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J. Biol. Chem., Vol. 279, Issue 44, 46129-46134, October 29, 2004

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Targeted Gene Disruption Reveals the Role of the Cysteinyl Leukotriene 2 Receptor in Increased Vascular Permeability and in Bleomycin-induced Pulmonary Fibrosis in Mice^*

Thomas C. Beller¶, Akiko Maekawa¶, Daniel S. Friend||**, K. Frank Austen, and Yoshihide Kanaoka

From the Departments of Medicine and ^||Pathology, Harvard Medical School, and the Division of Rheumatology, Immunology, and Allergy and the ^**Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115

The cysteinyl leukotrienes (cys-LTs) mediate both acute and chronic inflammatory responses in mice, as demonstrated by the attenuation of the IgE/antigen-mediated increase in microvascular permeability and of bleomycin-induced pulmonary fibrosis, respectively, in a strain with targeted disruption of leukotriene C₄ synthase to prevent cys-LT synthesis. Our earlier finding that the acute, but not the chronic, injury was attenuated in a strain with targeted disruption of the cysteinyl leukotriene 1 (CysLT₁) receptor suggested that the chronic injury might be mediated through the CysLT₂ receptor. Thus, we generated CysLT₂ receptor-deficient mice by targeted gene disruption. These mice developed normally and were fertile. The increased vascular permeability associated with IgE-dependent passive cutaneous anaphylaxis was significantly reduced in CysLT₂ receptor-null mice as compared with wild-type mice, whereas plasma protein extravasation in response to zymosan A-induced peritoneal inflammation was not altered. Alveolar septal thickening after intratracheal injection of bleomycin, characterized by interstitial infiltration with macrophages and fibroblasts and the accumulation of collagen fibers, was significantly reduced in CysLT₂ receptor-null mice as compared with the wild-type mice. The amounts of cys-LTs in bronchoalveolar lavage fluid after bleomycin injection were similar in the CysLT₂ receptor-null mice and the wild-type mice. Thus, in response to a particular pathobiologic event the CysLT₂ receptor can mediate an increase in vascular permeability in some tissues or promote chronic pulmonary inflammation with fibrosis.

Received for publication, June 23, 2004 , and in revised form, July 26, 2004.

^* This work was supported by National Institutes of Health Grants AI-07306, AI-31599, and HL-36110. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this work.

To whom correspondence should be addressed: Brigham and Women's Hospital, Smith Bldg., Rm. 626C, One Jimmy Fund Way, Boston, MA 02115. Tel.: 617-525-1263; Fax: 617-525-1310; E-mail: ykanaoka{at}rics.bwh.harvard.edu.

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