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 language | English |
|---|---|
| Article number | 34560 |
| Journal | Scientific reports |
| Volume | 6 |
| DOIs | |
| Publication status | Published - Oct 5 2016 |
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All Science Journal Classification (ASJC) codes
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Leukotriene B4 receptor type 2 protects against pneumolysin-dependent acute lung injury. / Shigematsu, Misako; Koga, Tomoaki; Ishimori, Ayako; Saeki, Kazuko; Ishii, Yumiko; Taketomi, Yoshitaka; Ohba, Mai; Jo-Watanabe, Airi; Okuno, Toshiaki; Harada, Norihiro; Harayama, Takeshi; Shindou, Hideo; Li, Jian Dong; Murakami, Makoto; Hoka, Sumio; Yokomizo, Takehiko.
In: Scientific reports, Vol. 6, 34560, 05.10.2016.Research output: Contribution to journal › Article
}
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
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.
UR - http://www.scopus.com/inward/record.url?scp=84990243300&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990243300&partnerID=8YFLogxK
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 -