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(American Journal of Pathology. 2005;167:651-661.)
© 2005 American Society for Investigative Pathology

Human Neutrophil Elastase Induces Hypersecretion of Mucin from Well-Differentiated Human Bronchial Epithelial Cells in Vitro via a Protein Kinase C-Mediated Mechanism

Jin-Ah Park^*, Fang He^*, Linda D. Martin^*, Yuehua Li^*, Brian N. Chorley^* and Kenneth B. Adler^*

From the Department of Molecular Biomedical Sciences,^* College of Veterinary Medicine, and the Department of Molecular and Environmental Toxicology, North Carolina State University, Raleigh, North Carolina

The presence of mucus obstruction and neutrophil-predominant inflammation in several lung disorders, such as cystic fibrosis, suggests a relationship between neutrophils and excess mucus production. Mechanisms of human neutrophil elastase (HNE)-induced mucin secretion by well-differentiated normal human bronchial epithelial (NHBE) cells maintained in air/liquid interface culture were investigated. HNE increased mucin secretion in a concentration-dependent manner, with maximal stimulation (more than twofold) occurring within a short (15 minutes) time period. Mucins MUC5AC and MUC5B, but not MUC2, were released in response to HNE. Stimulation of mucin secretion required partial elastase enzymatic activity and did not appear to involve a soluble product released by the cells. HNE-stimulated secretion involved activation of protein kinase C (PKC), as HNE exposure rapidly provoked PKC enzymatic activity that was attenuated by the general PKC inhibitors calphostin C and bisindoylmaleimide I. Of the different isoforms, PKC, , , , , and were constitutively expressed in NHBE cells while PKCß, , and µ were PMA-inducible. PKC was the only isoform to translocate from cytoplasm to membrane in response to HNE. Inhibition of PKC attenuated HNE-mediated mucin secretion. The results suggest HNE stimulation of mucin release by human airway epithelial cells involves intracellular activation of PKC, specifically the isoform.

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