title: Leukotriene B4receptor type 2 protects against pneumolysin-dependent acute lung injury.
abstract: Although pneumococcal infection is a serious problem worldwide and has a high mortality rate, the molecular mechanisms underlying the lethality caused by pneumococcus remain elusive. Here, we show that BLT2, a G protein-coupled receptor for leukotriene B4and 12(S)-hydroxyheptadecatrienoic acid (12-HHT), protects mice from lung injury caused by a pneumococcal toxin, pneumolysin (PLY). Intratracheal injection of PLY caused lethal acute lung injury (ALI) in BLT2-deficient mice, with evident vascular leakage and bronchoconstriction. Large amounts of cysteinyl leukotrienes (cysLTs), classically known as a slow reactive substance of anaphylaxis, were detected in PLY-treated lungs. PLY-dependent vascular leakage, bronchoconstriction, and death were markedly ameliorated by treatment with a CysLT1 receptor antagonist. Upon stimulation by PLY, mast cells produced cysLTs that activated CysLT1 expressed in vascular endothelial cells and bronchial smooth muscle cells, leading to lethal vascular leakage and bronchoconstriction. Treatment of mice with aspirin or loxoprofen inhibited the production of 12-HHT and increased the sensitivity toward PLY, which was also ameliorated by the CysLT1 antagonist. Thus, the present study identifies the molecular mechanism underlying PLY-dependent ALI and suggests the possible use of CysLT1 antagonists as a therapeutic tool to protect against ALI caused by pneumococcal infection.
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.|Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Shigematsu
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Ishimori
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Taketomi
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Ohba
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Airi
authors.initials: A
authors.lastname: Jo-Watanabe
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Harada
authors.affiliation: Lipid Signaling Project, National Center for Global Health and Medicine, Tokyo, Japan.|Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harayama
authors.affiliation: Lipid Signaling Project, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Shindou
authors.affiliation: Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Hoka
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D001426:Bacterial Proteins / Q000633:toxicity; D002199:Capillary Permeability / Q000187:drug effects*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D013301:Streptolysins / Q000633:toxicity*
chemical_list: D001426:Bacterial Proteins; C412867:Ltb4r2 protein, mouse; D018102:Receptors, Leukotriene B4; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae