Published ahead of print on July 24, 2008, doi:10.1164/rccm.200712-1894OC Am. J. Respir. Crit. Care Med., Volume 178, Number 8, October 2008, 822-831 A more recent version of this article appeared on October 15, 2008
Submitted on December 26, 2007 Potential Role of High Mobility Group Box 1 in Cystic Fibrosis Airway DiseaseSteven M Rowe1*,1 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA, 2 Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA, 3 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA, 4 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 5 The Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 6 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; The Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 7 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA; The Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 8 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; The Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 9 Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA; The Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA * To whom correspondence should be addressed. E-mail: smrowe{at}uab.edu.
Introduction: 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.
Objective: To determine whether HMGB1 contributes to CF lung inflammation, including neutrophil chemotaxis and lung matrix degradation.
Methods: We utilized sputum and serum from CF subjects, and the Scnn1b-transgenic mouse model that overexpresses Key words: cystic fibrosis, HMGB1, inflammation, collagen fragmentation, proline-glycine-proline
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ENaC in the airways and mimics the CF phenotype. Human secretions and murine BALF was assayed for HMGB1 by Western blot and ELISA. Neutrophil chemotaxis was measured in vitro after incubation with 2 x 105 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 receptors, and could be duplicated by CF sputum and BAL fluid from the Scnn1b-Tg mice. Neutralization by anti-HMGB1 antibody in both the sputum and BAL fluid reduced chemotaxis, suggesting 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.
