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mTOR inhibitors disrupt endothelial cell barrier function, causing pneumonitis by increasing cell permeability. This involves myosin light chain phosphorylation and PKC signaling, highlighting a key mechanism in inflammatory lung diseases.

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Area of Science:

  • Cell Biology
  • Immunology
  • Pharmacology

Background:

  • Endothelial cell (EC) barrier dysfunction is central to inflammatory diseases.
  • mTOR inhibitors (mTORi) can cause pneumonitis via unknown mechanisms.
  • Understanding EC mechanisms in mTORi-induced pneumonitis is crucial for therapeutic safety.

Purpose of the Study:

  • To investigate the endothelial cell (EC) mechanisms underlying pneumonitis caused by mTOR inhibition (mTORi).
  • To elucidate the role of mTOR complex components in EC barrier function during inflammation.

Main Methods:

  • Mice with EC-specific deletion of mTOR components (Mtor, Rptor, Rictor) were used.
  • Pulmonary injury was induced by LPS administration.
  • EC barrier function was assessed in vivo (Evans blue assay) and in vitro (TEER, albumin flux).
  • Cultured ECs were treated with mTOR inhibitors, siRNA, or overexpression plasmids.

Main Results:

  • mTORi increased basal and TNFα-induced EC permeability by promoting myosin light chain (MLC) phosphorylation-dependent cell contraction.
  • mTORi inactivated mTOR kinase, activating PKCδ/p38/NF-κB signaling and upregulating MLC kinase (MLCK) expression.
  • Raptor promoted PKCα/MYPT1 phosphorylation, suppressing MLCP activity.
  • EC-specific deficiency of mTOR, Raptor, or Rictor worsened LPS-induced lung inflammation.

Conclusions:

  • mTOR inhibition leads to endothelial hyperpermeability through PKC-dependent MLC phosphorylation and cell contraction.
  • These findings reveal a critical EC-mediated pathway contributing to mTORi-induced pneumonitis.
  • Targeting these EC mechanisms may offer strategies to mitigate mTORi-related lung toxicity.