Potential role of high-mobility group box 1 in cystic fibrosis airway disease.
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.
Rowe
Steven M
SM
Department University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA. smrowe@uab.edu
Jackson
Patricia L
PL
Liu
Gang
G
Hardison
Mathew
M
Livraghi
Alessandra
A
Solomon
G Martin
GM
McQuaid
D Brent
DB
Noerager
Brett D
BD
Gaggar
Amit
A
Clancy
J P
JP
O'Neal
Wanda
W
Sorscher
Eric J
EJ
Abraham
Edward
E
Blalock
J Edwin
JE
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
D024243:HMGB1 Protein