Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum.

Abstract

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.

• Authors: A J Ghio, B C Marshall, J L Diaz, T Hasegawa, W Samuelson, D Povia, T P Kennedy, C A Piantodosi
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 154 Issue 3 Pt 1 Pg. 783-8 (Sep 1996) ISSN: 1073-449X [Print] United States
• PMID: 8810619 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Free Radical Scavengers
• NF-kappa B
• Surface-Active Agents
• Transcription Factors
• Polyethylene Glycols
• Hypochlorous Acid
• DNA
• tyloxapol

Topics

• Adult
• Animals
• Base Sequence
• Cells, Cultured
• Cystic Fibrosis (drug therapy, immunology, physiopathology)
• Cytokines (metabolism)
• DNA (metabolism)
• Free Radical Scavengers (pharmacology)
• Humans
• Hypochlorous Acid (metabolism)
• Male
• Molecular Sequence Data
• Monocytes (drug effects, metabolism)
• NF-kappa B (metabolism)
• Polyethylene Glycols (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sputum (drug effects, metabolism)
• Surface-Active Agents (pharmacology, therapeutic use)
• Transcription Factors
• Viscosity (drug effects)