TY - JOUR
T1 - Leukotriene B4 receptor type 2 protects against pneumolysin-dependent acute lung injury
AU - Shigematsu, Misako
AU - Koga, Tomoaki
AU - Ishimori, Ayako
AU - Saeki, Kazuko
AU - Ishii, Yumiko
AU - Taketomi, Yoshitaka
AU - Ohba, Mai
AU - Jo-Watanabe, Airi
AU - Okuno, Toshiaki
AU - Harada, Norihiro
AU - Harayama, Takeshi
AU - Shindou, Hideo
AU - Li, Jian Dong
AU - Murakami, Makoto
AU - Hoka, Sumio
AU - Yokomizo, Takehiko
N1 - Funding Information:
This work was supported by MEXT/JSPS KAKENHI Grant Numbers, 22116001, 22116002, 15H05901, 15H05904, 15H04708, 15H06604, 25860223, 15K19032, 24590386, 15K08316, and 25460374, and grants from the Naito Foundation, the Ono Medical Research Foundation, the Uehara Memorial Foundation, the Mitsubishi Foundation, the Nakatomi Foundation and the Takeda Science Foundation. This study was supported in part by a Grant-in-Aid (S1311011) from the Foundation of Strategic Research Projects in Private Universities from the MEXT and a grant from the Institute for Environmental and Gender-Specific Medicine. We thank Dr. Atsushi Furuhata (Division of Biomedical Imaging Research, Juntendo University), Dr. Yukari Asai (Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University) and the Support Center for Education and Research (Kyushu University) for technical supports.
Publisher Copyright:
© The Author(s) 2016.
PY - 2016/10/5
Y1 - 2016/10/5
N2 - 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 B4 and 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.
AB - 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 B4 and 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.
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U2 - 10.1038/srep34560
DO - 10.1038/srep34560
M3 - Article
AN - SCOPUS:84990243300
VL - 6
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 34560
ER -