Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum.
Cystic fibrosis (CF) patients develop progressive cytokine-mediated inflammatory lung disease, with abundant production of thick, tenacious, protease- and oxidant-rich purulent airway secretions that are difficult to clear even with physiotherapy. In the search for a potential treatment, we have tested tyloxapol, an alkylaryl polyether alcohol polymer detergent previously used as a mucolytic agent in adult chronic bronchitis. Tyloxapol inhibits activation of the transcription factor nuclear factor-kappa B (NK-kappa B), reduces resting secretion of the cytokine interleukin-8 (IL-8) in cultured human monocytes, and inhibits lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the eiconsanoids thromboxane A2 and leukotriene B4 (LTB4). We have previously shown that tyloxapol is a potent antioxidant for hydroxyl radicals ( OH). Tyloxapol (0.05 to 0.1% wt/vol) effectively scavenges the oxidant hypochlorous acid (HOCl; 1 to 7.5 mM) in vitro, and protects from HOCl-mediated lung injury in rats. Tyloxapol also reduces the viscosity of CF sputum (from 463 +/- 133 to 128 +/- 52 centipoise). We conclude that tyloxapol is potentially useful as a new antiinflammatory therapy for CF lung disease, and could possibly promote clearance of secretions in the CF airway.
Ghio
A J
AJ
Department of Internal Medicine, Carolinas Medical Center, Charlotte, North Carolina, USA.
Marshall
B C
BC
Diaz
J L
JL
Hasegawa
T
T
Samuelson
W
W
Povia
D
D
Kennedy
T P
TP
Piantodosi
C A
CA
D000328:Adult; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013183:Sputum / Q000187:drug effects* / Q000378:metabolism; D013501:Surface-Active Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors; D014783:Viscosity / Q000187:drug effects
D016207:Cytokines; D016166:Free Radical Scavengers; D016328:NF-kappa B; D013501:Surface-Active Agents; D014157:Transcription Factors; D011092:Polyethylene Glycols; D006997:Hypochlorous Acid; D004247:DNA; C016811:tyloxapol