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Chillappagari, S.* ; Müller, C.* ; Mahavadi, P.* ; Guenther, A.* ; Nahrlich, L.* ; Rosenblum, J.* ; Rubin, B.K.* ; Henke, M.O.

A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation.

J. Cyst. Fibros. 15, 325-331 (2016)

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BACKGROUND: Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro. METHODS: Sputa were collected from CF patients (n=5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1-PI Prolastin®) and KRP-109. Elastase activity assays were performed using spectrophotometry. RESULTS: There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109. CONCLUSION: Inhibitors of neutrophil and Pseudomonas-derived elastases might rescue mucus clearance and reverse airway obstruction in CF.

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