MAP kinases in lung endothelial permeability induced by microtubule disassembly

Anna A. Birukova, Konstantin G. Birukov, Boris Gorshkov, Feng Liu, Joe G.N. Garcia, Alexander D. Verin

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Lung endothelial barrier function is regulated by multiple signaling pathways, including mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinases (ERK) 1/2 and p38. We have recently shown involvement of microtubule (MT) disassembly in endothelial cell (EC) barrier failure. In this study, we examined potential involvement of ERK1/2 and p38 MAPK in lung EC barrier dysfunction associated with MT disassembly. MT inhibitors nocodazole (0.2 μM) and vinblastine (0.1 μM) induced sustained activation of Ras-Raf-MEK1/2-ERK1/2 and MKK3/6-p38-MAPKAPK2 MAPK cascades in human and bovine pulmonary EC, as detected by phosphospecific antibodies and in MAPK activation assays. These effects were linked to increased permeability assessed by measurements of transendothelial electrical resistance and cytoskeletal remodeling analyzed by morphometric analysis of EC monolayers. MT stabilization by taxol (5 μM, 1 h) attenuated nocodazole-induced ERK1/2 and p38 MAPK activation and phosphorylation of p38 MAPK substrate 27-kDa heat shock protein and regulatory myosin light chains, the proteins involved in actin polymerization and actomyosin contraction. Importantly, only pharmacological inhibition of p38 MAPK by SB-203580 (20 μM, 1 h) attenuated nocodazole-induced MT depolymerization, actin remodeling, and EC barrier dysfunction, whereas the MEK/ ERK1/2 inhibitor U0126 (5 μM, 1 h) exhibited no effect. These data suggest a direct link between p38 MAPK activation, remodeling of MT network, and EC barrier regulation.

Original languageEnglish (US)
Pages (from-to)L75-L84
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume289
Issue number1 33-1
DOIs
StatePublished - Jul 1 2005

Keywords

  • Actin
  • Extracellular signal-regulated kinases 1/2
  • Mitogen-activated protein
  • Pulmonary endothelium

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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