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

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

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Published inAmerican journal of respiratory and critical care medicine Vol. 178; no. 8; pp. 822 - 831
Main Authors Rowe, Steven M, Jackson, Patricia L, Liu, Gang, Hardison, Mathew, Livraghi, Alessandra, Solomon, G. Martin, McQuaid, D. Brent, Noerager, Brett D, Gaggar, Amit, Clancy, J. P, O'Neal, Wanda, Sorscher, Eric J, Abraham, Edward, Blalock, J. Edwin
Format Journal Article
LanguageEnglish
Published New York, NY Am Thoracic Soc 15.10.2008
American Lung Association
American Thoracic Society
Subjects
Adult
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Biological and medical sciences
Blotting, Western
Bronchoalveolar Lavage Fluid - chemistry
C. Cystic Fibrosis
Chemotaxis, Leukocyte - physiology
Cystic Fibrosis - metabolism
Disease Models, Animal
Disease Progression
Emergency and intensive respiratory care
Enzyme-Linked Immunosorbent Assay
Female
HMGB1 Protein - biosynthesis
Humans
Intensive care medicine
Male
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Neutrophils - metabolism
Spectrometry, Mass, Electrospray Ionization
Sputum - metabolism
Intensive care
Respiratory disease
Glycoprotein
Proline
Metabolic diseases
Cystic disease
Cystic fibrosis
Inflammation
HMGB1
Glycine
fragmentation
Genetic disease
Aminoacid
Collagen
proline-glycine-proline
Neurotransmitter
Digestive diseases
Resuscitation
Pancreatic disease
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Summary: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. To determine whether HMGB1 contributes to CF lung inflammation, including neutrophil chemotaxis and lung matrix degradation. 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. 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. 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.
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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@uab.edu
Supported by National Institutes of Health grants 1K23DK075788-01 (S.M.R.), 1P30DK072482-01A1 (E.J.S.), R01HL077783 (J.E.B.), R01HL090999 (J.E.B.), 1P01HL068743 (E.A.), P50GM049222 (E.A.), P30CA13148 (University of Alabama at Birmingham Comprehensive Cancer Center Core Support Grant); and Cystic Fibrosis Foundation grants R464-CR02 (J.E.B. and E.J.S.), GAGGAR07A0 (A.G.), LIVRAG04I0 (A.L.), and ONEAL07GO (W.O.). This project was supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; or the National Institutes of Health.
Conflict of Interest Statement: S.M.R. received $147,000 for a research grant with Novartis. P.L.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.B.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.D.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.P.C. has received honorarium for grant reviews from the Cystic Fibrosis Foundation, and reimbursement from the National Institute of Health for serving on the Rare Disease Network Data Safety Monitoring Board. W.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.E.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Originally Published in Press as DOI: 10.1164/rccm.200712-1894OC on July 24, 2008
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.200712-1894OC