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Cell–Cell Communication in Heterocellular Cultures of Alveolar Epithelial Cells

Department of Physiology, Arizona Respiratory Center, University of Arizona Health Sciences Center, Tucson, Arizona; Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming; Division of Pulmonary and Critical Care Medicine, University of Southern California Keck School of Medicine, Los Angeles, California; and Department of Medical Biochemistry, Wales Heart Research Institute, University of Wales College of Medicine, Cardiff, Wales, United Kingdom

Address correspondence to: Scott Boitano, Arizona Respiratory Center, Department of Physiology, University of Arizona Health Sciences Center, Room 2341 AHSC, 1501 N. Campbell Ave., Tucson, AZ 85724. E-mail: sboitano{at}email.arizona.edu

The mammalian alveolar epithelium is composed of alveolar type I (AT1) and alveolar type II (AT2) cells that together coordinate tissue function. We used a heterocellular culture model of AT1 and AT2 cells to determine pathways for intercellular signaling between these two phenotypes. Gap junction protein (connexin) profiles of AT1 and AT2 cells in heterocellular cultures were similar to those seen in rat lung alveolar sections. Dye coupling studies revealed functional gap junctions between and among each cell phenotype. Localized mechanical stimulation resulted in propagated changes of intracellular Ca²⁺ to AT1 or AT2 cells independent of the stimulated cell phenotype. Ca²⁺ communication that originated after AT1 cell stimulation was inhibited by gap junction blockers, but not by an inhibitor of extracellular nucleotide signaling (apyrase). Conversely, Ca²⁺ communication after stimulation of AT2 cells was not significantly reduced by gap junction inhibitors. However, apyrase significantly reduced Ca²⁺ communication from AT2 to AT1 cells, but not from AT2 to AT2 cells. In conclusion, AT1 and AT2 cells have unique connexin profiles that allow for functional coupling and distinct intercellular pathways for coordination of Ca²⁺ signaling.

Abbreviations: Alexa Fluor 350, A350 • 18 -glycyrrhetinic acid, -GA • alveolar type I pneumocyte, AT1 cell • alveolar type II pneumocyte, AT2 cell • intracellular Ca²⁺ concentration, [Ca²⁺]_i • connexin, cx • Dulbecco's Modified Eagle's Medium, DMEM • 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'-amino-5'methylphenoxy)-ethane-N,N,N',N'-tetraacetic acid, 5Na, Fura-2 • Hanks' Balanced Saline Solution, HBSS • Lucifer Yellow, LY • phosphate-buffered saline, PBS

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