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Phosphorylated ERM Mediates Lipopolysaccharide Induced Pulmonary Microvascular Endothelial Cells Permeability Through

Liming Fei1, Gengyun Sun1, Zhongming Zhu1

  • 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.

Archivos De Bronconeumologia
|November 19, 2018
PubMed
Abstract

Insights

Lipopolysaccharide (LPS) disrupts the pulmonary endothelial barrier by increasing phosphorylated ERM proteins, which in turn reduces Rac1 activity, leading to acute lung injury.

Area of Science:

  • Pulmonary vascular research
  • Cellular biology
  • Pathophysiology of lung injury

Background:

  • Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are significant causes of respiratory failure.
  • Endotoxin lipopolysaccharide (LPS) is a key factor in ALI/ARDS pathogenesis, primarily by disrupting the pulmonary endothelial barrier.
  • The precise molecular mechanisms of LPS-induced pulmonary microvascular endothelial cell (PMVEC) permeability remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which LPS impairs the permeability of pulmonary microvascular endothelial cells (PMVECs).
  • To investigate the roles of Ras-related C3 botulinum toxin substrate 1 (Rac1) and Ezrin/Radixin/Moesin (ERM) proteins in LPS-induced PMVEC hyperpermeability.

Main Methods:

  • Primary rat PMVECs were cultured and exposed to varying doses of LPS.
  • Endothelial barrier integrity was assessed using trans-endothelial electrical resistance (TER).
  • Rac1 activity and ERM protein phosphorylation were measured via pulldown assays and Western blotting, respectively.
  • Small interfering RNA (siRNA) was used to inhibit Rac1 and Moesin to evaluate their impact on PMVEC permeability.

Main Results:

  • LPS exposure led to a dose- and time-dependent decrease in TER, indicating increased permeability.
  • LPS treatment increased threonine phosphorylation of ERM proteins and decreased Rac1 activity in PMVECs.
  • siRNA-mediated inhibition of Rac1 and Moesin confirmed their involvement in LPS-induced PMVEC hyperpermeability.
  • A reciprocal regulatory relationship was observed between Rac1 and Moesin.

Conclusions:

  • Phosphorylated ERM proteins play a crucial role in mediating LPS-induced PMVEC permeability.
  • This mediation occurs through the negative regulation of Rac1 activity by phosphorylated ERM proteins.
  • Understanding this pathway offers potential therapeutic targets for ALI and ARDS.
Keywords:
Células endoteliales de la microvasculatura pulmonarERMErzina/raxidina/moesinaLPSLipopolisacáridoPMVECsPermeabilidadPermeabilityRac1Sustrato 1 de la toxina botulínica C3 relacionado con Ras

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