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P38/MAPK contributes to endothelial barrier dysfunction via MAP4 phosphorylation-dependent microtubule disassembly in

Lingfei Li1, Jiongyu Hu2, Ting He1

  • 1Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.

Scientific Reports
|March 10, 2015
PubMed

Insights

Microtubule-associated protein 4 (MAP4) plays a key role in acute lung injury (ALI) by disrupting endothelial cell junctions. Inhibiting p38/MAPK signaling protects against this MAP4-mediated damage.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Pathology

Background:

  • Acute lung injury (ALI) involves inflammation and disruption of the lung vascular endothelial barrier.
  • Microtubule-associated protein 4 (MAP4) stabilizes microtubules and cell junctions, but its role in ALI is unclear.

Purpose of the Study:

  • To investigate the mechanism of MAP4 in endothelial barrier disruption during ALI.
  • To identify therapeutic targets for ALI.

Main Methods:

  • Human pulmonary microvascular endothelial cells (HPMECs) were stimulated with lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α).
  • MAP4 phosphorylation, p38/MAPK pathway activation, microtubule stability, and cell permeability were assessed.
  • Pharmacological inhibitors and genetic manipulation were used to explore the role of MAP4 and p38/MAPK.

Main Results:

  • LPS and TNF-α induced MAP4 phosphorylation (at Ser696 and Ser787) and p38/MAPK activation in HPMECs.
  • This led to microtubule disassembly and increased endothelial permeability.
  • Taxol, MAP4 (Ala) mutant overexpression, and p38/MAPK inhibition (SB203580) prevented microtubule disruption and barrier dysfunction.
  • MKK6 (Glu) constitutively activated p38/MAPK, causing microtubule depolymerization and hyperpermeability.

Conclusions:

  • MAP4 phosphorylation, mediated by p38/MAPK activation, contributes to endothelial barrier dysfunction in ALI.
  • Targeting the p38/MAPK pathway or MAP4 may offer a therapeutic strategy for ALI.

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