BLTR1 signaling effects airway remodeling in a chronic asthma model; 5) if the newly described receptor BLTR2 has any functional role in this murine model of asthma. Using a model of asthma in BLTR1-/- mice we hope to precisely define the role of BLTR1 in asthma pathogenesis. Repeat experiments in the presence of a BLTR2 antagonist will also allow characterization of the role of this receptor in asthma.