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J. Biol. Chem., Vol. 279, Issue 37, 38854-38860, September 10, 2004

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Regulation of Antiprotease and Antimicrobial Protein Secretion by Airway Submucosal Gland Serous Cells^*

Nam Soo Joo, Dennis J. Lee, Kimberly M. Winges, Arjun Rustagi, and Jeffrey J. Wine

From the Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California 94305-2130

Airway submucosal gland serous cells express the cystic fibrosis transmembrane conductance regulator (CFTR) and secrete antimicrobial, anti-inflammatory, and antioxidant molecules. In cystic fibrosis, diminished gland secretion may impair innate airway host defenses. We used Calu-3 cells as a serous cell model to study the types of proteins released, the pathways that release them, and the possible involvement of CFTR activity in protein release. Many proteins were secreted constitutively into the apical fluid and showed increased release to agonists. We identified some of them by high pressure liquid chromatography-mass spectrometry and reverse transcriptase PCR, including lysozyme, siderocalin (the protein NGAL), which inhibits bacterial growth by binding iron-containing siderophores, HSC-71, which is thought to have anti-inflammatory properties, and the serine protease inhibitors -1-antitrypsin and -1-antichymotrypsin, which may function as antimicrobials as well as play a potential role in diminishing the activation of epithelial Na⁺ channels by serine proteases. We used an enzyme-linked immunosorbent assay to quantify lysozyme secretion by Calu-3 cells in response to various agonists and inhibitors. Forskolin increased the lysozyme secretion rate (J_lyz) from 32 to 77 ng/hr/cm² (n = 36, p < 0.005). Thapsigargin increased J_lyz from 40 to 63 ng/h/cm² (n = 16, p < 0.005), and forskolin plus thapsigargin further increased the forskolin-stimulated J_lyz by 48% (n = 9, p < 0.05). 1-Ethyl-benzimidazolinone and carbachol were less effective. Glibenclamide inhibited basal and stimulated J_lyz, but clotrimazole was without effect. CFTR_inh172 caused a small (15%) but significant inhibition of forskolin-stimulated J_lyz without affecting basal J_lyz. Thus, Calu-3 cells secrete diverse proteins that in aggregate would be expected to suppress microbial growth, protect the airways from damage, and limit the activation of epithelial Na⁺ channels via serine proteases.

Received for publication, June 24, 2004

^* This work was supported by National Institutes of Health Grant DK-51817 and the Cystic Fibrosis Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Cystic Fibrosis Research Laboratory, Rm. 516, Bldg. 420, Main Quad, Stanford University, Stanford, CA 94305-2130. Tel.: 650-725-2468; Fax: 650-725-5699; E-mail: nsjoo{at}psych.stanford.edu.

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