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Potential Role of High-Mobility Group Box 1 in Cystic Fibrosis Airway Disease

¹ Departments of Medicine, ² Pediatrics, ³ Physiology and Biophysics, and ⁴ Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama; ⁵ Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and the ⁶ Department of Biology, Chemistry, and Mathematics, University of Montevallo, Montevallo, Alabama

Correspondence and request for reprints should be addressed to Steven M. Rowe, M.D., M.S.P.H., Assistant Professor, University of Alabama at Birmingham, MCLM 768, 1918 University Blvd., Birmingham, AL 35294-0006. E-mail: smrowe{at}uab.edu

Rationale: High-mobility group box 1 (HMGB1) is a potent inflammatory mediator elevated in sepsis and rheumatoid arthritis, although its role in cystic fibrosis (CF) lung disease is unknown.

Objectives: To determine whether HMGB1 contributes to CF lung inflammation, including neutrophil chemotaxis and lung matrix degradation.

Methods: We used sputum and serum from subjects with CF and a Scnn1b-transgenic (Scnn1b-Tg) mouse model that overexpresses β-epithelial Na⁺ channel in airways and mimics the CF phenotype, including lung inflammation. Human secretions and murine bronchoalveolar lavage fluid (BALF) was assayed for HMGB1 by Western blot and ELISA. Neutrophil chemotaxis was measured in vitro after incubation with human neutrophils. The collagen fragment proline-glycine-proline (PGP) was measured by tandem mass spectroscopy.

Measurements and Main Results: HMGB1 was detected in CF sputum at higher levels than secretions from normal individuals. Scnn1b-Tg mice had elevated levels of HMGB1 by Western blot and ELISA. We demonstrated that dose-dependent chemotaxis of human neutrophils stimulated by purified HMGB1 was partially dependent on CXC chemokine receptors and that this could be duplicated in CF sputum and BALF from Scnn1b-Tg mice. Neutralization by anti-HMGB1 antibody, in both the sputum and BALF-reduced chemotaxis, which suggested that HMGB1 contributed to the chemotactic properties of these samples. Intratracheal administration of purified HMGB1 induced neutrophil influx into the airways of mice and promoted the release of PGP. PGP was also elevated in Scnn1b-Tg mice and CF serum.

Conclusions: HMGB1 expression contributes to pulmonary inflammation and lung matrix degradation in CF airway disease and deserves further investigation as a biomarker and potential therapeutic target.

Key Words: cystic fibrosis • HMGB1 • inflammation • collagen; • fragmentation • proline-glycine-proline

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject High mobility group box 1 (HMGB1) is elevated in cystic fibrosis airways, significantly contributes to neutrophil influx, and contributes to lung matrix degradation. What This Study Adds to the Field We show that HMGB1 contributes to pulmonary inflammation and lung matrix degradation in cystic fibrosis, and that it may be a potential biomarker and therapeutic target.