Yoshihide Kanaoka

Harvard Medical School
Division of Rheumatology, Immunology, and Allergy
Brigham and Women's Hospital
Smith Building, Room 626C
One Jimmy Fund Way
Boston MA 02115
Phone: 617-525-1272
Fax: 617-525-1310
Email: ykanaoka@rics.bwh.harvard.edu

Eicosanoids are lipid mediators derived from arachidonic acid that have been implicated in diverse inflammatory and immune responses. The cysteinyl leukotrienes (cys-LTs), leukotriene (LT) C4, LTD4, and LTE4, are a group of bioactive eicosanoids that are produced by hematopoietic cells, such as mast cells and macrophages. They constrict bronchial smooth muscle, increase vascular permeability, and promote fibrosis. LTC4 synthase is the critical enzyme for the cys-LT biosynthesis. There are two distinct G protein-coupled receptors for the cys-LTs, termed CysLT1 receptor and CysLT2 receptor. We are focused on elucidating the role of cys-LTs in several models of innate and adaptive immunity and inflammation with mice null for LTC4 synthase and on clarifying the particular receptor functions in these models with mice null for CysLT1 receptor or CysLT2 receptor. Ongoing projects include (1) the role of cys-LTs in antigen-induced pulmonary inflammation and (2) the mechanism of cys-LT-mediated pulmonary fibrosis.

Prostaglandin (PG) D2 is another proinflammatory eicosanoid of our interest. PGD2 relaxes vascular smooth muscle, constricts bronchial smooth muscle, and attracts eosinophils, basophils, and T helper type 2 cells. Hematopoietic PGD2 synthase is the key biosynthetic enzyme that is expressed by mast cells and antigen-presenting cells. We are also investigating the role for this lipid mediator in antigen-induced pulmonary inflammation.

Papers & Publications:

1. Kanaoka Y, Maekawa A, Penrose JF, Austen KF, Lam BK. Attenuated zymosan-induced peritoneal vascular permeability and IgE-dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4 synthase. J. Biol. Chem. 2001;276:22608-22613.
2. Fujitani Y, Kanaoka Y, Aritake K, Uodome N, Okazaki-Hatake K, Urade Y. Pronounced eosinophilic lung inflammation and Th2 cytokine release in human lipocalin-type prostaglandin D synthase transgenic mice. J. Immunol. 2002;168:443-449.
3. Maekawa A, Austen KF, Kanaoka Y. Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses. J. Biol. Chem. 2002;277:20820-20824.
4. Beller TC, Friend DS, Maekawa A, Lam BK, Austen KF, Kanaoka Y. Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis. Proc. Natl. Acad. Sci. U.S.A. 2004;101:3047-3052.
5. Beller TC, Maekawa A, Friend DS, Austen KF, Kanaoka Y. Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J. Biol. Chem. 2004;279:46129-46134.