title: Potential role of high-mobility group box 1 in cystic fibrosis airway disease.
abstract: BACKGROUND
  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 used sputum and serum from subjects with CF and a Scnn1b-transgenic (Scnn1b-Tg) mouse model that overexpresses beta-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.
  
  
  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.
authors.affiliation: Department University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA. smrowe@uab.edu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Mathew
authors.initials: M
authors.lastname: Hardison
authors.forename: Alessandra
authors.initials: A
authors.lastname: Livraghi
authors.forename: G Martin
authors.initials: GM
authors.lastname: Solomon
authors.forename: D Brent
authors.initials: DB
authors.lastname: McQuaid
authors.forename: Brett D
authors.initials: BD
authors.lastname: Noerager
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.forename: J P
authors.initials: JP
authors.lastname: Clancy
authors.forename: Wanda
authors.initials: W
authors.lastname: O'Neal
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D003550:Cystic Fibrosis / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D024243:HMGB1 Protein / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009504:Neutrophils / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013183:Sputum / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein