mTOR Inhibition Promotes Pneumonitis through Inducing Endothelial Contraction and Hyperpermeability

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.