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Direct factor Xa inhibition attenuates acute lung injury progression via modulation of the PAR-2/NF-κB signaling

Meng Shi1,2, Linlin Wang3,2, Jian Zhou3,2

  • 1Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University Shanghai, China.

American Journal of Translational Research
|September 14, 2018
PubMed

Insights

Rivaroxaban, a factor Xa inhibitor, reduces inflammation and lung injury in acute lung injury (ALI) models. It works by inhibiting the protease-activated receptor 2 (PAR-2) and nuclear factor kappa B (NF-κB) signaling pathway.

Area of Science:

  • Coagulation and Inflammation Research
  • Pulmonary Medicine
  • Pharmacology

Background:

  • The role of blood coagulation in acute lung injury (ALI) is not fully understood.
  • Protease-activated receptor 2 (PAR-2), a target in coagulation, is implicated in inflammatory processes.
  • Factor Xa inhibitors, like rivaroxaban, may offer therapeutic potential for ALI.

Purpose of the Study:

  • To investigate the efficacy of rivaroxaban in an in vivo mouse model of ALI.
  • To examine the effects of rivaroxaban on inflammatory markers and cell signaling pathways in vitro.
  • To determine if rivaroxaban attenuates ALI by inhibiting the PAR-2/NF-κB pathway.

Main Methods:

  • Acute lung injury (ALI) was induced in C57BL/6 mice using lipopolysaccharide (LPS).
  • Mice were treated with rivaroxaban (0.2 or 0.4 mg/g) orally for 10 days.
  • In vitro studies used LPS-stimulated human umbilical vein endothelial cells treated with rivaroxaban.
  • Measurements included plasma coagulation indices, lung histology, bronchoalveolar lavage fluid analysis, and Western blotting for signaling proteins.

Main Results:

  • Rivaroxaban treatment significantly reduced neutrophil sequestration and preserved lung tissue architecture in ALI mice.
  • Levels of inflammatory cytokines (TNF-α, IL-1β, IL-6), protein, and Evans blue were decreased in bronchoalveolar lavage fluid.
  • Rivaroxaban ameliorated LPS-induced increases in PAR-2 expression and NF-κB activation.
  • In vitro, rivaroxaban improved cell viability, reduced membrane permeability, decreased cytokine release, and inhibited apoptosis.
  • Rivaroxaban inhibited the phosphorylation of TAK1 and p65, key components of the NF-κB pathway.

Conclusions:

  • Rivaroxaban effectively attenuates acute lung injury (ALI) in a mouse model.
  • The anti-inflammatory effects of rivaroxaban are mediated through the inhibition of the PAR-2/NF-κB signaling pathway.
  • Rivaroxaban demonstrates potential as a therapeutic agent for ALI by targeting coagulation and inflammation crosstalk.
Keywords:
Acute lung injuryNF-κbendothelial cellsfactor Xarivaroxaban

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