Eosinophil-Derived Cationic Proteins Activate the Synthesis of Remodeling Factors by Airway Epithelial Cells

Eosinophil cationic proteins influence several biological functions of the respiratory epithelium, yet their direct contribution to airway remodeling has not been established. We show that incubation of the human bronchial epithelial cell line, BEAS-2B, or primary cultured human bronchial epithelial cells, normal human bronchial epithelial cells, with subcytotoxic concentrations (0.1, 0.3, and 1 microM) of major basic protein (MBP), or eosinophil peroxidase (EPO), augmented the transcripts of endothelin-1, TGF-alpha, TGF-beta1, platelet-derived growth factor (PDGF)-beta, epidermal growth factor receptor, metalloproteinase (MMP)-9, fibronectin, and tenascin. A down-regulation of MMP-1 gene expression was observed exclusively in BEAS-2B cells. Cationic protein-induced transcriptional effects were followed by the release of endothelin-1, PDGF-AB in the supernatants by ELISA, and by a down- and up-regulation, respectively, in the levels of MMP-1 and MMP-9 in cell lysates, by Western blot. Cell stimulation with the synthetic polycation, poly-L-arginine, reproduced some but not all effects of MBP and EPO. Finally, simultaneous cell incubation with the polyanion molecules, poly-L-glutamic acid or heparin, restored MMP-1 gene expression but incompletely inhibited MBP- and EPO-induced transcriptional effects as well as endothelin-1 and PDGF-AB release, suggesting that cationic proteins act partially through their cationic charge. We conclude that eosinophil-derived cationic proteins are able to stimulate bronchial epithelium to synthesize factors that influence the number and behavior of structural cells and modify extracellular matrix composition and turnover.