Leukotriene B4 receptor type 2 protects against pneumolysin-dependent acute lung injury

Misako Shigematsu, Tomoaki Koga, Ayako Ishimori, Kazuko Saeki, Yumiko Ishii, Yoshitaka Taketomi, Mai Ohba, Airi Jo-Watanabe, Toshiaki Okuno, Norihiro Harada, Takeshi Harayama, Hideo Shindou, Jian Dong Li, Makoto Murakami, Sumio Hoka, Takehiko Yokomizo

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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 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.

Original languageEnglish
Article number34560
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Oct 5 2016

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'Leukotriene B<sub>4</sub> receptor type 2 protects against pneumolysin-dependent acute lung injury'. Together they form a unique fingerprint.

Cite this