Critical involvement of p38 MAP kinase in pertussis toxin-induced cytoskeletal reorganization and lung permeability

Joe G.N. Garcia, Peiyi Wang, Kane L. Schaphorst, Patrice M. Becker, Talaibek Borbiev, Feng Liu, Anna Birukova, Keri Jacobs, Natalia Bogatcheva, Alexander D. Verin

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Bordetella pertussis is an important cause of infection in humans worldwide, with full expression of the syndrome associated with characteristic increases in lung permeability and airway edema. The exact cellular mechanisms by which pertussis toxin (PTX) exerts pulmonary toxicity remain unknown, but may involve its ability to ADP-fibosylate-specific G-proteins. We determined that PTX directly and reproducibly reduced lung endothelial and epithelial cell barrier function in vitro and in vivo assessed by decreases in transmonolayer electrical resistance (TER) and isolated perfused lung preparations. Alterations in lung permeability began ∼30 min after PTX and were dependent on intrinsic ADP-ribosyltransferase activity, as neither the cell binding β-oligomer subunit or a genetically engineered PTX mutant (devoid of ADP-ribosyltransferase activity) altered TER. PTX-induced barrier dysfunction was associated with mild increases in F-actin stress fiber formation and causally linked to p38 MAP kinase activities. PTX-mediated p38 MAP kinase activation did not involve either p42/p44 ERK, p60src, Rho family of GTPases, or phosphatidylinositol-3′ kinase pathways. PTX-mediated decreases in TER were temporally linked to phosphorylation of the actin binding proteins Hsp27 and caldesmon, known substrates for the Ser/Thr kinase MAPKAP2, whose activity is regulated by p38 MAP kinase. In addition to defining novel signaling pathways involved in PTX-induced respiratory pathophysiology, these data suggest that the direct cell-activating effects of PTX be carefully considered as a potential limitation to its use as a tool in signal transduction analysis.-Garcia, J. G. N., Wang, P., Schaphorst, K. L., Becker, P. M., Borbiev, T., Liu, F., Birukova, A., Jacobs, K., Bogatcheva, N., Verin, A. D. Critical involvement of p38 map kinase in pertussis toxin-induced cytoskeletal reorganization and lung permeability.

Original languageEnglish (US)
Pages (from-to)1064-1076
Number of pages13
JournalFASEB Journal
Volume16
Issue number9
DOIs
StatePublished - Jul 22 2002

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Keywords

  • ADP-ribosyltransferase
  • Caldesmon
  • Endothelial cell
  • HSP 27
  • Transendothelial electrical resistance
  • β-oligomer

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Garcia, J. G. N., Wang, P., Schaphorst, K. L., Becker, P. M., Borbiev, T., Liu, F., Birukova, A., Jacobs, K., Bogatcheva, N., & Verin, A. D. (2002). Critical involvement of p38 MAP kinase in pertussis toxin-induced cytoskeletal reorganization and lung permeability. FASEB Journal, 16(9), 1064-1076. https://doi.org/10.1096/fj.01-0895com