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

Sci Rep. 2016 Oct 5:6:34560. doi: 10.1038/srep34560.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / genetics
  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / prevention & control*
  • Animals
  • Bacterial Proteins / toxicity
  • Capillary Permeability / drug effects*
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Mast Cells / metabolism
  • Mast Cells / pathology
  • Mice
  • Mice, Knockout
  • Receptors, Leukotriene B4 / genetics
  • Receptors, Leukotriene B4 / metabolism*
  • Streptolysins / toxicity*


  • Bacterial Proteins
  • Ltb4r2 protein, mouse
  • Receptors, Leukotriene B4
  • Streptolysins
  • plY protein, Streptococcus pneumoniae