The airway epithelium may be damaged by inhalation of noxious agents, in response to pathogens, or during endotracheal intubation and
mechanical ventilation. Maintenance of an intact epithelium is important for lung fluid balance, and the loss of epithelium may stimulate inflammatory responses. Epithelial repair in the airways following injury must occur on a substrate that undergoes cyclic elongation and compression during respiration. We have previously shown that cyclic mechanical strain inhibits
wound closure in the airway epithelium (Savla and Waters, 1998b). In this study, we investigated the stimulation of epithelial
wound closure by
keratinocyte growth factor (KGF) in vitro and the mechanisms by which KGF overcomes the inhibition due to mechanical strain. Primary cultures of normal human bronchial epithelial cells (NHBE) and a cell line of human airway epithelial cells, Calu 3, were grown on
Silastic membranes, and a
wound was scraped across the well. The wells were then exposed to cyclic strain using the Flexercell Strain Unit, and
wound closure was measured. While cyclic elongation (20% maximum) and cyclic compression (approximately 2%) both inhibited
wound closure in untreated wells, treatment with KGF (50 ng/ml) significantly accelerated
wound closure and overcame the inhibition due to cyclic strain. Since
wound closure involves cell spreading, migration, and proliferation, we investigated the effect of cyclic strain on cell area, cell-cell distance, and cell velocity at the
wound edge. While the cell area increased in unstretched monolayers, the cell area of monolayers in compressed regions decreased significantly. Treatment with KGF increased the cell area in both cyclically elongated and compressed cells. Also, when cells were treated with KGF, cell velocity was significantly increased in both static and cyclically strained monolayers, and cyclic strain did not inhibit cell migration. These results suggest that KGF is an important factor in epithelial repair that is capable of overcoming the inhibition of repair due to physiological levels of cyclic strain.