Am. J. Respir. Crit. Care Med., Vol 154, No. 3, Sep 1996, 783-788.
Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum
AJ Ghio, BC Marshall, JL Diaz, T Hasegawa, W Samuelson, D Povia, TP Kennedy and CA Piantodosi
Department of Internal Medicine, Carolinas Medical Center, Charlotte, North Carolina, USA.
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.
