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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

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