This Article Full Text Full Text (PDF) All Versions of this Article: 2003-0053OCv1 30/3/261    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Serikov, V. B. Articles by Widdicombe, J. H. Search for Related Content PubMed PubMed Citation Articles by Serikov, V. B. Articles by Widdicombe, J. H.

Activation of Extracellular Regulated Kinases Is Required for the Increase in Airway Epithelial Permeability during Leukocyte Transmigration

Children's Hospital Oakland Research Institute, Oakland; and Department of Human Physiology and Department of Medicine, University of California Davis, Davis, California

Address correspondence to: Dr. J. H. Widdicombe, Department of Human Physiology, Tupper Hall, 4136, School of Medicine, University of California Davis, Davis, CA 95616. E-mail: jhwiddicombe{at}ucdavis.edu

The goal of this study was to determine whether the extracellular regulated kinases (ERK1/2) are involved in leukocyte transmigration across airway epithelium and the associated changes in epithelial permeability. In vitro, we used formyl-methionyl-leucyl-phenylalanine (fMLP) to induce migration of HL-60 cells (a human leukocyte cell line) across sheets of polarized Calu-3 airway epithelial cells and also to induce migration of human neutrophils across primary cultures of cow tracheal epithelial cells. In both systems, leukocyte migration decreased transepithelial electrical resistance (R_te), increased epithelial permeability to albumin (P_alb), and increased ERK1/2 phosphorylation in epithelial cells. Leukocyte migration and the associated changes in R_te, P_alb, and ERK1/2 phosphorylation were inhibited by calphostin C, a blocker of protein kinase C (PKC), and by PD98059 (a blocker of ERK1/2). Leukocyte transmigration in rat tracheas in vivo was induced with fMLP, and was associated with increased P_alb and phosphorylation of epithelial ERK1/2. Again, migration and the associated changes were inhibited by luminal PD98059 or calphostin C though neither agent affected rat leukocyte migration in Boyden chambers in vitro. We conclude that PKC and ERK1/2 pathways are activated in airway epithelial cells during migration of leukocytes and are important regulators of airway epithelial permeability.

Abbreviations: bovine serum albumin, BSA • extracellular regulated kinases, ERK1/2 • fetal calf serum, FCS • formyl-methionyl-leucyl-phenylalanine, fMLP • mitogen-activated protein kinase, MAPK • permeability to albumin, P_alb • phosphate-buffered saline, PBS • protein kinase C, PKC • transepithelial electrical resistance, R_te • tight junction, TJ