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MAP kinases in lung endothelial permeability induced by microtubule disassembly

Anna A Birukova1, Konstantin G Birukov, Boris Gorshkov

  • 1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, MFL Center Tower, Baltimore, MD 21224, USA.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|March 22, 2005
PubMed

Insights

p38 MAPK activation directly links microtubule disassembly to lung endothelial cell barrier dysfunction. Inhibiting p38 MAPK prevents barrier failure, suggesting it as a therapeutic target.

Area of Science:

  • Cell Biology
  • Physiology
  • Biochemistry

Background:

  • Lung endothelial barrier integrity is crucial for respiratory health.
  • Microtubule (MT) disassembly contributes to endothelial cell (EC) barrier failure.
  • Mitogen-activated protein kinases (MAPK), including ERK1/2 and p38, regulate cellular processes.

Purpose of the Study:

  • To investigate the role of ERK1/2 and p38 MAPK in lung EC barrier dysfunction caused by MT disassembly.
  • To elucidate the signaling pathways connecting MT dynamics to EC barrier regulation.

Main Methods:

  • Human and bovine pulmonary EC were treated with MT inhibitors (nocodazole, vinblastine).
  • MAPK activation was assessed using phosphospecific antibodies and in vitro assays.
  • EC permeability was measured by transendothelial electrical resistance.
  • Cytoskeletal remodeling was analyzed morphometrically.
  • Pharmacological inhibitors of p38 MAPK (SB-203580) and ERK1/2 (U0126) were used.

Main Results:

  • MT inhibitors induced sustained activation of ERK1/2 and p38 MAPK cascades.
  • This activation correlated with increased EC permeability and cytoskeletal remodeling.
  • MT stabilization partially reduced MAPK activation.
  • Selective p38 MAPK inhibition, but not ERK1/2 inhibition, attenuated MT depolymerization, actin remodeling, and barrier dysfunction.

Conclusions:

  • p38 MAPK activation is a key mediator of MT disassembly-induced lung EC barrier dysfunction.
  • The p38 MAPK pathway plays a critical role in regulating MT network dynamics and EC barrier function.
  • Targeting p38 MAPK may offer a therapeutic strategy for conditions involving lung endothelial barrier failure.

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